Seizure risk factors and management approaches in patients with brain metastases

Abstract

A significant proportion of patients with brain metastases experience a seizure event during their disease course, which can impact morbidity and long-term outcomes. A host of factors elevate the risk for seizures in patients with brain metastases, including patient factors, metabolic imbalances, tumor burden, and treatment modality. While reducing tumor burden via local and systemic therapies remains a critical component to mitigating seizure events, select patients may remain at risk. The use of prophylactic anti-seizure medications may be warranted in a subset of patients, though several clinical trials and guidelines from medical societies currently recommend against prophylactic use. Variability in the use of prophylactic anti-seizure medications in clinical practice underscores the need to update our current understanding of seizure risk in the era of multi-modality treatment and to identify opportunities to improve risk stratification and management. Herein, we provide a comprehensive literature review summarizing the current standard for seizure management in patients with brain metastases and assess the impact of multi-modal therapies on seizure risk. We additionally highlight gaps in the literature and present opportunities for future investigation.

Key Points.

1. Seizure risk is low with systemic and local therapies, though the potential increased risk for neurotoxicity with combined-modality therapy remains understudied.

2. Practice patterns around seizure prophylaxis vary considerably, leading to potential under treatment and overtreatment.

Seizures are the presenting symptom in 15%–20% of patients with brain metastases, with increased risk among patients with multiple lesions.^1–3 A similar proportion experience seizures during the course of their disease.⁴ For patients with brain tumors, post-operative seizures are associated with higher readmission rates, longer hospital stays, and greater morbidity,⁵ and the development of epilepsy is considered a significant risk factor for long-term disability.⁶ For patients without a seizure history, prophylactic anti-seizure medication (ASM) is not recommended, even following a craniotomy. The overall low seizure rate with CNS-directed therapies informs this recommendation. However, there is debate regarding whether select patients with high-risk features, such as large intracranial tumor volumes, may benefit from prophylactic ASM treatment. As the incidence of brain metastases rises, awareness of the mechanisms, risk factors, and management options for seizures in the era of combined-modality therapy is essential.⁷

Methods and Materials

Following the PRISMA guidelines for systematic analyses, a systematic search for original studies and reviews reporting seizure outcomes and management strategies in patients with brain metastases was manually conducted on PubMed/MEDLINE, Embase, and Google Scholar. Publications were screened based on methodology, study quality, patient sample size, and relevance. Study data and endpoints were manually extracted, resulting in a total of 97 original studies and reviews to be included.

Clinical Presentation and Mechanisms of Seizures

The clinical presentation of seizures depends on the extent of cortical involvement and the affected brain region. Accordingly, seizures are classified as focal onset or generalized onset, with focal onset seizures further defined by the presence or absence of awareness (Figure 1). Focal seizures begin as abnormal electrical activity in one area of the brain and can propagate diffusely to cause secondary generalization of seizure activity. Patients can often experience a premonitory event called an aura that can herald the onset of a seizure, called the pre-ictal period. Depending on the ictal focus for the seizure, patients may have a myriad of symptoms, including focal shaking, focal weakness, focal sensory changes, focal visual dysfunction, moments of confusion, and transient speech changes and aphasia. After the seizure, also known as the post-ictal period, patients may remain confused, have focal deficits, and experience headaches. Generalized onset seizures originate in bilateral distributed neuronal networks, and include multiple subtypes with the most common being generalized tonic–clonic seizures. For patients with brain metastases, focal onset seizures with or without awareness are the most commonly associated type of seizure unless the patient has an underlying generalized onset seizure disorder.⁸

Figure 1.

Seizure definitions and EEG patterns. Created in BioRender. Maingi, S. (2025) https://BioRender.com/l86w975.

Seizure events are likely mediated by neuronal hyperactivity, disturbances in neuronal membrane properties, and imbalances of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. Excessive, prolonged electrical activation, as seen with status epilepticus, can be damaging to the brain. Seizures occur when a seizure threshold is exceeded, typically due to provoking factors (Figure 2). Studies suggest that this seizure threshold is lower for patients with brain metastases.⁹ Tissue hypoxia, inflammation, acidosis, mechanical tumor-related effects, alterations in electrolytes, perfusion, and metabolism, and imbalances in excitatory neurotransmission contribute to this elevated seizure risk. In addition, tumor-specific features including histology, location, molecular features, and disease burden may also impact seizure risk.¹⁰ Critical evaluation of the contributions to seizure risk from CNS-directed therapies, including radiation, systemic therapies, and surgery, is warranted in the era of multi-modal therapy.

Figure 2.

Mechanisms of seizure activity and therapeutic targets. Created in BioRender. Maingi, S. (2025) https://BioRender.com/u11d593

Treatment-Specific Seizure Risk

Radiation Therapy

The risk of seizure events following whole-brain radiotherapy (WBRT) is low based on a limited set of prospective and retrospective series. Several seminal clinical trials evaluating WBRT omitted seizure outcomes from their secondary endpoints.^11–18 Gondi et al. reported only three grade 1–2 seizure events in a cohort of 113 patients treated with hippocampal avoidance-WBRT (HA-WBRT).¹⁹ JROSG99-1, a prospective trial of 132 patients randomized to WBRT plus stereotactic radiosurgery (SRS) or SRS alone, observed only one grade 4 seizure event in the SRS arm.²⁰ Likewise, Chang et al. reported only one grade 3 seizure event in a single-arm trial of 58 brain metastasis patients treated with SRS plus WBRT.²¹

Similarly, seizure events occur infrequently following SRS. In a cohort of 289 patients treated with SRS or fractionated SRS (also known as hypofractionated stereotactic radiotherapy), Minniti et al. reported a 1.7% incidence of seizures after treatment.²² Likewise, a series of 156 patients documented two generalized seizures and three focal seizures within ten days of SRS or fractionated SRS.²³ Radiation dose and fractionation were not predictive of seizure risk. Proton SRS was associated with a 5.8% incidence of seizures in a series of 370 patients with a median follow-up of 9.2 months.²⁴ In the post-operative setting, seizure incidence also appears low with an incidence of 5.9% according to a series of 87 resection cavities treated with photon-based SRS.²⁵

Taken together, these studies highlight the safety of SRS with respect to seizure risk in patients with CNS neoplasms. However, retrospective analyses suggest that tumor volume, specifically planning target volume, should be accounted for when considering individual risk for toxicity with SRS.^26,27 While tumor location, particularly in eloquent regions such as the motor cortex, should also be factored in when counseling patients, a recent study by Prasad and colleagues reported only 3 seizures in a series of 208 patients with metastases confined to the motor strip.²⁸ Though reassuring, these studies predate the era of multi-modal treatment, underscoring the need for continued monitoring and comprehensive reporting of patient outcomes in the modern era.

Immunotherapy

As immunotherapy is increasingly incorporated into the management of brain metastases, attention to treatment-related neurotoxicity has gained attention.²⁹ A recent German single-institution population-based study by Urban et al. suggested that the introduction of immune-checkpoint inhibitors preceded an increase in epileptic events among patients with brain metastases at their institution.³⁰ While seizure events are not consistently reported in immunotherapy trials, several prospective studies suggest a low seizure incidence with immune-checkpoint blockade. The phase II ABC trial enrolled 76 melanoma patients with either asymptomatic, untreated metastases or progressive disease, symptomatic lesions, or leptomeningeal disease.³¹ Cohort A received dual immune-checkpoint blockade with ipilimumab/nivolumab while Cohort B and C received a single immune-checkpoint blockade with nivolumab. Prophylactic ASMs were not given, yet only one (1.3%) seizure event occurred in the entire study (Cohort A). Likewise, the Checkmate 204 trial reported only two (1.7%) seizures in Cohort A, which evaluated dual immune-checkpoint blockade with ipilimumab/nivolumab for untreated melanoma brain metastases. Notably, patients had had at least one unirradiated brain metastasis and the majority (91%) had no prior SRS history.³² Future trials should report the incidence of pseudoprogression with immunotherapy and the potential impact on seizure incidence.

Patients with a prior history of radiation therapy may be at increased seizure risk. In a phase II study, Kluger et al. evaluated outcomes with pembrolizumab in 23 patients with at least one asymptomatic, untreated 5–20 mm brain metastasis.³³ Five and 12 patients were previously treated with WBRT and SRS, respectively. Most neurologic adverse events were grade 1–2 and three (13%) grade 1–2 seizures occurred. Following the first seizure event, prophylactic ASMs were initiated in all study patients and the authors recommended this practice for all patients with untreated brain metastases receiving immunotherapy. In a larger cohort of 42 patients with asymptomatic NSCLC brain metastases receiving pembrolizumab, only 2 (5%) grade 1–2 and 1 (2%) grade 3 seizure events were reported.³⁴ Notably, 50% of patients had received prior SRS. Seizure events were also rare in a phase I dose-escalation study of ipilimumab delivered concurrently with either WBRT (Arm A, n = 5) or SRS (Arm B, n = 11).³⁵ Only one grade 1 seizure event occurred in the study (SRS cohort). Multiple retrospective series with larger sample sizes confirm these findings. In a series of 480 patients receiving SRS, the incidence of seizures was 2% with and without the addition of an immune-checkpoint inhibitor.³⁶ Likewise, Minniti et al. reported only 3 (3.4%) patients with seizures after receiving single-agent immune-checkpoint blockade within one week of either SRS or fractionated SRS.³⁷

Despite these encouraging findings, the potential neurotoxicities associated with combining dual immune-checkpoint blockade (eg, ipilimumab/nivolumab) and SRS are gaining increased attention. Treatment-induced brain tissue necrosis, often referred to as radionecrosis, is the dose-limiting side effect of SRS and represents a delayed form of normal brain tissue injury, with implications for patient morbidity and mortality.^38,39 Nearly half of patients will present with symptoms including altered mental status, focal deficits, cognitive changes, and seizures, necessitating treatment ranging from corticosteroids to surgical resection to resolve mass effects secondary to vasogenic edema. Recent studies suggest that concurrent treatment with SRS and immunotherapy may increase necrosis risk.^39–41 Phase II trials evaluating pembrolizumab in patients with active melanoma or NSCLC brain metastases report a 14%–30% incidence of necrosis.^33,34 As seizures are a well-characterized presenting feature of necrosis, future trials must consistently report the incidence of necrosis and assess the optimal sequencing and fractionation of therapies to mitigate adverse effects without compromising tumor control. Results of the open ABC-X (NCT03340129) and NRG-BN013 (NCT06500455) trials are eagerly awaited and will inform clinical practice in the era of multi-modality therapy. Whether seizure events are increased with concurrent immunotherapy and SRS is critical to ensuring that patients and providers remain fully informed of the risks and benefits of these novel approaches.

Targeted Therapy

According to the literature, seizure events are uncommon following the use of targeted systemic therapies in patients with brain metastases. However, trials which excluded patients with brain metastases infrequently reported seizure outcomes, limiting the assessment of treatment-induced seizure risk.^42–45 As survival improves for patients with metastatic disease in the era of multi-modality therapy, there is an urgent need for routine incorporation of neurotoxicity endpoints in clinical trials. Among patients with brain metastases receiving radiotherapy, retrospective series suggest an acceptable safety profile. However, patients with HER2+ breast cancer receiving concurrent anti-body drug conjugate therapy and SRS may be at elevated risk of symptomatic radionecrosis, which may increase seizure risk.^46,47 Standard practice is to withhold targeted agents, especially tyrosine kinase inhibitors, for several half-lives before and after radiotherapy. The following subsections detail the current data on seizure risk with targeted agents in patients with lung, breast, and melanoma brain metastases.

Non-small Cell Lung Cancer

In the non-small cell lung cancer (NSCLC) literature, seizure endpoints were not explicitly reported by trials assessing the efficacy of epidermal growth factor receptor (EGFR) inhibitors, specifically erlotinib and gefinitib,^48–52 or anaplastic lymphoma kinase (ALK) inhibitors.^53–55 However, a phase II trial evaluating alectinib in ALK-positive, crizotinib-resistant NSCLC patients reported only two (2.3%) grade 1–2 and one (1.1%) grade 3 seizure event in a cohort of 87 patients.⁵⁶ Patients on the trial had progressed on crizotinib and were permitted to have untreated or treated brain or leptomeningeal metastases, so long as they remained asymptomatic and neurologically stable. The intracranial overall response rate and median duration of CNS response were 75% and 11.1 months (95% CI: 5.8 to 11.1), respectively. Notably, 34 (65%) patients had received prior radiotherapy, and only 16 completed radiotherapy more than six months before receiving alectinib.

Breast Cancer

For patients with breast cancer, seizure outcomes are infrequently reported by trials evaluating trastuzumab or TDM-1. In a multicenter phase II study of HER2+ breast cancer patients with unequivocal evidence of new or progressive brain metastases after radiotherapy and prior treatment with a trastuzumab-based regimen, only four patients developed seizures while receiving the tyrosine kinase inhibitor lapatinib.⁵⁷ Only 15 (6%) patients demonstrated a CNS objective response to lapatinib monotherapy; however, 21% of patients experienced at least a 20% reduction in CNS tumor volume, suggesting modest intracranial activity. In total, 64 (26%) patients received prior SRS and 229 (95%) received prior WBRT either alone or in combination with SRS. On the phase II LANDSCAPE trial of 45 HER2+ patients with previously untreated brain metastases, only 1 (2%) seizure event occurred with lapatinib plus capecitabine.⁵⁸ 29 (66%) patients had an objective CNS response to lapatinib plus capecitabine. Likewise, the randomized phase II LUX-Breast 3 trial of 121 HER2+ breast cancer patients with progressive brain metastases after trastuzumab, lapatinib, or both reported only one seizure event in the afatinib plus vinorelbine arm.⁵⁹ At 12 weeks, 27 (68%) patients in the afatinib arm and 27 (71%) patients in the afatinib plus vinorelbine arms had stable CNS disease; however, only three patients in the latter arm had an objective intracranial response. 84% of patients received prior radiotherapy and 59% had more than three progressing brain metastases at the time of enrollment. It is unclear whether neratinib carries a similar safety profile to lapatinib and afatinib, as seizure events were not reported in a recent phase II study.⁶⁰

Melanoma

Limited data are available regarding targeted agents and seizure risk for patients with metastatic melanoma. Seizure events were not reported in the COMBI-MB trial evaluating dabrafenib and trametinib.⁶¹ Vemurafenib, an oral BRAF inhibitor, was evaluated in an open-label pilot study for 24 patients with progressing and symptomatic BRAF V600E mutant brain metastases.⁶² All patients were receiving steroids, and 14 (58%) and 6 (25%) patients received prior WBRT or SRS, respectively. Six (25%) of the patients developed grade 1–2 seizures. Of 19 patients with measurable intracranial disease, a partial response or stable disease with vemurafenib was reported in 16% and 68% of patients, respectively. In contrast, a larger phase II single-arm trial of patients with either untreated brain metastases (Cohort 1: n = 90) or with measurable disease progression following SRS, WBRT, or surgery (Cohort 2: n = 56) reported a seizure incidence of 1%–2% with vemurafenib across cohorts.⁶³ Notably, symptomatic patients were permitted on the study but were neurologically stable and on a stable or decreasing steroid dose. Forty-one (73%) of the patients in Cohort 2 had received prior WBRT or SRS. At a median follow-up of 9.6 months, complete response, partial response, and stable disease were reported in 2 (1%), 24 (16%), and 62 (43%) patients, respectively, across cohorts.

Chemotherapy

Immunotherapy and targeted therapy continue to replace chemotherapy for the treatment of brain metastases. There are limited contemporary clinical trials to inform seizure risk with chemotherapy. Minniti et al. reported outcomes from 206 patients with lung, melanoma, or breast cancer brain metastases.⁶⁴ All patients received SRS and chemotherapy. Of the patients, 75.7% received chemotherapy in the neoadjuvant or adjuvant setting and only three (1.5%) patients experienced seizures. While these findings are encouraging, careful surveillance is appropriate.

Surgery

The incidence of post-craniotomy seizures ranges from 1% to 29% for patients with primary and metastatic brain tumors.^5,65 In a prospective randomized trial, 123 patients without a prior seizure history were randomized to either observation or seven days of phenytoin for seizure prophylaxis after surgery.⁶⁶ 77 patients were treated for brain metastases. Primary outcomes were seizures and other adverse events. The study was terminated early due to a lower-than-expected seizure incidence. Only 8% of patients experienced seizures within 30 days of surgery and only 3% developed clinically significant seizures without prophylaxis. However, phenytoin-related adverse events were high, driven by neurologic and gastrointestinal side effects. While most patients can likely be spared from prophylactic ASMs, patients are still at risk in the post-surgical period, likely due to acute surgery-related tissue damage, edema, and hypoxia. Additionally, a pooled meta-analysis of four randomized trials suggested that perioperative ASM prophylaxis may reduce early post-operative seizure risk for brain tumor patients.⁶⁷

Data on seizure incidence following minimally invasive procedures, such as laser interstitial thermal therapy (LITT), are emerging. LITT is increasingly integrated into clinical practice to manage intracranial tumors and radiation necrosis. In a recent retrospective analysis of 86 consecutive patients, 19 (22%) patients experienced seizures within 90 days of LITT.⁶⁸ Notably, 43 (50%) patients had documented seizures prior to LITT. Patients experiencing seizures within 90 days were significantly more likely to have received pre-LITT WBRT (32% vs. 9%, P = .02). Ongoing investigation is warranted to identify which patients undergoing LITT require closer monitoring or more prolonged ASM use following ablation.

Seizure Management

Prophylaxis

Patients with brain metastases are at elevated risk for seizures and select patients may benefit from prophylaxis with ASMs.⁶⁶ Retrospective studies propose that patients with high-risk features, including larger tumor volumes, melanoma histology, tumors in eloquent locations, or baseline neurologic deficits, may benefit most from prophylactic ASMs.^9,27 However, the benefit is likely small, as several prospective randomized trials failed to observe a clinical benefit with prophylactic treatment in both surgical and non-surgical patients. In 2000, the American Academy of Neurology (AAN) recommended against prophylactic ASMs in patients with newly diagnosed brain tumors due to a lack of demonstrated efficacy and risk of treatment-related toxicity.⁶⁹ In surgical patients with no seizure history, tapering and discontinuing ASMs within 1 week postoperatively was advised. In 2021, guidelines from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO) similarly noted insufficient evidence to support peri- or postoperative ASMs in brain tumor patients.⁷⁰ Moreover, there was insufficient evidence to support the prophylactic use of ASMs based on tumor location, histology, grade, or molecular and imaging features. These recommendations align with the 2019 Congress of Neurological Surgeons (CNS) guidelines and the updated 2024 SNO guidelines.^71,72

These guidelines incorporate studies of non-enzyme-inducing ASMs and expertise from neurosurgeons, neuro-oncologists, neurologists, neurophysiologists, and epileptologists. They concur with several randomized trials that failed to show a benefit with prophylactic ASMs in patients with both primary and metastatic brain tumors.^66,73,74 Many of these patients were surgical candidates diagnosed with brain metastases and were treated with phenytoin, phenobarbital, or levetiracetam. Several systematic reviews and meta-analyses also support these conclusions,^75–77 and similar inferences are made for non-surgical patients.^78,79 Even so, existing data on prophylactic ASM prescription patterns reveal significant variation among healthcare providers, underscoring the need for improved knowledge translation and consistent implementation of clinical guidelines. For example, 63% of surveyed neurosurgeons prescribe prophylactic ASMs to patients without an antecedent seizure history.⁸⁰ In contrast, a survey of 500 radiation oncologists found that less than 10% recommend ASMs after SRS. Among radiation oncologists prescribing ASMs, 41% recommend a duration of more than two weeks of ASMs following SRS. Given the adverse effects associated with ASMs, future work should aim to increase awareness among healthcare professionals around current practice guidelines, determine the underlying causes of variation in clinical practice, and identify non-pharmacologic strategies to reduce seizure risk, particularly among those with potential risk factors.

Secondary Prevention

ASM use is warranted for secondary prevention following a new seizure or in patients with a history suggestive of seizures (Figure 3). When counseling patients with brain metastases about management options, a thoughtful conversation about the risks and benefits of various treatment approaches is necessary (Table 1).⁸¹ Providers should additionally be prepared to counsel patients on the impact of a seizure history on their ability to hold a driver’s license. In the United States, State laws vary considerably, with some mandating physician reporting of seizure events and others requiring periodic medical updates for patients to maintain a driver’s license (Table 2).⁸²

Figure 3.

Management strategy for seizures in patients with brain metastases.

Table 1.

Overview of Commonly Used Antiseizure Medications

Agent	Mechanism	Indication	Clinical considerations	Systemic toxicity	Neurological toxicity
Brivaracetam	Selective inhibition of S2VA protein	Monotherapy or adjunctive for focal-onset seizures	Metabolized via CYP pathways	Nausea, vomiting, constipation, fatigue	Headache, somnolence, dizziness, ataxia, abnormal coordination, nystagmus
Levetiracetam	Decreases rate of vesicle-membrane fusion via S2VA protein	First-line monotherapy for focal and generalized tonic-clonic seizures	Favorable toxicity profile, broad efficacy against partial and generalized seizures, long-acting with predictable dose-serum concentration relationship	Fatigue, infection, anemia	Neuropsychiatric events (particularly for patients with frontal lobes tumor), somnolence, dizziness, agitation, anxiety, irritability, depression
Carbamazepine	Extends inactivated phase of sodium channels	Focal and generalized tonic-clonic seizures	Metabolized via CYP pathways, also has extended-release formulation with twice-daily dosing	Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, hepatotoxicity	Drowsiness, dizziness, blurred or double vision, lethargy, headache, ataxia
Lacosamide	Promotes slower inactivation of sodium channels	Monotherapy or adjunctive for focal-onset, primary generalized tonic-clonic seizures	Extended-release formulation available for partial-onset seizures, alternative dosing schedule can help with achieving maintenance dosage more rapidly	Nausea, vomiting, fatigue	Ataxia, dizziness, headache, diplopia
Lamotrigine	Inactivates sodium channels	Adjunctive for focal-onset, primary generalized tonic-clonic seizures	Alternative dosing schemes are necessary if taking other drugs that induce glucuronidation	Rash, nausea	Dizziness, tremor, diplopia
Phenytoin	Blocks sodium channels	Focal and generalized tonic-clonic seizures	Metabolized via CYP pathways, prodrug fosphenytoin (administered in phenytoin equivalents) can be given intravenously	Gingival hypertrophy, rash, peripheral neuropathy, osteoporosis	Confusion, slurred speech, double vision, ataxia
Zonisamide	Blocks sodium channels	Adjunctive for focal and generalized tonic-clonic seizures	Long half-life allows for once-daily dosing	Nausea, anorexia, weight loss	Somnolence, dizziness, ataxia, confusion, difficulty concentrating, depression
Pregabalin	Mediates calcium influx through alpha-2-delta subunit of calcium channel	Adjunctive for focal seizures	No significant interactions with other ASMs	Weight gain, peripheral edema, dry mouth	Dizziness, somnolence, ataxia, tremor
Perampanel	Noncompetitive inhibition of AMPAR	Focal-onset with/without secondary generalization, adjunctive for primary generalized tonic-clonic seizures	Very long half-life, extensive metabolism by CYP and glucuronidation pathways causes interactions with other enzyme-inducing ASMs	Weight gain, fatigue, nausea	Dizziness, somnolence, irritability, gait disturbance, falls, aggression, mood alteration
Topiramate	Antagonizes AMPAR/KAR, blocks sodium channels, increases GABA activity at GABA(A) receptor	Monotherapy for focal or primary generalized tonic-clonic seizures	Careful titration required to minimize adverse cognitive effects (no clinically established therapeutic level), once-daily formulation also available	Weight loss, paresthesia, fatigue	Nervousness, difficulty concentrating, confusion, depression, anorexia, language problems, anxiety, mood problems, tremor
Benzodiazepines	Increases chloride permeability of GABA(A) receptors	Focal and generalized tonic-clonic seizures, acute status epilepticus	Primarily metabolized via CYP pathways, discontinuation may lead to withdrawal seizures	Tolerance, respiratory depression, nausea, constipation, muscle weakness	Irritability, depression, ataxia, sedation, drowsiness, behavioral changes
Phenobarbital	Improves GABA’s capacity to open Cl- channels through GABA(A) receptor	Focal and generalized tonic-clonic seizures	Metabolized via CYP pathways, clinical utility limited by side effect profile	Nausea, rash	Alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence

Table 2.

State Driving Requirements in the United States

Required duration of seizure-free period for driver’s license
≥3 months
	Arizona*
	California*
	Kentucky
	Maine
	Maryland*
	Minnesota
	Nevada*
	Oregon
	Texas*
	Utah*
	Wisconsin
≥6 months
	Alabama
	Alaska
	Florida (less time possible at physician discretion)
	Georgia
	Hawaii*
	Iowa
	Kansas*
	Massachusetts*
	Michigan*
	Mississippi
	Missouri
	New Jersey
	New Mexico
	North Carolina
	North Dakota (restricted license available after 3 months)
	Oklahoma*
	Pennsylvania*
	South Carolina
	South Dakota (less time possible at physician recommendation)
	Tennessee*
	Virginia*
	Vermont*
	West Virginia
≥12 months
	Arkansas*
	District of Columbia
	New Hampshire (less time possible at DMV discretion)
	New York (less time possible at DMV discretion)
≥18 months
	Rhode Island (less time possible at DMV discretion)
Frequency of required medical updates to maintain driver’s license
Every 6 months
	Iowa (at 6 months and again at license renewal)
	Minnesota (depending on individual case)
	New Jersey (for 2 years, then annually)
	South Carolina (for 6 months, then annually)
	South Dakota (until seizure free for 1 year)
Annually
	Delaware
	District of Columbia (until seizure free for 5 years)
	Kansas (until seizure free for 3 years)
	Nevada (for 3 years)
	North Dakota (for at least 3 years)
Physician requirement to report epilepsy
	California
	Delaware
	Nevada
	New Jersey
	Oregon
	Pennsylvania

*With exceptions.

Non-enzyme-inducing ASMs are preferred, including levetiracetam, lamotrigine, and lacosamide, as these have favorable safety profiles and fewer drug-drug interactions.^1,83–85 Fifty percent of patients with tumor-related epilepsy are adequately controlled with monotherapy,⁸⁶ which is preferred over multi-drug regimens that can undermine compliance and increase toxicity. Levetiracetam, a modulator of synaptic vesicle protein SV2A, is frequently prescribed due to its favorable side effect profile and efficacy against partial and generalized seizures. Additionally, routine monitoring of serum drug concentrations is unnecessary with levetiracetam.⁸⁷ Levetiracetam and lacosamide, a selective inhibitor of voltage-gated sodium channels, are also commonly favored by clinicians because they can be delivered orally or intravenously. Inducers of cytochrome P450, such as carbamazepine, phenobarbital, and phenytoin, are avoided as they decrease the concentrations of chemotherapeutic agents and dexamethasone, which is problematic for patients with brain metastases.^88–91

If seizures are refractory, drug serum levels should be verified and potential seizure triggers should be addressed, such as physical or psychological stress, excess alcohol use, lack of sleep, or use of medications that lower the seizure threshold. If drug levels are appropriate, adherence is confirmed, and seizure triggers are addressed, the ASM dose should be increased before switching to an alternative agent with a different mechanism or adding a second agent (eg, dual therapy). Alternative preferred ASMs include lacosamide or lamotrigine, with selection often dependent on the side-effect profile of each drug and the individual patient. Non-enzyme-inducing ASMs should be prioritized when considering switching agents or adding a second agent (eg, dual therapy). Referral to a neurologist and epileptologist should be considered for complicated or refractory seizures in patients with therapeutic drug levels and maximal doses of commonly prescribed non-enzyme-inducing ASMs.

Awareness of the toxicities associated with ASMs is crucial. Prolonged treatment with ASMs can significantly impact quality of life and is associated with greater patient distress, worsened perceptions of cognition and social function, and greater drug side effects.⁶ The incidence of adverse effects from ASMs may be elevated in patients with brain tumors.⁶⁹ For example, levetiracetam is associated with neuropsychiatric effects and patients with frontal lobe tumors may be at greater risk for neuropsychiatric adverse events.⁹² As seizures are frequently due to tumor-related effects, local therapy with surgery or radiotherapy may be preferred over ASMs to achieve tumor control and reduce seizure risk.⁹³ Additionally, for uncomplicated seizures or suspected seizures that do not recur within six months of local brain metastasis treatment in patients without residual or progressive disease, gradual withdrawal of ASM treatment can be considered (Figure 3). Consistent with the 2024 SNO consensus statement, the decision to withdraw ASMs must be patient-centered and account for individual tumor characteristics, treatment response, prognosis, and other clinical and radiographic features.⁷²

Future Directions and Recommendations

Identification of patients with brain metastases most at risk for seizure events is critical, given the morbidity associated with epileptic seizures. Moreover, the issue of secondary chemoprevention of brain metastases is increasingly being addressed in prospective studies and is critical for the prevention of seizures.⁹⁴ Standardized, validated predictors of seizure risk that incorporate the potential impact of immunotherapies and targeted therapies are needed to guide conversations around prophylactic ASM, as current assessments rely on clinical and radiographic features. According to a retrospective series of 348 patients, patients treated post-operatively with immune-checkpoint inhibitors and patients with tumors in the parietal lobe may be at elevated risk for post-operative seizures.¹⁰ Another series of 1949 patients reported an 8.6% incidence of seizures, which varied by tumor histology.⁹⁵ The seizure incidence was most elevated in patients with metastatic melanoma (19.8%). Finally, a retrospective series of 305 patients suggested a similar 8.5% incidence of seizures, and reported symptomatic brain metastases and the total irradiated tumor volume as significant predictors of seizure risk.²⁷

These retrospective series highlight the need for prospectively validated guidelines, accounting for individualized risk factors and exposure to multi-modal therapies, to inform clinical practice and mitigate overuse and underuse of ASMs. Additionally, future investigations must evaluate how the sequencing of local and systemic therapies impacts tumor control and toxicity, including seizure risk. As local therapies such as radiotherapy and LITT are increasingly integrated with novel systemic agents, prospective trials must incorporate and report neurotoxicity endpoints and patient-reported outcomes. Additionally, cancer neuroscience suggests an important role for the tumor-nerve axis in mediating not only seizure risk, but also tumor proliferation, immunomodulation, and metastasis.^96,97 This nascent field warrants ongoing investigation as the electrical integration of neural networks with brain metastases could represent a future target for both seizure and tumor control.

Due to improvements in survival with more effective systemic therapies, patients and providers will increasingly be tasked with managing the long-term effects of treatments. Increased awareness, reporting, and investigation of neurotoxicities, particularly seizures, in the setting of multi-modal therapy is therefore essential to improving clinical management and patient outcomes. Our critical literature review reports the following novel findings:

• Tumor location, tumor histology, disease burden, and symptomatic intracranial disease may predict seizure risk.

• Small phase II trials suggest that immunotherapy (pembrolizumab) and targeted therapies (vemurafenib), while well tolerated, may reduce the seizure threshold.

• Local therapies, including stereotactic radiosurgery and laser interstitial thermal therapy, are well tolerated, though the potential interaction with novel systemic agents and risk for neurotoxicity remains understudied.

• While standardized guidelines regarding seizure prophylaxis exist and are unequivocal in their recommendations, practice patterns around seizure prophylaxis vary considerably, leading to potential overtreatment and undertreatment based on perceived risk factors.

Conclusions

Seizures occur in approximately 15%–20% of patients with brain metastases and are associated with significant morbidity. Radiation therapy, systemic therapy, and surgery are essential treatment modalities to achieve durable tumor control and reduce seizure risk secondary to uncontrolled cancer. Data from multiple clinical trials suggest that treatment-related seizure events are uncommon. Nonetheless, seizure outcomes are infrequently reported, highlighting an unmet need to strengthen data collection and research efforts in this area. While prophylactic ASM use is not routinely recommended, it plays an important role in secondary seizure prevention. Efforts to identify seizure-naïve patients most likely to benefit from prophylaxis are crucial. Medical societies should continue to increase awareness and understanding of the appropriate use and management of ASMs. Future clinical trials should incorporate neurotoxicity endpoints, including seizure events, particularly as combined-modality treatment approaches are increasingly integrated into clinical practice. The optimal timing of multi-modal therapies to mitigate toxicity, without compromising oncologic outcomes, should also be assessed.

Funding

National Institutes of Health [5R38-CA245204 to E.J.V., 1K38CA292995-01 to E.J.V., K08-CA2560450 to Z.J.R].

Conflict of interest statement

J.D. has a consultant or advisory role with Amgen, Novartis, and Janssen.

Authorship statement

In accordance with ICMJE criteria for authorship, all authors (1) substantially contributed to the conception or design of the work, or the acquisition, analysis, or interpretation of data, (2) contributed to the drafting and critical review of the study findings, (3) approved the version to be published, and (4) agreed to be accountable for all aspects of the work to ensure the accuracy and integrity of the study.

Data availability

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.