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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
411
add-on therapy for
patients with drug-
refractory adult partial
epilepsy who have failed
ve or more treatments;
most frequent side
effects are drowsiness,
100–200mg/day May be added as an
Adjunctive treatment
of partial seizures with
or without secondary
generalized seizures in
patients 16years of age
and older
modulating the release of
SV2A receptor-bound
presynaptic neurotransmitters,
but with 15–30 times the
afnity of levetiracetam, a
fast-acting drug
dizziness, headache, and
fatigue.
effects are drowsiness,
20mg/day The most common side
May be used as
adjunctive therapy for
Cannabidiol, whose mechanism
of action is unknown, binds to
loss of appetite and
diarrhea, and increased
liver enzymes
seizures associated
with Dravet syndrome
and Lennox-Gastaut
syndrome in children
both cannabinoid receptors 1
and 2; some clinical studies
have found that it effectively
increases the concentration of
the clobazam metabolite,
N-desmethylclobazam, to
enhance antiepileptic effects
Boissetin Controls seizures by
Cannabidiol
More information, including side effects
Abbreviations: AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
a
412
Second, monitoring the side effects of medicines is essential to minimize their
impact on patients and to ensure patient safety and health. Regular monitoring
should include the following: a. Adverse event reporting: primarily through regular
follow-up revisits, specialists should proactively ask individuals and their caregivers
about any potential side effects. b. Clinical examination: regular clinical examinations, including physical and neurological assessments, can help to detect any
adverse physical reactions or neurological abnormalities associated with treatment;
c. Laboratory tests: depending on the specic medication used, blood tests, such as
liver function tests and complete blood count, follow-up check of abdominal organs
(ultrasound once a year), electrocardiogram (once every 6months), complete blood
count and urinalysis once every 3months, and biochemical blood tests once every
6months [65], may be required to monitor potential drug-related side effects.
4.2.3.7 Future Prospects andResearch Directions inDrug Therapy
Following the intensive study of the genetics of epilepsy, a foundation has been laid
for the early realization of individualized and precision therapy [82, 83]. In terms of
drug research and development, through the study of DRE mechanisms, we can
transform the current epilepsy animal models for anti-seizure medication screening
to make their manifestations more similar to those of real patients and to more effectively screen effective anti-seizure medications with different mechanisms [84, 85].
In the future, more attention should be given to understanding the etiology of DRE,
such as immunity, genetics, the development of immunosuppressive drugs targeting
brain (and peripheral) inammation, and inhibitors of the mTOR pathway, and
exploring more options for refractory epilepsy pharmacotherapy from different
approaches [86–88].
L. Zhou and Z. Chen
4.3 Drug Therapy forSeizures ofDifferent Etiologies
4.3.1 Selection ofAnti-seizure Medications forEpileptic
Seizures andEpilepsy After Cerebrovascular Disease
Cerebrovascular diseases encompass a spectrum of conditions characterized by
functional impairment of the brain due to vascular alterations, including ischemic
and hemorrhagic types, which predominantly affect middle-aged and elderly individuals. Common manifestations include motor, language, sensory, and consciousness impairments. According to the 2019 Global Burden of Diseases (GBD) report,
stroke remains a leading cause of disability and mortality globally. In China, there
were 39.4million new stroke cases in 2019, indicating a signicant disease burden.
Ischemic stroke/cerebral infarction accounts for 83% of hospitalized cerebrovascular disease patients. Acute cerebral infarction is associated with numerous
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
413
complications, among which poststroke seizures signicantly increase mortality
and disability rates, prolong hospitalization [89], and exacerbate the burden of
stroke [90].
4.3.1.1 Denition ofEpilepsy andEpileptic Attacks
inCerebrovascular Diseases
Cerebrovascular diseases can be classied into ischemic and hemorrhagic types,
with the former comprising approximately 80%, including conditions such as cerebral infarction, cerebral embolism, and transient ischemic attacks, and the latter
constituting approximately 20%, including conditions such as cerebral hemorrhage,
subarachnoid hemorrhage, epidural hemorrhage, and subdural hemorrhage. Disease
progression can be acute or chronic, with the former encompassing ischemic and
hemorrhagic cerebrovascular diseases and the latter, including cerebral small vessel
disease, atherosclerosis, aneurysms, cerebral vascular malformations, and
Moyamoya disease.
Epilepsy in cerebrovascular diseases primarily refers to seizures arising from
acute stroke events. The ILAE proposed a clinical practical denition of epilepsy in
2017 [91], which species that epilepsy comprises at least two nonprovoked seizures occurring more than 24h apart within 1year, with a risk of more than 60% for
two unprovoked seizures to recur within 10years after a single seizure and a diagnosis of epilepsy syndrome. The risk of epilepsy recurrence is even greater if a
single seizure occurs after 1 month of acute cerebral infarction [92]. Therefore,
according to this practical denition, patients who experience a single unprovoked
seizure within 30days after a stroke and have a subsequent risk of more than 60%
for another seizure may be considered for a diagnosis of poststroke epilepsy (PSE).
In 2010, the ILAE Working Group proposed a denition for acute symptomatic
seizures, specifying them as seizures closely related to acute central nervous system
damage, with the time interval between injury and seizure varying depending on
different clinical circumstances [93]. This literature explicitly states that seizures
induced by structural or metabolic changes within 7days after a stroke should be
classied as acute symptomatic seizures, since seizures during this period do not
represent changes in neural networks and do not necessarily indicate the occurrence
of poststroke epilepsy [92].
The time boundaries for early-onset seizures (ESs) and late-onset seizures (LSs)
after stroke remain controversial in the literature. Recent meta-analyses have indicated that the longer the time after a stroke event, the lower the incidence of seizure
events. Considering the epidemiological characteristics of early-onset and lateonset seizures, 14days has been proposed as the ideal boundary between the two. A
2021 retrospective study revealed a signicantly greater proportion of subsequent
PSEs in ischemic stroke patients who experienced seizures 4–7days after stroke
than in those who experienced seizures 1–3days after stroke (35.5% vs. 10.0%,
p=0.002). Cox risk modeling conrmed the association between seizures occurring
4–7 days after stroke and PSE (HR 3.84, 95% CI 1.77–8.31; p = 0.001) [94].
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L. Zhou and Z. Chen
Moreover, more than 70% of poststroke seizures following endovascular treatment
occur within 1–3days after stroke. Thus, a second perspective suggests that the
boundary between ESs and LSs is 3days. Additionally, multiple studies have shown
that the initial 24h after ischemic stroke represent the peak period for seizure occurrence [95, 96]. Therefore, there is currently no consensus on the classication of ES
and LS, but a trend has been observed indicating that the longer the time after a
stroke event is, the lower the incidence of acute symptomatic seizures and the
greater the likelihood of subsequent PSE.
Reperfusion therapy for ischemic stroke, including intravenous thrombolysis and
endovascular treatment, is currently the only clearly effective rescue strategy. In
1995, the National Institute of Neurological Disorders and Stroke (NINDS) rst
proposed the efcacy of intravenous infusion of recombinant tissue plasminogen
activator (rtPA) within 3h of onset for acute ischemic stroke [97]. Three consecutive 2015 articles in the New England Journal of Medicine conrmed that bridging
intravenous thrombolysis with endovascular treatment signicantly improved the
prognoses of patients with ischemic stroke. Endovascular treatment can be performed within 6h of anterior circulation occlusion onset and within 24h of posterior circulation occlusion onset. There is currently no unied international guideline
or consensus regarding poststroke seizures after reperfusion therapy. The denition
of thrombolysis-related poststroke seizures still needs to be rened in conjunction
with factors such as stroke type, responsible vascular location, etiology, and reperfusion intervention time. Based on the integration of the above denitions and the
literature in this eld, poststroke seizures following reperfusion therapy are limited
to patients with cerebral infarction who have received intravenous thrombolysis
and/or endovascular treatment, without any other obvious causes or a history of
seizures before stroke, who experienced two or more seizures within 7days after the
stroke event, or who experienced one or more seizures within 30days after the
stroke event.
4.3.1.2 Epidemiology
The incidence of epilepsy varies greatly among different populations with cerebrovascular diseases. The incidence of epileptic seizures associated with ischemic cerebrovascular disease ranges from 1.5% to 12.4%, while that following cerebral
hemorrhage ranges from 6.6% to 15%, and after subarachnoid hemorrhage, it is
11%. The incidence of seizures caused by cerebral venous sinus thrombosis is as
high as 50%. The incidence of seizures after thrombolysis ranges from 5% to 13.5%,
similar to that of stroke-related seizures; early seizures occur at a rate of 2–5.5%,
and late seizures occur at a rate of 3–12%. Due to differences in the stroke types
included, follow-up times, and denitions of early and late seizures in different
studies, the incidence rates vary. Currently, most studies lack neurophysiological
assessments, and the frequency of acute symptomatic seizures may be
underestimated.
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
415
Stroke and epilepsy have a bidirectional and inseparable relationship and inuence each other. Stroke is a major cause of epilepsy in middle-aged and elderly
people. Due to the trend toward an increase in the global aging population and the
high incidence of cerebrovascular diseases, the number of patients with epilepsy
caused by stroke is expected to continue to increase in the coming decades. A 2018
report from the International League Against Epilepsy Prevention Task Force mentioned that stroke is the most common preventable cause of epilepsy in elderly people in both high-income and low-income countries. A 25-year prospective study
based on a community population revealed that premature death in epilepsy patients
is mainly associated with three major causes, including stroke, with very few deaths
related directly to epilepsy. Patients with epilepsy, especially young patients or
those taking high doses of anti-seizure medications, have a greater risk of cerebrovascular disease than does the general population [98]. The risk is highest in the rst
year after epilepsy diagnosis [99]. A retrospective 2019 study in Sweden analyzed
the number of seizures patients experienced before stroke and the expected number
of seizures in Sweden over the past 10years and revealed that approximately 5–20%
of cases of epilepsy onset after age 60 are indicative of stroke occurrence [100].
Early clinical trials proposed that epilepsy is a contraindication for thrombolysis
in patients with acute ischemic stroke [97]. In current clinical practice, a case-bycase analysis is needed: if a patient has a history of epilepsy and experiences an
acute stroke, a thrombolysis assessment should be initiated; if acute symptomatic
seizure is the initial symptom of stroke and Todd’s paralysis is conrmed through
clinical and imaging examinations, immediate consideration of vascular reperfusion
therapy is warranted; if the patient is in status epilepticus and limb muscle strength
cannot recover to the preonset level between seizures, the possibility of Todd’s
paralysis should be taken into consideration, although CT perfusion (CTP) and
magnetic resonance imaging (MRI) with arterial spin labeling (ASL), diffusionweighted imaging (DWI), or perfusion-weighted imaging (PWI) often show
increased perfusion due to status epilepticus. Further, the quality of imaging results
may be compromised due to interference from status epilepticus, requiring careful
consideration of thrombolysis feasibility.
4.3.1.3 Pathogenetic Mechanisms ofEpilepsy Related toEtiology
The pathogenetic mechanisms of epilepsy related to cerebrovascular diseases are
complex and varied, and are temporally associated with the occurrence of stroke
and epileptic seizures. Early poststroke seizures are mainly caused by hypoperfusion with or without reperfusion, leading to increased excitability mediated by glutamate due to cerebral tissue hypoxia and reduced inhibition by GABA.After the
stroke, blood–brain barrier disruption activates astrocytes, releasing inammatory
factors such as transforming growth factor-β (TGF-β), tumor necrosis factor-α
(TNF-α), and interleukin-6 (IL-6), while proteinase-activated receptor-1 (PAR-1)
expression is upregulated. Ion channel dysfunction occurs following stroke, particularly in the ischemic penumbra, leading to intracellular sodium and calcium efux
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L. Zhou and Z. Chen
and extracellular potassium inux, resulting in cellular depolarization. Thrombin
can induce increased depolarization. Immediate changes in gene expression are
observed, with upregulation of the expression of factors related to verication and
cell death and alterations in the expression of neuroplasticity-related factors. During
reperfusion, some blood leaks into ischemic necrotic vascular neuronal units, leading to hemosiderin deposition. These factors all contribute to the occurrence of early
poststroke seizures.
The pathophysiological mechanisms of late poststroke seizures involve several
factors, such as chronic inammatory responses, glial scar formation, hemosiderin
deposition, increased neuronal excitability, and neural network formation. White
matter rarefaction, vascular regeneration, neural regeneration, and selective neuronal loss occur in glial scar lesions. A series of subtle changes result in increased
excitability and neuronal synchrony, including changes in synaptic plasticity, afferent nerve tissue, and collateral sprouting. Stroke comorbidities, such as hyperglycemia, dementia, hypertension, depression, antidepressant treatment, and alcohol
abuse, also inuence the occurrence of poststroke epilepsy.
The mechanisms of epilepsy formation after reperfusion therapy for stroke are
more complex than the pathological mechanisms of poststroke epilepsy. A research
team from the University of São Paulo rst discovered that seizures may occur after
intravenous thrombolysis in patients with acute myocardial infarction. The study
included 348 patients with acute myocardial infarction and used three different
thrombolysis regimens: t-PA plus urokinase (43 patients), t-PA alone (142 patients),
and streptokinase (163 patients). Two patients experienced seizures while receiving
t-PA combined with urokinase, and neither patient had a history of stroke [101].
Chronic alcohol abuse can upregulate the expression of NMDA receptors, leading
to seizures after ethanol withdrawal (EW). A 2005 animal experiment revealed
increased expression levels and activity of tPA in brain slices during ethanol intoxication and EW in wild-type mice, consistent with the upregulation of NMDA receptor expression, while no such changes were found in tPA-decient mice. Upregulation
of expression of the NR2B subunit of NMDA receptors during the ethanol response
requires tPA expression mediation, and tPA-decient mice or specic antagonists of
NR2B subunits can eliminate the expression-promoting effect of tPA-mediated EW
seizures [102]. Tissue plasminogen activator (tPA) is one of the immediate early
genes (IEGs) whose expression is induced by neuronal activity in rat hippocampal
neurons, with signicantly increased tPA mRNA expression levels observed
throughout the brain 1–4h after seizures [103]. tPA-decient mice are resistant to
neuronal degeneration and seizures induced by excitotoxicity in the hippocampus
[104]. Neuroserpin is a serine protease inhibitor that is mainly expressed in the
central nervous system and inhibits tPA activity. Increased expression levels of neuroserpin antigen and tPA antigen are observed early after seizures, and inhibiting the
increase in tPA activity by injecting neuroserpin or knocking out expression of the
tPA gene in mice signicantly reduces seizure activity [105].
Vascular reperfusion leading to cortical reperfusion and hyperperfusion in some
regions can result in acute symptomatic seizures. In 2004, an animal model of acute
occlusion and reperfusion injury of the middle cerebral artery (MCA) was
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
417
established by transient occlusion of the middle cerebral artery using microvascular
clamps in cats for 1h. Subsequent observations on FLAIR, DWI, and PWI revealed
prolonged hyperperfusion lasting up to 48h (including certain noninfarcted areas),
leading to delayed cellular perfusion injury [106]. Both hypertensive encephalopathy (HTE) [107] and postcarotid endarterectomy [108] can cause seizures due to
cerebral hyperperfusion. The occurrence of acute symptomatic seizures indicates
effective improvement in cortical perfusion in the corresponding area; therefore,
seizures during thrombolysis may be a favorable indicator of intracranial artery
reperfusion during thrombolysis [109].
4.3.1.4 Risk Factors forPoststroke Epilepsy
More precise predictors of poststroke epilepsy include cortical involvement, hemorrhagic transformation, disease severity, and etiology, such as large artery atherosclerosis [96, 110, 111]. In 2018, a study proposed using the SeLECT score (including
stroke severity, etiology of large artery atherosclerosis, early seizure onset, cortical
involvement, and affected area of the middle cerebral artery) to identify individuals
at high risk for late-onset poststroke epilepsy for early prevention [112]. A retrospective study in 2021 developed a nomogram to predict the individual risk of poststroke epilepsy after early seizures (the nomogram showed a c-index of 0.73),
suggesting that an NIHSS score >14, early seizures 4–7 days after stroke, the
involvement of multiple brain lobes, and multiple early seizures within the rst
week after stroke are independently associated with the occurrence of poststroke
epilepsy [94].
The predictive value of EEG for poststroke epilepsy is currently inconsistent. A
2020 study published in JAMA Neurology proposed the 2HELPS2B score to assist
in monitoring seizures in hospitalized patients. For patients with any highly epileptiform EEG patterns within the rst hour of EEG examination (i.e., a 2HELPS2B
score of 2), recording for at least 24h is recommended [113]. A prospective study
revealed that poststroke epilepsy can be predicted by EEG, with the rst EEG showing asymmetric background activity or interictal epileptiform activity being potential predictors of poststroke epilepsy, and periodic discharges on the rst EEG being
an independent predictor of seizure-like activity during hospitalization [114]. A
2021 multicenter study reported negative results: EEG abnormalities observed
within 7days of stroke onset did not predict the risk of poststroke epilepsy after
multivariate correction [110].
There is currently no consensus on whether reperfusion therapy leads to more
seizures. A 2013 single-center cohort study revealed a signicant association
between rt-PA thrombolysis and seizures, with up to 12 of 28 thrombolysis patients
experiencing early seizures [115]. Thrombolysis is an independent risk factor for
early seizures [116]. Endovascular treatment, including arterial thrombolysis and
mechanical thrombectomy, has been reported to increase the risk of seizures in
patients [117], but there are also contradictory research ndings suggesting that
endovascular treatment does not lead to more seizures [110, 118]. More high- quality
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L. Zhou and Z. Chen
RCTs or prospective studies are needed to explore their correlation. The predictors
of epilepsy in patients undergoing reperfusion therapy, including high NIHSS score,
hemorrhage, younger age, and large artery atherosclerotic stroke, are similar to
those of poststroke epilepsy [119, 120]. The Code Stroke system is an effective
measure used to shorten reperfusion time, enabling rapid identication and timely
intervention of acute stroke patients regarding blood pressure, temperature, and
blood glucose levels, thereby preventing poststroke epilepsy [119]. The relationship
between risk factors for stroke and poststroke epilepsy is not yet clear, but high
blood glucose levels on admission may be associated with seizure occurrence [121],
and both high and low cholesterol levels may have an impact [115]. However, some
studies have suggested that baseline characteristics such as blood glucose and lipid
levels are not associated with early or late poststroke epilepsy [112]. Currently,
there is a lack of research on predictors related to changes in the internal environment during reperfusion therapy.
4.3.1.5 Drug Selection
(1) Based on clinical evidence, expert consensus, guidelines, etc.
There is limited clinical research on drug treatment for poststroke epilepsy.
Long-term follow-up has shown favorable efcacy, safety, and retention rates in
patients with single late-onset epileptic seizures after stroke who are treated
with gabapentin [122]. A meta-analysis revealed that levetiracetam and
lamotrigine are more effective than carbamazepine, with the fewest side effects
associated with lamotrigine [123]. However, due to the small number of patients
included in these studies, more denitive conclusions cannot be drawn. In
recent years, randomized double-blind clinical trials have been conducted on
cohorts of patients with cerebrovascular disease-related seizures. The results
have indicated that lacosamide is safer and more effective than carbamazepine
for controlling poststroke epilepsy, and it is a candidate drug [124].
(2) Limitations of etiology on drug selection and interactions between concomitant
medications and anti-seizure medications.
Age, cerebrovascular disease status, and underlying disease status, as well as
interactions between concomitant medications and anti-seizure drugs, need to
be considered in the treatment of seizures caused by cerebrovascular disease.
These patients often have concurrent conditions such as hypertension, diabetes,
dyslipidemia, coronary artery disease, arrhythmia, chronic bronchitis, and
osteoporosis, and may require long-term intervention with two or more antiseizure drugs in addition to other medications. Drug treatment is also inuenced by factors such as aging, pharmacokinetic and pharmacodynamic
changes, poor compliance, and the level of caregiver support.
Among anti-seizure drugs, voltage-gated sodium channel blockers can interfere with action potentials, leading to arrhythmias. Drugs such as carbamazepine
and lamotrigine can cause electrocardiographic abnormalities, such as mild prolongation of the PQ interval and bradycardia, and severe cases may present with
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
Brugada syndrome. The use of carbamazepine and oxcarbazepine in combination with drugs for treating ventricular arrhythmias should be avoided.
Additionally, carbamazepine and oxcarbazepine may cause asymptomatic hyponatremia, which can become severe in patients using diuretics or consuming lowsodium diets due to hypertension or congestive heart failure [125]. Carbamazepine
can increase total cholesterol and low-density lipoprotein cholesterol levels and
may reduce the efcacy of warfarin. In combination with antiplatelet drugs, valproate may increase the hepatotoxicity of statins and increase the risk of bleeding. Levetiracetam may reduce the efcacy of the novel anticoagulants dabigatran
and rivaroxaban by inducing p-glycoprotein expression. Furthermore, continuous anti-seizure medication use is signicantly associated with accelerated atherosclerosis and increased intima-media thickness of the carotid artery in patients
with epilepsy [125]. Balancing the efcacy of anti-seizure medication and the
risk of stroke-related adverse effects remains a challenge.
In summary, the treatment of cerebrovascular disease-related epilepsy
requires consideration of etiology and disease resolution, whether the epileptic
seizures caused by these factors meet the diagnosis of epilepsy, and the effects
of underlying diseases, comorbidities, and medication use.
4.3.2 Selection ofAnti-seizure Medications forPosttraumatic
Seizures andEpilepsy
419
Traumatic brain injury (TBI) refers to damage to the brain caused by external
mechanical forces, including impacts, collisions, acceleration–deceleration forces,
penetrating injuries, or diffuse axonal injuries [126]. TBI can lead to a range of
sequelae in patients, including seizures and epilepsy.
4.3.2.1 Classication andDenition ofPosttraumatic Seizures (PTS)
Posttraumatic seizures occurring after TBI are classied based on the time elapsed
since the initial seizure following the injury: those occurring within 24h are termed
immediate posttraumatic seizures, those occurring between 24h and 1week are
classied as early posttraumatic seizures, and those occurring more than 1week
after the injury are categorized as late posttraumatic seizures [127]. Currently, international terminology predominantly employs the concepts of PTS and posttraumatic epilepsy (PTE). Specically, PTS refers to seizures occurring within 1week
after TBI, encompassing both immediate and early posttraumatic seizures [128].
PTE, in line with the latest ILAE denition of epilepsy, refers to the occurrence of
nonprovoked seizures for the rst time 1week after TBI, with a minimum interval
of 24h between the rst and second nonprovoked seizures, and a causal relationship
with prior TBI [128].
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L. Zhou and Z. Chen
4.3.2.2 Epidemiology
Approximately 69million individuals suffer from TBI annually worldwide. The
incidence rates in the United States and Europe are 1299/100,000 and 1012/100,000
individuals, respectively [129]. Epidemiological data on TBI in China are incomplete, with the latest available data from 1983 to 1985 indicating incidence rates
ranging from 118 to 1419/100,000 individuals across 23 provinces and municipalities, showing signicant regional disparities in TBI occurrence. The annual incidence rate of posttraumatic seizures is approximately 200 cases per 100,000 people
[130, 131], making it the most common etiology of acquired epilepsy, accounting
for 20% of all epilepsy cases and representing the most frequent cause among adult
patients [132, 133]. Data from some epilepsy centers indicate that seizures due to
TBI represent 20% of cases [127, 134]. A multicenter study from western China
reported posttraumatic epilepsy rates of 6.2% within 1 year and 10.6% within
8years after TBI [135]. Early posttraumatic seizures occurring within 1month after
TBI are observed within the rst week in 90% of patients, with more than half
occurring within 24h [136]. Approximately 10% of patients who experience early
posttraumatic seizures progress to posttraumatic epilepsy. Approximately 40% of
posttraumatic epilepsy patients experience seizures within 6months of TBI, approximately 50–80% experience seizures within 1 year, and approximately 75–90%
experience seizures within 2years after TBI [127, 137, 138]. Although the risk of
PTE decreases as the interval between injury and seizure onset lengthens, late-onset
seizures can occur up to 15years after the initial injury [139–141]. TBI severity is
associated with the likelihood of developing posttraumatic epilepsy, with 5-year
risk estimates of 0.7%, 1.2%, and 10% for mild, moderate, and severe TBI, respectively [140, 142]. In patients with different severity levels of TBI and follow- up
periods exceeding 30years, the 5-year risk estimates for posttraumatic epilepsy are
2.1%, 4.2%, and 16.7% [142, 143]. Data from a population of military veterans with
penetrating head injuries indicate a high incidence (50%) of late-onset nonprovoked
posttraumatic epilepsy, with a greater proportion of clinical and subclinical seizures
in these patients than in nonpenetrating head injury patients [144].
4.3.2.3 Pathophysiological Mechanisms ofPosttraumatic Seizures
andEpilepsy
Pathophysiological Mechanisms ofPosttraumatic Seizures
Seizures occurring within 1week after injury are predominantly attributed to acute
trauma or subsequent complications [140]. The underlying mechanisms include
acute brain injury resulting from shearing forces, direct cranial impact, diffuse axonal injury, brain tissue displacement, or contusion [145]. Damaged axons swell and
retract, leading to secondary axonal injury and distal Wallerian degeneration [146].
Subsequent brain tissue death may result from cytotoxic processes such as the
release of oxygen free radicals and cytokines, as well as intracellular calcium inux