Association of carotid revascularization with epilepsy and seizures in patients with carotid stenosis

Ming‐Tsung Chuang; Yu Chang; Chia‐En Wong; Chih‐Yuan Huang; Pang‐Shuo Perng

doi:10.1002/epi.70237

. 2026 Apr 8;67(7):3523–3532. doi: 10.1002/epi.70237

Association of carotid revascularization with epilepsy and seizures in patients with carotid stenosis

Ming‐Tsung Chuang ¹, Yu Chang ², Chia‐En Wong ², Chih‐Yuan Huang ², Pang‐Shuo Perng ^2,^✉

PMCID: PMC13361049 PMID: 41948863

Abstract

Objective

The potential influence of carotid stenosis on seizure or epilepsy outcomes and whether revascularization modifies this risk remain understudied.

Methods

Using a large real‐world database, we identified adults diagnosed with carotid stenosis and excluded those with prior seizures, epilepsy, or common provoking conditions. Patients were classified according to whether they underwent carotid endarterectomy or carotid artery stenting within 1 month of diagnosis. Propensity score matching was performed based on demographic variables and major vascular comorbidities. The primary outcome was a composite of new onset seizures or epilepsy at 1 month, 3 months, and 2 years of follow‐up.

Results

Among 848 939 eligible patients, 41 225 were matched. Carotid revascularization was associated with significantly lower risk of seizures or epilepsy. Incidence in the revascularization group was .3% at 1 month, .4% at 3 months, and .8% at 2 years, corresponding to hazard ratios of .30 (95% confidence interval [CI] = .24–.38), .36 (95% CI = .30–.43), and .41 (95% CI = .36–.47), respectively. These associations remained consistent across symptomatic and asymptomatic subgroups and between procedural modalities. In sensitivity analysis including patients who experienced ischemic or hemorrhagic stroke after carotid stenosis diagnosis, seizure or epilepsy incidence remained lower in the revascularization group, with hazard ratios of .27 (95% CI = .18–.41) at 3 months and .35 (95% CI = .28–.45) at 2 years.

Significance

Beyond its established role in stroke prevention, carotid revascularization was associated with reduced incidence of seizures or epilepsy in this real‐world analysis. This association persisted even among patients who experienced cerebrovascular events following the procedure. The potential protective effect of revascularization and its underlying mechanisms warrant further investigation.

Keywords: atherosclerosis, endarterectomy, outcome, stenting

Key points.

Carotid revascularization is associated with a reduced risk of seizures or epilepsy in patients with carotid stenosis.
Both carotid artery stenting and carotid endarterectomy confer comparable protective effects.
The reduction in seizure and epilepsy risk is significant in both short‐ and long‐term follow‐up, with benefits evident as early as 1 month after diagnosis.

1. INTRODUCTION

Carotid stenosis plays a critical role in the epidemiology and prevention of ischemic stroke. Over the past decades, approximately 10%–15% of ischemic strokes have been attributed to atherosclerotic disease of the carotid bifurcation. ¹ Therapeutic options include carotid endarterectomy (CEA), carotid artery stenting, and contemporary intensive medical management. Recent large randomized trials have further refined treatment strategies for both symptomatic and asymptomatic carotid stenosis. ² , ³ As modern medical therapy has continued to advance, particularly through improvements in lipid‐lowering agents, antithrombotic regimens, and comprehensive vascular risk‐factor control, the indications for revascularization and the magnitude of its incremental benefit in stroke prevention have become increasingly debated. ⁴

Beyond stroke risk reduction, the potential influence of carotid revascularization on other neurological outcomes has also drawn attention. Prior studies have suggested that CEA may confer long‐term cognitive benefits, including lower rates of dementia and Alzheimer disease. ⁵ , ⁶ Improvements in cerebral perfusion and reductions in microembolic events have been proposed as key mechanisms underlying these effects. ⁷ , ⁸ However, the relationship between carotid revascularization and the risk of early or late seizures has been far less explored. Whether increased cerebral blood flow following revascularization is associated with short‐ or long‐term seizure or epilepsy outcomes has not been evaluated. To address this gap, we conducted a large database study to investigate the impact of carotid revascularization on subsequent seizure and epilepsy outcomes.

2. MATERIALS AND METHODS

2.1. Inclusion and exclusion

This study was approved by the institutional review board of our institution and utilized data from the TriNetX research network, a federated health research network providing access to deidentified electronic health record data. ⁹ , ¹⁰ At the time of this analysis, the TriNetX network included data from more than 110 million patients across more than 60 health care organizations, primarily in the United States, including academic medical centers, community hospitals, and specialty practices. ¹¹ The database aggregates longitudinal patient data including demographics, diagnoses (International Classification of Diseases, 10th Revision [ICD‐10]), procedures (Current Procedural Terminology [CPT], ICD‐10‐Procedure coding system [PCS]), medications, laboratory values, and vital signs. Data are updated regularly, approximately every 2 weeks, by participating institutions. Patient records are linked across encounters within each health care organization using deterministic and probabilistic matching algorithms.

The inclusion criteria were patients diagnosed with carotid stenosis (ICD‐10 code I65.2). Exclusion criteria included patients younger than 18 years, those with a prior diagnosis of epilepsy or seizure, and those whose carotid stenosis diagnosis was made more than 20 years previously. Additional exclusion criteria of seizure‐provoking factors included primary or secondary tumors, sepsis, electrolyte imbalances, head trauma, hyperglycemia, hypoglycemia, alcohol withdrawal, and drug abuse. Patients were then categorized according to whether they underwent carotid revascularization within 1 month after diagnosis. For patients who did not receive carotid revascularization, at least one visit had to be documented within 1 month to reduce the immortal bias.

For subgroup analysis, symptomatic and asymptomatic patients were defined by the presence or absence of transient ischemic attack or stroke within 6 months prior to the diagnosis of carotid stenosis. In addition, patients were stratified according to the type of revascularization procedure. Carotid artery stenting and CEA were identified using ICD‐10 and Systematized Nomenclature of Medicine codes. See Tables S1–S4 for detailed inclusion and exclusion criteria.

A second subgroup analysis was conducted, including only patients who developed ischemic stroke or intracranial hemorrhage after a diagnosis of carotid stenosis. This analysis aimed to assess whether postdiagnosis cerebrovascular events influenced the association between carotid revascularization and the risk of seizures or epilepsy. Patients who developed seizures or epilepsy between the diagnosis of carotid stenosis and the subsequent cerebrovascular event were excluded to prevent misclassification (Table S5). The incidence of seizures or epilepsy was then compared between the revascularization and nonrevascularization groups.

2.2. Outcomes and statistical analysis

The primary outcome was defined as development of composite endpoint of epilepsy (ICD‐10 code G40) or seizures (ICD‐10 code R56). ¹² Follow‐up time points were set at 1 month, 3 months, and 2 years to capture short‐term and long‐term outcomes, which align with clinical follow‐up schedules and practice guidelines. ¹³ , ¹⁴

Comparisons between cohorts were performed using independent‐sample t‐tests for continuous variables and chi‐squared tests for categorical variables. The TriNetX platform utilizes user identified covariates and conducts logistic regression analysis to obtain propensity scores for individual subjects. One‐to‐one matching was performed using a greedy nearest neighbor algorithm with a caliper width of .1 pooled standard deviations (SDs) to generate propensity scores. TriNetX randomizes the order of rows to eliminate bias resulting from nearest neighbor algorithms. This methodology has been previously studied. ¹⁵ , ¹⁶ , ¹⁷ Matching was conducted based on age, sex, race, body mass index, and comorbidities including hypertension, heart failure, atrial fibrillation and flutter, ischemic heart disease, diabetes mellitus, chronic obstructive lung disease, chronic kidney disease, depression history, and liver disease. Histories of alcohol‐related disorders, tobacco use, and prior cerebrovascular events were also included. In symptomatic patients, the National Institutes of Health Stroke Scale score was additionally incorporated into the matching model. Propensity score density plots were generated (Figures S1–S6). A standardized mean difference < .1 was considered indicative of adequate balance between the two groups. ¹⁸ Proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after propensity score matching. Kaplan–Meier event‐free survival curves were plotted using R 4.5.2 (R Core Team). A p‐value of <.05 was considered statistically significant.

3. RESULTS

A total of 848 939 patients were included in the study. Among them, 41 921 patients underwent carotid revascularization within 1 month of diagnosis, including 12 078 who received carotid artery stenting and 29 843 who underwent CEA (Figure 1). Overall, 41 225 patients were successfully matched. Before matching, significant differences were observed between the groups in all variables except age and body mass index. After matching, the two groups were well balanced, with standardized mean differences < .1 (Table 1).

TABLE 1.

Baseline characteristics of patients with carotid stenosis who underwent revascularization before and after propensity score matching.

Characteristic	Before matching					After matching
Characteristic	Revascularization, n = 41 225		Control, n = 781 217		p	Revascularization, n = 41 225		Control, n = 41 225		p	SMD
Age at index, years	70.0 ± 9.51		70.0 ± 11.8		.62	70.0 ± 9.51		70.1 ± 10.1		.37	.006
White	27 385	66.4%	563 674	72.2%	<.01	27 385	66.4%	27 283	66.2%	.45	.005
Male	26 421	64.1%	408 514	52.3%	<.01	26 421	64.1%	26 361	63.9%	.66	.003
Not Hispanic or Latino	23 430	56.8%	548 074	70.2%	<.01	23 430	56.8%	23 368	56.7%	.66	.003
Body mass index	28.4 ± 5.45		28.4 ± 6.00		.49	28.4 ± 5.45		28.5 ± 5.67		.06	.02
Hypertensive diseases	12 632	30.6%	358 639	45.9%	<.01	12 632	30.6%	12 548	30.4%	.53	.004
Ischemic heart diseases	7956	19.3%	189 370	24.2%	<.01	7956	19.3%	7919	19.2%	.74	.002
Heart failure	1555	3.8%	55 694	7.1%	<.01	1555	3.8%	1562	3.8%	.90	.001
Diabetes mellitus	4113	10.0%	122 623	15.7%	<.01	4113	10.0%	3981	9.7%	.12	.011
COPD	2125	5.2%	53 672	6.9%	<.01	2125	5.2%	1969	4.8%	.01	.017
Atrial fibrillation and flutter	1917	4.7%	69 047	8.8%	<.01	1917	4.7%	1937	4.7%	.74	.002
Chronic kidney disease	1691	4.1%	59 522	7.6%	<0.01	1691	4.1%	1678	4.1%	.82	.002
Diseases of liver	854	2.1%	39 162	5.0%	<.01	854	2.1%	809	2.0%	.26	.008
Depressive episode	1513	3.7%	56 055	7.2%	<.01	1513	3.7%	1449	3.5%	.23	.008
Tobacco use	1044	2.5%	22 727	2.9%	<.01	1044	2.5%	886	2.1%	<.01	.025
Alcohol‐related disorders	546	1.3%	12 713	1.6%	<.01	546	1.3%	453	1.1%	<.01	.021
Spontaneous ICH	116	.3%	3743	.5%	<.01	116	.3%	91	.2%	.08	.012
Cerebral infarction	4076	9.9%	63 708	8.2%	<.01	4076	9.9%	3920	9.5%	.07	.013
Platelet aggregation inhibitors	10 338	25.1%	232 229	29.7%	<.01	10 338	25.1%	10 184	24.7%	.21	.009
Anticoagulants	7089	17.2%	169 196	21.7%	<.01	7089	17.2%	6970	16.9%	.27	.008

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Note: Numbers are presented as mean ± SD.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICH, intracranial hemorrhage; SMD, standard mean difference.

Among patients who received revascularization, 25 542 were asymptomatic and 16 379 were symptomatic. These patients were matched 1:1 with control patients of the same symptomatic status who did not undergo revascularization. The final matched cohorts consisted of 5815 patients in the symptomatic carotid stenting group, 10 563 in the symptomatic CEA group, 6262 in the asymptomatic carotid stenting group, and 19 280 in the asymptomatic CEA group.

In the overall cohort, patients who underwent revascularization had significantly lower risks of epilepsy or seizures than those who did not. The incidence of epilepsy or seizures in the revascularization group was .3% (n = 112) at 1 month (HR = .30, 95% CI = .24–.38), .4% (n = 167) at 3 months (HR = .36, 95% CI = .30–.43), and .8% (n = 339) at 2 years (HR = .41, 95% CI = .36–.47; Figure 2).

Kaplan–Meier event‐free survival curves at 1 month (A), 3 months (B), and 2 years (C) comparing patients who underwent carotid revascularization with those who did not.

3.1. Subgroup analysis by symptomatic status

The association between revascularization and reduced seizure or epilepsy risk was consistent across symptomatic and asymptomatic patients who underwent different revascularization procedures (Table 2).

TABLE 2.

Hazard ratios of epilepsy or seizure for carotid stenosis patients who underwent revascularization.

	Carotd stenosis	Procedure	Revascularization outcome, n	%	Control outcome, n	%	Hazard ratio	95% CI
One month	Symptomatic	CAS, n = 5815	34	.6	102	1.8	.32	.22	.48
	Symptomatic	CEA, n = 10 563	32	.3	192	1.8	.16	.11	.23
	Asymptomatic	CAS, n = 6262	16	.3	34	.5	.49	.27	.88
	Asymptomatic	CEA, n = 19 280	31	.2	91	.5	.33	.22	.50
Three months	Symptomatic	CAS, n = 5815	51	.9	125	2.1	.39	.28	.54
	Symptomatic	CEA, n = 10 563	48	.5	229	2.2	.20	.14	.27
	Asymptomatic	CAS, n = 6262	25	.4	42	.7	.62	.38	1.02
	Asymptomatic	CEA, n = 19 280	45	.2	117	.6	.38	.27	.53
Two years	Symptomatic	CAS, n = 5815	95	1.6	205	3.5	.44	.35	.56
	Symptomatic	CEA, n = 10 563	110	1.0	374	3.5	.26	.21	.33
	Asymptomatic	CAS, n = 6262	34	.5	75	1.2	.48	.32	.72
	Asymptomatic	CEA, n = 19 280	103	.5	209	1.1	.47	.37	.60

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Abbreviations: CAS, carotid stenting; CEA, carotid endarterectomy; CI, confidence interval.

Among symptomatic patients who underwent carotid stenting, the incidence of epilepsy or seizures was .6% (HR = .32, 95% CI = .22–.48) at 1 month, .9% (HR = .39, 95% CI = .28–.54) at 3 months, and 1.6% (HR = .44, 95% CI = .35–.56) at 2 years. In symptomatic patients who underwent CEA, the corresponding rates were .3% (HR = .16, 95% CI = .11–.23), .5% (HR = .20, 95% CI = .14–.27), and 1.0% (HR = .26, 95% CI = .21–.33), respectively.

Among asymptomatic patients who underwent carotid stenting, the incidence was .3% (HR = .49, 95% CI = .27–.88) at 1 month, .4% (HR = .62, 95% CI = .38–1.02) at 3 months, and .5% (HR = .48, 95% CI = .32–.72) at 2 years. Similarly, in asymptomatic patients who underwent CEA, the incidence was .2% (HR = .33, 95% CI = .22–.50), .2% (HR = .38, 95% CI = .27–.53), and .5% (HR = .47, 95% CI = .37–.60), respectively.

3.2. Patients with post‐carotid stenosis cerebrovascular events

Among patients who experienced cerebrovascular events after the diagnosis of carotid stenosis, the number of seizure or epilepsy events at 1 month was too small for meaningful analysis; therefore, this analysis was not performed.

At 3 months, carotid revascularization was associated with a significantly lower incidence of epilepsy or seizures (.3% vs. 1.2%; HR = .27, 95% CI = .18–.41). This association persisted at 2 years (1.1% vs. 3.0%; HR = .35, 95% CI = .28–.45; Table 3).

TABLE 3.

Hazard ratios for epilepsy or seizure in carotid stenosis patients with poststenosis ischemic stroke or spontaneous hemorrhage.

	Procedure	Revascularization outcome, n	%	Control outcome, n	%	Hazard ratio	95% CI
One month	CAS + CEA, n = 8568	N/A		N/A
	CAS, n = 3300	N/A		N/A
	CEA, n = 5498	N/A		N/A
Three months	CAS + CEA, n = 8568	27	.3	100	1.2	.27	.18	.41
	CAS, n = 3300	15	.5	34	1.0	.44	.24	.81
	CEA, n = 5498	12	.2	63	1.1	.19	.10	.35
Two years	CAS + CEA, n = 8568	92	1.1	259	3.0	.35	.28	.45
	CAS, n = 3300	43	1.3	103	3.1	.42	.30	.61
	CEA, n = 5498	50	.9	163	3.0	.30	.22	.41

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Abbreviations: CAS, carotid stenting; CEA, carotid endarterectomy; CI, confidence interval; N/A, not applicable.

4. DISCUSSION

In this large, multicenter database study, carotid revascularization was associated with significantly lower short‐ and long‐term risks of seizures or epilepsy. This association persisted across multiple analytic strategies, including propensity score matching and subgroup stratification by symptom status and procedural modality. Notably, both CEA and carotid artery stenting demonstrated similar protective effects. To our knowledge, this is the first large‐scale study to evaluate seizure and epilepsy outcomes following carotid intervention, expanding an underrecognized dimension of carotid disease treatment.

When interpreting our observed cumulative risk of new onset seizures or epilepsy (.4% in the revascularization group and .8% in the entire cohort at 3 months), these findings should be considered in the context of established background rates in both the general population and disease‐specific populations. Population‐based studies estimate the annual incidence of a first unprovoked seizure in adults at approximately 56.8 per 100 000 person‐years, ¹⁹ with rates nearly tripling among individuals older than 75 years. In contrast, the rate of post‐ischemic stroke seizures has been reported to be approximately 6%–7%. ²⁰ , ²¹ Because we excluded major provoking conditions, such as brain tumors, metabolic disturbances, alcohol withdrawal, systemic infection, and traumatic brain injury, our cohort is more comparable to studies of unprovoked seizures. The incidence identified in our analysis aligns with prior epidemiologic studies.

One of the strengths of our study is the use of propensity score matching to minimize confounding. In addition to confounders addressed through propensity score matching, we conducted a sensitivity analysis to account for ischemic stroke or hemorrhagic events occurring after carotid stenosis diagnosis. Although time‐varying analysis to establish the relationship between stroke prevention and reduced epilepsy or seizure risk could not be performed using the TriNetX database, this additional analysis provides indirect evidence that the association between carotid revascularization and reduced seizure or epilepsy risk persists even among patients who developed postdiagnosis stroke or hemorrhage.

Several mechanisms have been proposed to contribute to this condition. Chronic cerebral hypoperfusion associated with high‐grade carotid stenosis leads to compromised cerebral energy metabolism and blood–brain barrier (BBB) dysfunction, as demonstrated by increased permeability and alterations in tight junction proteins in experimental models and patients with carotid stenosis. ²² , ²³ , ²⁴ This BBB disruption allows extravasation of serum albumin into the brain parenchyma, which activates transforming growth factor‐beta signaling in astrocytes, leading to impaired ability to buffer extracellular potassium and clearance of glutamate, thereby promoting neuronal hyperexcitability. ²⁵ , ²⁶ , ²⁷ Silent embolic events from unstable plaques may further compound these effects through microinfarcts that contribute to cumulative brain injury. ²⁸ Additionally, BBB dysfunction facilitates infiltration of peripheral immune cells, amplifying neuroinflammatory responses characterized by microglial activation and release of proinflammatory cytokines including IL‐1β, TNF‐α, and IL‐6. ²⁹ , ³⁰ This neuroinflammatory process creates a proconvulsant microenvironment, potentially contributing to epileptogenesis. ³¹ , ³²

Carotid revascularization through CEA or carotid stenting has been shown to reverse many of these pathological mechanisms. Studies demonstrate that CEA significantly improves cerebral blood flow, restores global cerebral energy metabolism with normalization of oxygen extraction, and enhances white matter integrity as measured by diffusion tensor imaging. ⁸ , ³³ Revascularization may also reduce systemic and neuroinflammatory markers, with documented decreases in blood inflammatory markers, suggesting reversal of epileptogenic mechanisms. ⁸ , ³⁴ , ³⁵ Furthermore, unstable carotid plaques contribute to systemic inflammation independent of their hemodynamic effects. ³⁶ Our findings parallel prior reports demonstrating that carotid intervention is associated with improved cognitive outcomes and lower incidence of both Alzheimer disease and non‐Alzheimer dementia. ⁶ , ³⁷

Several limitations warrant consideration. First, the constraints of the database precluded detailed assessment of stenosis severity and plaque characteristics at the individual patient level. Therefore, these clinically important variables could not be incorporated into the matching process. Second, although National Institutes of Health Stroke Scale scores were incorporated into the propensity score matching model, the final infarct size and severity of the baseline stroke in symptomatic patients who did not undergo revascularization procedures may still represent a residual confounding factor in our analysis. In addition, residual confounding from unmeasured factors, such as medication adherence, cannot be excluded. Third, administrative coding may misclassify seizure events or procedural details. Fourth, due to database limitations, we were unable to further classify epilepsy subtypes. Fifth, the definition of symptomatic disease in our analysis may have encompassed patients with stroke territories not directly attributable to ipsilateral carotid stenosis, potentially introducing misclassification bias. Sixth, patients had varying lengths of follow‐up, which may have resulted in unequal detection of seizure and epilepsy events between groups.

5. CONCLUSIONS

This study demonstrates that carotid revascularization is associated with a reduced risk of subsequent seizures and epilepsy in patients with carotid stenosis, regardless of symptomatic status or procedural modality. These findings suggest that the benefits of carotid intervention may extend beyond stroke prevention. Clinically, incorporating seizure risk into the broader outcome profile of carotid revascularization may help refine patient counseling and inform treatment selection.

AUTHOR CONTRIBUTIONS

Pang‐Shuo Perng and Chih‐Yuan Huang contributed to conception and design of the study, analysis of data, and drafting the text. Pang‐Shuo Perng, Chih‐Yuan Huang, Ming‐Tsung Chuang, Chia‐En Wong, and Yu Chang contributed to drafting the text. All coauthors provided significant input on interpretation of data, reviewed the paper, and revised it. The final manuscript was approved by all authors.

FUNDING INFORMATION

The authors declare that no funds, grants, or other support was received during the preparation of this article.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Supporting information

Figure S1. Propensity score density plots before (A) and after (B) matching for entire cohort who underwent revascularization and those who did not.

Figure S2. Propensity score density plots before (A) and after (B) matching for symptomatic patients who underwent carotid stenting and those who did not.

Figure S3. Propensity score density plots before (A) and after (B) matching for symptomatic patients who underwent carotid endarterectomy and those who did not.

Figure S4. Propensity score density plots before (A) and after (B) matching for asymptomatic patients who underwent carotid stenting and those who did not.

Figure S5. Propensity score density plots before (A) and after (B) matching for asymptomatic patients who underwent carotid endarterectomy and those who did not.

Figure S6. Propensity score density plots before (A) and after (B) matching for patients who developed ischemic or hemorrhagic stroke after carotid stenosis diagnosis, comparing those who underwent revascularization with those who did not.

Table S1. Inclusion criteria for patients in the revascularization group.

Table S2. Inclusion criteria for patients in the control group.

Table S3. Inclusion criteria for carotid stenting patients in the asymptomatic group.

Table S4. Inclusion criteria for carotid endarterectomy patients in the asymptomatic group.

Table S5. Inclusion criteria for patients who underwent carotid revascularization and experienced postdiagnosis cerebrovascular events.

EPI-67-3523-s001.docx^{(737.1KB, docx)}

ACKNOWLEDGMENTS

We are grateful to Dr. Sheng‐Hsiang Lin and Ms. Wan‐Ni Chen for providing the statistical consulting services from the Biostatistics Consulting Center, Clinical Medicine Research Center, National Cheng Kung University Hospital.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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