Anti‐seizure prophylaxis in brain tumors: An Italian survey among epileptologists

In order to elucidate any differences in the therapeutic approach in patients with epilepsy affected by cerebral tumors, we conducted a brief survey to Italian epileptologists (neurologists and neurosurgeons) affiliated with the Italian League Against Epilepsy (LICE). Epilepsy is the most common symptom associated with cerebral tumors, occurring in the 35%–75% of cases. The incidence is even higher in low-grade tumors, although it may also be influenced by tumor size, location and protein expression.1 According to ILAE guidelines, a diagnosis of epilepsy in the presence of a consistent cerebral lesion requires at least only a single ictal event in order to justify initiation of anti-seizure medication (ASM), whereas the prophylactic use of ASMs in seizure-naïve brain tumor is not recommended.2 Similarly, according to SNO (the Italian Neurohospitalist Society) and EANO (European Association of Neuro-Oncology) practice guidelines; there is no evidence to support the routine prescription of ASM in the perioperative or postoperative period.3 Finally, in recent years, many studies have focused on the hypothetical anti-epileptogenic effect of ASMs, although promising data have so far been limited to preclinical studies.4-6 In addition, available guidelines and literature revisions suggest the prescription of newer drugs in order to avoid interactions and reduce side effects.3 In the real-world clinical practice, however, adherence to these recommendations is often inconsistent. This may be due to variations in healthcare organization, institutional protocols, and individual prescribing habits. Our survey was a cross-sectional study targeting experienced epileptologists routinely involved in the management of tumor-related epilepsy. The aim was to identify the gap between current guidelines and real-world therapeutic approaches for patients with epilepsy and primary brain tumors in Italy. The survey consisted of six items (full text in Table 1). The first four were multiple-choice questions with closed responses, whereas the last two were open-ended. The survey data collection and analysis were performed using Microsoft Excel software. Only epileptologists belonging to a qualified center for the treatment of brain tumor patients were invited to participate. The survey was distributed in February 2023 with a span of 14 day window for completion. A total of 57 LICE members answered the survey (see the Figure 1 for a geographical representation of participating centers). The first question explored the attitude to introduce an ASM in High-Grade Gliomas (HGG) after a first seizure. Fifty-two epileptologists (91.2%) confirmed the attitude to introduce an ASM after the first seizure. Two (3.5%) preferred to wait for a second seizure, one (1.8%) decided on EEG results basis, and two (3.5%) chose not to initiate treatment at all. The second question explored the therapeutic attitude in HHG without seizures. Twenty-seven epileptologists (47.4%) reported not prescribing prophylactic therapy, 17 (29.8%) deferred the decision to the neurosurgeon, 8 (14%) introduced therapy during the perioperative period to prevent symptomatic postcraniotomy seizures and 5 (8.8%) prescribed long-term prophylaxic ASMs. The third question asked about ASM duration after a single seizure at HGG onset. Most responders (48, the 84.2%) favored long-term therapy, while 9 (15.8%) recommended withdrawal after the perioperative or radiotherapy phase. The fourth question concerned the diagnostic pathways of Low-Grade Gliomas (LGG)/Long-Term Epilepsy-Associated Tumors (LEAT). Forty respondents (70.2%) preferred a tailored surgery after appropriate diagnostic investigations or referred the patient to an epilepsy surgery center. Twelve (21.1%) decided upon a quick surgery without prior epileptological evaluation and 5 (8.8%) chose for the medical therapy until pharmacoresistance emerged. The final two questions explored preferred ASMs for HHG and LGG/LEAT patients. For HHG, first-line treatment was levetiracetam (43, 75.4%) followed by lacosamide (7, 12.3%) and valproate. Second-line choices were lacosamide (31, 54.4%), levetiracetam (9, 15.8%) and valproate (4, 7.0%). Third-line options included valproate (10, 17.5%), lacosamide (8, 14.0%) and perampanel (7, 12.3%). For LGG/LEAT, first-line treatment was levetiracetam (34, 59.6%), followed by lacosamide (10, 17.5%) and carbamazepine (7, 12.3%). Second-line choices were lacosamide (25, 43.9%), levetiracetam (19.3%) and carbamazepine (8, 14.0%). Third-line treatments were equally distributed among lacosamide (10, 17.5%), oxcarbazepine (9, 15.8%) and carbamazepine (7, 12.3%) (see Figure 2 for full details). This brief survey assessed the current therapeutic attitudes of Italian epileptologists regarding ASM management in patients with brain tumors. First, the results confirm the alignment of the epileptologists to ILAE and neuro-oncological guidelines for the treatment of the first seizure in the contest of brain tumors, reflecting awareness of the high risk of seizure recurrence. ASM initiation after a single seizure remains widely accepted among specialists. However, the management of seizure-naïve HGG remains controversial. Despite guideline recommendations against prophylactic treatment, nearly half of the responders seem to prefer ASM prophylaxis, at least temporarily, or defer the decision to the neurosurgeon. This tendency is likely driven by a desire to prevent early postoperative seizures, as suggested in studies of postcraniotomy seizures following traumatic brain injury.7 Regarding long-term prophylaxis, despite a lack of demonstrated benefit, this practice persists, likely due to the paucity of robust, well-designed trials and the historical use of older ASMs. Considering the high incidence of seizures in cerebral tumors (at the onset or during the course), as well as the ease of handling new drugs, prospective controlled trials are urgently needed to evaluate ASM prophylaxis, with attention to quality of life and healthcare costs. When a cerebral tumor presents with one or more seizures, the duration of therapy is debated, but most responders (85%) seem to favor long-term ASM therapy. Since tumors are an on-going developing pathology, one could opt for a lifelong therapy. Nevertheless, 15.8% of the interviewed declared that they withdraw therapy after the perioperative/radiotherapy phase, possibly viewing the seizures as acute symptomatic rather than indicative of chronic epilepsy. Concerning the therapeutic management of patients with LGG/LEATs, over 70% of the respondents favored tailored surgery aimed at both seizure control and histological diagnosis. Indeed, patients affected by LGG/LEATs show a high incidence of drug-resistant epilepsy despite a relatively low risk of oncological progression. For this reason, the epilepsy must be taken into account as the main problem for the patient's quality of life and deserves a specific neurosurgical approach, consisting of tailored surgery, sometimes preceded by a long-term video-EEG monitoring. In this study, the choice of an epilepsy surgery approach was probably influenced by the preponderance of epileptologists over neurosurgeons who answered the survey. This underscores the need for a national network to share case management and promote interdisciplinary decision-making. Concerning the pharmacological choices in these patients, levetiracetam and lacosamide emerged, as expected, as the most widely used drugs for prophylaxis in both HGG and LGG/LEATs. Their favorable pharmacokinetic and pharmacodynamic profiles—minimal drug interactions, good tolerability, and high efficacy—make them the preferred options. The third-line use of valproate in HGG likely reflects historical interest in its potential antitumor effects, while the inclusion of perampanel may relate to its potential modulation of glutamatergic neurotransmission.8 Despite the existence of several consensus statements and guidelines, this survey confirmed a significant variability in the therapeutic approach of these patients and further supports the need of prospective controlled trials to better define standardized treatment strategies. EP: conceptualization; formal analysis; data curation; writing original draft. MR: conceptualization; methodology; supervision; validation; visualization; review & editing. PG: conceptualization; methodology; supervision; review & editing. MM: conceptualization; review & editing. The authors have nothing to report. None of the authors has something 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. Umberto Aguglia, Cinzia Costa, Giuseppe Didato, Vincenzo Esposito, Enrico Franceschi, Anna Teresa Giallonardo, Angela La Neve, Marta Maschio, Giada Pauletto, Flavio Villani, Paolo Vitali, Matteo Martinoni, Marta Piccioli. 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.