Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
Patients with anti-LGI-1 encephalitis commonly experience intractable hyponatremia. Therefore, when using oxcarbazepine to control seizures caused by anti-LGI-1
encephalitis, careful monitoring of blood sodium levels is essential to prevent exacerbation of hyponatremia [286]. In contrast, patients with anti-NMDAR encephalitis who have undergone sufcient immunotherapy generally do not require long-term
ASM treatment. Several factors, including the use of multiple ASMs during the
acute phase, the presence of epileptiform discharges in electroencephalography
(EEG) monitoring, and delayed initiation of immunotherapy, are identied as the
primary risk factors for the development of chronic epilepsy in the later phase [287].
The intricacies of ASM management highlight the importance of tailored therapeutic approaches based on the specic characteristics of each AE subtype.
Early recognition of ASSAEs is crucial for effective management. An APE2
score≥4 is indicative of an ASSAE, necessitating early initiation of immunotherapy. Early intervention with immunotherapy is closely linked to successful ASSAE
control and favorable long-term outcomes in AE patients [288]. In the context of
ASMs, the preference is for selecting appropriate agents based on the adequacy of
immunotherapy. Sodium channel blockers are not the rst choice, and caution is
advised when using them in patients with anti-LGI-1 encephalitis due to the potential for adverse effects such as skin irritation and severe hyponatremia. This underscores the importance of tailoring treatment approaches to the specic characteristics
of the autoimmune subtype to optimize therapeutic outcomes.
441
4.3.6 Medication forSeizures Caused by Other
Immune Factors
The role of autoimmunity in the development of epilepsy has long been recognized,
dating back to the identication of immune inammation in Rasmussen’s encephalitis in 1958 [289]. Subsequent ndings included the inltration of inammatory
cells in pathologic specimens from patients with temporal lobe epilepsy. In the
1980s and 1990s, clinical evidence demonstrated the effectiveness of glucocorticoid
and adrenocorticotropic hormone therapy in treating clinical infantile spasms, and
paraneoplastic antibodies were found to be associated with epilepsy due to limbic
encephalitis. These observations have led to an increased understanding of the signicant role of immunity in epilepsy development [290].
The term “autoimmune epilepsy” was rst introduced at the International
Congress of Immunology in Geneva in 2002 [291]. In 2017, the ILAE identied
autoimmunity as one of the six major causes of epilepsy [292]. The 2020 ILAE
Autoimmunity and Inammation Working Group claried the concept of
autoimmune- associated epilepsy (AAE), dened as chronic epileptic seizures
caused by autoimmune encephalitis (AE) occurring due to persistent immune
responses or structural changes in the brain resulting from the acute phase of
encephalitis [263]. In 2023, Rada et al. proposed the term autoimmune
442
L. Zhou and Z. Chen
encephalopathy- associated epilepsy (AEAE), encompassing conditions such as
Rasmussen’s encephalitis, glutamic acid decarboxylase 65 (GAD65) antibodyassociated epilepsy, and paraneoplastic antibody-associated epilepsy. For autoimmune encephalitis patients receiving anti-neuronal surface antigen immunotherapy,
seizures persisting for at least 2years after immunotherapy, with no apparent signs
of encephalitis on cranial magnetic resonance imaging (MRI), normal cerebrospinal
uid (CSF) cell counts, or a substantial decrease in antibody titer, are categorized as
AEAE in the chronic phase of AE [293].
4.3.6.1 Rasmussen Encephalitis
(1) Denitions: Rasmussen encephalitis (RE) is a rare chronic disease of the ner-
vous system that was rst described by the neurosurgeon Theodore Rasmussen
in 1958. It is characterized by chronic inammation leading to progressive cortical atrophy in one cerebral hemisphere, with clinical manifestations of drugrefractory epilepsy, progressive neurological decits, and persistent cognitive
decline.
(2) Epidemiological Information: RE is uncommon clinically and primarily affects
children, with onset typically occurring at approximately 6years of age. An
epidemiologic survey in Germany indicated an annual incidence of RE of 2.4
per ten million individuals under 18years of age [292].
(3) Pathologic Mechanisms: The typical histopathological changes in RE are per-
sistent inammatory stimulation of the cortex of one cerebral hemisphere leading to loss of neurons and proliferation of glial cells [289]. Microglia and
lymphocyte inltration, the appearance of perivascular cuffs composed of lymphocytes and phagocytes, and neuronal death and phagocytosis are the most
common pathological changes seen in RE; as the disease progresses, end-stage
pathological changes include spongy cortical cavitation, marked astrocyte proliferation, and neuronal cell loss [294].
(4) Clinical Manifestations: The clinical manifestations of RE progress through the
prodromal, acute, and chronic phases. The prodromal phase involves less frequent seizures and mild hemiparesis symptoms. The acute phase is characterized by frequent focal seizures, with 50% of patients developing partial epilepsy
continua (PEC). Without intervention, PEC can lead to hemiparesis, hemianopsia, and cognitive decline within a year. In the chronic phase, seizure frequency
is stabilized with severe neurological decits, cognitive decline, and drugrefractory focal epilepsy [295].
(5) Medication: The therapeutic goals for RE are to minimize seizure severity and
frequency and to greatly improve motor and cognitive function. The efcacy of
ASMs against RE is generally poor, and their primary role is to prevent the
occurrence of severe seizures and PEC.
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
443
Case reports and uncontrolled studies have suggested that glucocorticoids,
gamma globulin, and immunomodulatory drugs such as tacrolimus, rituximab, and
anabolic acid can improve cognitive function and seizure control in patients with
RE, thereby improving the overall prognosis [296–298]. The results are summarized in the following table.
In pediatric patients with RE, hemispheric dissociation surgery is an important
treatment modality that not only provides effective seizure control but also improves
motor function [299].
4.3.6.2 Anti-GAD65-Associated Epilepsy
(1) Denitions: Gamma-aminobutyric acid (GABA) is an enzyme present in neu-
rons and pancreatic islet β cells that plays a role in converting glutamate to
gamma-aminobutyric acid through decarboxylation. There are two isoforms of
GABA, namely, GAD65 and GAD67. Antibodies against GAD65 have not only
been linked to type 1 diabetes mellitus but also to various neurological disorders, such as stiff-man syndrome, cerebellar ataxia, and limbic encephalitis. In
the case of anti-GAD65 encephalitis, recurrent poorly controlled seizures can
be the primary or sole clinical manifestation, leading to the term “anti-GAD65associated epilepsy” [300].
(2) Epidemiological Information: Clinical anti-GAD65-associated epilepsy is con-
sidered uncommon, with an estimated prevalence of approximately 1.9 cases
per 100,000 individuals with limbic encephalitis [265].
(3) Pathogenesis: Surgical resection specimens from patients with anti-GAD65-
associated epilepsy have revealed the presence of cytotoxic T lymphocytes. It is
currently understood that tissue damage mediated by cytotoxic T lymphocytes
is a major contributing factor to the pathogenesis of this condition, particularly
related to anti-neuronal intracellular antigens [301].
(4) Clinical Manifestations: Patients with anti-GAD65-associated epilepsy can
present with acute or subacute onset, exhibiting clinical features reminiscent of
limbic encephalitis. These manifestations may include seizures, mental and
behavioral abnormalities, and cognitive decline. However, a more common presentation involves a chronic, insidious onset of recurrent seizures without evident clinical or imaging signs of active inammatory changes in the brain [302].
Cranial magnetic resonance imaging (MRI) during the acute phase may
reveal swelling and abnormal signals in the limbic system. In the chronic phase,
there may be high signal in the hippocampus accompanied by reduced hippocampal volume on uid-attenuated inversion recovery (FLAIR) sequences.
These imaging ndings contribute to the diagnostic evaluation of anti-GAD65associated epilepsy.
(5) Medication: Anti-GAD65-associated epilepsy is predominantly characterized
by drug-refractory seizures, and the limited number of cases contributes to a
scarcity of high-quality studies. Research has indicated that this form of epi-
444
L. Zhou and Z. Chen
lepsy is not only unresponsive to ASMs but also shows reduced response to
rst-line immunotherapy interventions [303]. A recent study demonstrated that
a combination of phenobarbital and clobazam therapy was effective in reducing
seizure frequency in patients with anti-GAD65-associated epilepsy when
administration of multiple ASMs failed to produce the desired outcome [304].
Although surgical outcomes for patients with anti-GAD65-related epilepsy are
reportedly less favorable than those for patients with other causes of medial temporal lobe epilepsy, surgical intervention may be considered following a thorough
surgical evaluation when ASMs and immunotherapy are shown to be ineffective
[301]. The decision for surgical intervention should involve careful weighing of
potential benets and risks.
4.3.6.3 Paraneoplastic Antibody-Associated Epilepsy
(1) Denitions: Paraneoplastic antibody (intracellular antibody)-mediated enceph-
alitis predominantly affects the limbic system and cerebral cortex, resulting in
seizures that are often poorly responsive to drugs. This tendency to resist treatment by medications can lead to the development of chronic epilepsy, termed
paraneoplastic antibody-associated epilepsy [305].
(2) Epidemiological Information: Information on paraneoplastic antibody-
associated epilepsy is primarily derived from case reports or analyses of small
sample sizes, and comprehensive epidemiological data are currently lacking.
(3) Pathogenesis: The pathogenesis of paraneoplastic antibody-associated epilepsy
is similar to that of anti-GAD65-associated epilepsy. Both conditions lead to
pathophysiological alterations through T lymphocyte-mediated immune
responses and the release of inammatory factors.
(4) Clinical Manifestations: The clinical manifestations of paraneoplastic antibody-
associated epilepsy closely resemble those of anti-GAD65-associated epilepsy,
often presenting with symptoms indicative of temporal lobe epilepsy. Focal
onset seizures with perceptual decits and focal progression to bilateral tonic–
clonic seizures are the most commonly observed seizure types. Seizures tend to
be more frequent in this context and, in severe cases, may progress to status
epilepticus. Recent studies have identied Hu antibody-associated epilepsy as
the most common type, primarily associated with small cell lung cancer, followed by Ma2 antibody-associated epilepsy, which is predominantly linked to
germ cell tumors [306].
(5) Medication: Patients with paraneoplastic antibody-associated epilepsy gener-
ally exhibit a poor response to ASMs. Early detection of tumors provides an
opportunity for tumor-specic therapy, potentially improving the overall prognosis [307]. First- and second-line immunotherapies are options for treating
paraneoplastic antibody-associated epilepsy. Surgical interventions can also be
considered if tumor-specic and immunotherapeutic approaches are shown to
be ineffective [301].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
445
4.3.7 Medication forSeizures Associated withDifferent Types
ofEncephalopathies
Encephalopathy is a brain dysfunction characterized by altered consciousness due
to a variety of causes, which can result from total brain damage or focal lesions
[308]. It describes a clinical state rather than a stand-alone disease diagnosis, and its
etiology is very diverse. Epileptic seizures are among the most common clinical
manifestations in patients with encephalopathy. This section focuses on the pharmacological management of seizures caused by different encephalopathies, such as
hypoxic-ischemic encephalopathy, metabolic encephalopathy, autoimmune-related
encephalopathy, toxic encephalopathy, and radiation encephalopathy.
4.3.7.1 Hypoxic-Ischemic Encephalopathy
Denition
Hypoxic-ischemic encephalopathy (HIE) refers to severe brain dysfunction caused
by cerebral ischemia and/or hypoxia. Neonatal HIE is usually caused by intrauterine
fetal distress, asphyxia, or neonatal pneumonia [309], while HIE in adults is most
likely caused by cardiac arrest and, occasionally, by drowning, hanging, carbon
monoxide poisoning, altitude sickness, respiratory failure, severe sleep apneahypopnea syndrome, etc.
Clinical Features andEpidemiology
Posthypoxic myoclonus is the main seizure manifestation of hypoxic-ischemic
encephalopathy and can be divided into acute and delayed forms. Acute myoclonus
occurs within 24 h after cerebral hypoxia-ischemia and manifests as coma with
myoclonic status epilepticus. Myoclonus is usually systemic, mainly in the face,
upper limbs, and diaphragm, and lasts for 1–31days, often suggesting a poor prognosis. Late-onset myoclonus occurs days to weeks after hypoxia and ischemia when
the patient’s consciousness is restored, manifests as intentional or action myoclonus, and may be accompanied by cognitive impairment, ataxia, dysarthria and other
symptoms. Delayed myoclonus after cerebral hypoxia, also known as Lance–Adams
syndrome, was rst described by Lance and Adams in 1963 [310]. Acute myoclonus
is more common after cerebral ischemia and hypoxia, accounting for approximately
16–37% of HIE cases, while the incidence of delayed myoclonus after recovery of
consciousness is much lower (less than 0.5%).
There is still some controversy about whether myoclonus after cerebral hypoxia
is caused by epileptic seizures. Jonathan Elmer et al. analyzed the scalp
446
L. Zhou and Z. Chen
electroencephalography (EEG) patterns of 401 patients who were in a coma after
cardiac arrest, 69 of whom (16%) had acute early myoclonus [311]. EEG changes
in these 69 patients can be categorized in four patterns: (1) burst-suppression background with high-amplitude polyspikes inlockstep with myoclonic jerks; (2) continuous background with narrow sharp waves distributed in the vertex inlockstep
with myoclonic jerks; (3) subcortical myoclonus (no epileptiform discharge associated with myoclonic jerks); and (4) an unclassiable pattern. Pattern 1 was most
common, occurring in 48 patients (74%); followed by pattern 2in 8 patients (12%);
and the remaining patients had subcortical myoclonus (n=2, 3%) or other types
(n=7, 11%). Of the 69 patients, 4 out of 8 (50%) with EEG pattern 2 survived and
subsequently developed classic Lance-Adams syndrome, while the remaining 61
patients with EEG patterns 1, 3, and 4 did not survive. Although there was a lockstep relationship between myoclonic jerks and EEG discharges in the majority of
patients, there were also a number of patients whose myoclonus was not clearly
related to EEG epileptic changes and whose seizure characteristics were different
from those of traditional “myoclonic epilepsies” and “status epilepticus” [312].
Therefore, many scholars suggest that post-hypoxic myoclonus is of cortical/subcortical origin and does not t the traditional denition of epileptic seizures.
In addition to myoclonus, some patients may experience generalized tonic–
clonic seizures after cerebral ischemia. If cerebral ischemia-hypoxia is not severe or
resuscitation is timely, only localized brain injury may persist. For example, hippocampal injury can cause hippocampal sclerosis, resulting in medial temporal lobe
epilepsy several years later. In addition, injury to the occipital lobe evolves into
encephalomalacia and gliosis, which might subsequently cause focal occipital lobe
epilepsy.
Pathogenic Mechanisms
The brain consumes the most oxygen of all organs in the human body, and the cerebral cortex, hippocampus, basal ganglia region, brainstem, and cerebellum are less
tolerant to hypoxia than other regions. Ischemia and hypoxia lead to a lack of oxygen and glucose in the brain, which causes anaerobic metabolism, leading to a
decrease in adenosine triphosphate (ATP) levels and an accumulation of lactic acid.
When the cell membrane depolarizes, the cell releases the excitatory amino acid
glutamate, which binds to the ligand-gated N-methyl-D-aspartate (NMDA) receptor
to open channels for a large amount of transmembrane calcium ions and sodium
ions to ow into the cell. However, when the cell membrane repolarizes, the depletion of ATP reduces the ionic transmembrane translocation of ions, leading to the
buildup of intracellular sodium, calcium, and water, in turn causing cellular excitotoxicity. Peroxidation of free fatty acids by oxygen radicals causes additional cellular damage. Energy depletion, acidosis, glutamate release, lipid peroxidation, and
the toxic effects of nitric oxide led to cell necrosis and the activation of apoptotic
cascades [309, 313].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
447
There are three phases of recovery based on the timing of injury and resuscitation. The rst phase is 30–60minutes after acute hypoxia-ischemia, during which
the main injuries are oxidative damage, inammation, and activation of the apoptotic cascade. In some patients, this phase can last up to 1–6h due to medical interventions such as cardiopulmonary resuscitation. The second phase of injury occurs
after approximately 6–15h. Cytotoxic edema, excitotoxicity, secondary energy failure, and loss of mitochondrial function characterize this phase. Seizures usually
occur during the second phase. The third phase occurs within months after acute
injury and is characterized by delayed cell death, brain remodeling, and astrocyte
proliferation [309, 314]. The pathogenesis of post-hypoxic myoclonus is unclear. It
may be due to abnormal cortical ring, abnormalities in the cerebellar-brainstem
and thalamocortical circuits, and impaired metabolism of the neurotransmitter
5-hydroxytryptamine (5-HT) [315].
Treatment
During the acute phase of cerebral hypoxia-ischemia, the administration of hypothermia therapy can reduce the extent of cerebral damage and the severity of seizures in the acute phase, increase the chances of resuscitation, and reduce the risk
of late-onset epilepsy [316]. A retrospective study that included 56 neonates with
HIE revealed that hypothermia therapy applied in the acute phase signicantly
reduced the incidence of seizures after 6months [317]. In neonates with focal cerebral ischemic-hypoxic lesions, hypothermia therapy also signicantly reduced the
risk of seizures [318]. In addition, phenobarbital is thought to have potential neuroprotective effects during the acute phase of cerebral hypoxia-ischemia and could
enhance the benecial effects of hypothermia; it should be initiated at the latent
stage before seizure onset [316]. In animal models of hypoxic-ischemic injury, phenobarbital plus hypothermia had signicantly better outcomes than hypothermia or
normothermia alone [319], but the results of this study need to be conrmed by
large clinical studies.
For the treatment of post-hypoxic myoclonus, the combination of clonazepam,
sodium valproate, piracetam and levetiracetam has a signicant effect on more than
50% of patients, and clonazepam is considered to be the most effective [320].
Moreover, these drugs are also effective in patients with generalized tonic clonic
seizures.
In addition, based on the doctrine of impaired 5-HT metabolism, some studies
have attempted to apply L-5-hydroxytryptophan (L-5-HTP), a direct precursor of
5-HT, in the treatment of myoclonus after cerebral hypoxia [321], and myoclonus
improved in some patients after the administration of L-5-HTP.The side effects of
L-5-HTP, such as nausea, vomiting, and diarrhea, can be reduced by combining it
with carbidopa, an aromatic L-amino acid decarboxylase inhibitor.
In recent years, there have been case reports of perampanel use improving posthypoxic myoclonus [322, 323]. Perampanel is a selective A-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, and the mechanism
448
L. Zhou and Z. Chen
underlying its effect on myoclonus is still unclear. More therapeutic experience is
needed in the future to elucidate its mechanisms.
For medial temporal lobe epilepsy caused by hippocampal sclerosis after ischemia and hypoxia, sodium channel blockers such as oxcarbazepine, carbamazepine,
and lamotrigine, or a combination of drugs with other mechanisms, can be used, but
such patients tend to be medically refractory as well. Treatment for epilepsy caused
by encephalomalacia in the occipital lobe is consistent with that for focal epilepsy.
4.3.7.2 Metabolic Encephalopathy
Hepatic Encephalopathy
(1) Denition: Hepatic encephalopathy (HE) is a disorder in which the central ner-
vous system is dysfunctional due to chronic liver disease. The liver is responsible for metabolism and detoxication under normal conditions, but when its
function is impaired due to a variety of liver diseases, toxins accumulate in the
blood, which in turn affects the normal function of the nervous system [324].
(2) Clinical Features and Epidemiology: There is a correlation between liver dis-
ease and the risk of epilepsy. A large population-based cohort study revealed
that the proportion of people with liver disorders who experienced seizures was
approximately 2.5%, and the risk of status epilepticus in patients with cirrhosis
was 1.3–2.8 times greater than that in patients without cirrhosis [325]. In 2020,
the NewYork State Inpatient Database showed that patients with worsening
liver disease had a two- to threefold increased risk of rehospitalization for seizures within 6months of discharge and a three- to vefold increased risk of
rehospitalization for status epilepticus [326].
The seizures of patients with HE can manifest as GTCSs or convulsive or
nonconvulsive status epilepticus. Marco Olivero etal. [327] described a case of
HE with nonconvulsive status epilepticus as the rst symptom, in which the
patient presented with persistent confusion and a decreased level of consciousness, and the EEG showed paroxysmal sharp wave rhythms superimposed on a
background of widespread slow waves. In stages III and IV of HE, EEG may
reveal typical triphasic waves.
Typical brain imaging changes in HE include symmetrical high signals in
the bilateral pallidum on magnetic resonance T1W sequences, accompanied by
high signals in the bilateral pyramidal tracts and the white matter of the subcortical hemispheres on T2-FLAIR sequences [328].
(3) Pathogenic Mechanisms: The mechanisms by which HE causes seizures can be
explained as follows [329–332]:
① Ammonia Toxicity: Chronic liver disease results in the inability of the liver to
metabolize ammonia effectively, leading to elevated blood ammonia con-
centrations. A high concentration of blood ammonia enters brain tissue
through the blood–brain barrier, and its inherent excitotoxicity affects the
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
normal function of neurotransmitters and interferes with neuronal excitabil-
ity, thus triggering seizures.
② Neurotransmitter Disorders: HE interferes with the synthesis, release, and
metabolism of a variety of neurotransmitters, such as glutamate and gamma-
aminobutyric acid (GABA), among which an increase in synaptic glutamate
is more closely associated with hyperammonemia. These abnormal changes
may lead to abnormal neuronal discharges and seizures.
③ Cerebral Edema: HE can lead to the development of cerebral edema.
Cerebral edema increases pressure in the brain, compresses nerve tissue, and
interferes with the normal function of neurons, which can lead to seizures.
④ Inammatory Response: Liver disease can lead to an inammatory response
and abnormal activation of the immune system. The inammatory response
can cause inammatory damage to neurons, affecting their normal function
and thus promoting seizures.
⑤ Treatment: For patients with HE and epileptic seizures, treating the primary
liver disease is the rst task, and it is also important to remove the HE-
inducing factors (e.g., infections, gastrointestinal hemorrhage, volume-
decient alkalosis, and electrolyte disorders) as soon as possible [333].
Lowering blood ammonia is an essential symptomatic treatment. Laxatives
such as lactulose and lactitol, antimicrobial agents that can inhibit the growth
of ammonia-producing bacteria (e.g., neomycin), and drugs that can pro-
mote the clearance of ammonia, such as L-ornithine, L-methionine, arginine
and glutamine, can all be used to reduce blood ammonia levels. Status epi-
lepticus caused by HE is sometimes difcult to control with intravenous
phenytoin or benzodiazepines, but lowering blood ammonia levels can dra-
matically stop it.
449
The use of ASMs should be individualized, and the use of hepatotoxic drugs such
as valproic acid needs to be avoided. Loss of hepatocytes and disturbances in hepatic
blood ow can decrease the metabolism of ASMs, and hypoproteinemia, decreased
albumin binding, and impaired metabolism of cytochrome P450 (CYP450) and glucosyltransferase can lead to increased serum levels of ASMs [334]. Therefore, the
doses of relevant drugs metabolized by the liver need to be adjusted. In addition,
phenobarbital and benzodiazepines have sedative effects and may aggravate
impaired consciousness in patients with HE and should be used with caution.
Low protein-binding ASMs, such as gabapentin, topiramate, aminocaproic acid,
and levetiracetam, induce very little hepatic metabolism and are therefore relatively
suitable. Topiramate is a selective enzyme inducer/inhibitor, whereas gabapentin,
levetiracetam, and aminoglutethimide have no signicant effects on CYP450.
Levetiracetam is predominantly metabolized by the kidneys with linear pharmacokinetics and reaches a steady state after 2days of twice-daily dosing [335].
Hepatolenticular degeneration (Wilson’s disease) rarely causes seizures, but
D-penicillamine treatment can lead to pyridoxine deciency, which can cause seizures, and treatment with pyridoxine or other copper chelators is recommended [336].
450
L. Zhou and Z. Chen
4.3.7.3 Uremic Encephalopathy
Denition
Uremic encephalopathy (UE) is a disorder of the central nervous system caused by
chronic kidney disease [337]. One of the main functions of the kidneys is the elimination of metabolites from the body and the regulation of uid balance. Chronic
kidney disease may lead to uremia (i.e., the accumulation of toxins and metabolites
in the body), which in turn affects the normal functioning of the nervous system.
Clinical Features andEpidemiology
The incidence of symptomatic seizures in patients with chronic kidney disease has
been reported to be approximately 10% [338]. Seizures may also be associated with
dialysis. Acute dialysis disequilibrium syndrome (DDS) is reversible and occurs
mainly in patients with severe hyperazotemia at the start of dialysis treatment.
During hemodialysis, urea is removed from the blood faster than from the brain,
leading to osmotic pressure gradients and cerebral edema, which can cause reversible posterior encephalopathy (PRES) with clinical manifestations of irritability,
headache, vomiting, blurred vision, seizures, and impaired consciousness. The seizures are mainly manifested as GTCSs and sometimes even status epilepticus.
Uncontrolled hypertension, electrolyte disturbances, erythropoietin, cytotoxic
drugs, and the use of immunosuppressants are risk factors for PRES [339–341]. In
addition, the high aluminum concentration in dialysis uids was once considered a
cause of seizures, so aluminum-free water is now routinely used [342].
Pathogenic Mechanisms
The mechanisms by which renal encephalopathy causes seizures may be related to
the following factors [337, 343]:
(1) Accumulation of Nitrogenous Substances: In chronic kidney disease, the kid-
neys are unable to effectively eliminate nitrogenous substances, such as urea
and creatinine, from the body. The accumulation of these substances in the
body can lead to nitrogen toxicity, which affects the normal function of the
nervous system, including the triggering of seizures.
(2) Electrolyte disorders: Kidney dysfunction can lead to disturbances in uid and
electrolyte balance. Abnormal changes in the concentrations of electrolytes
such as serum sodium, potassium, and calcium may affect the electrical activities of neurons, leading to abnormal discharges and the occurrence of seizures.