Antiepileptic drugs for treating seizures in people with brain tumours

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To compare the efficacy and tolerability of antiepileptic drugs (AEDs) taken as monotherapy or add‐on therapy for seizures in people with brain tumours.

Background

This protocol supercedes a published Cochrane Review (Kerrigan 2011).

Description of the condition

Each year around 12,100 people in the UK are diagnosed with brain and other central nervous system (CNS) tumours, according to Cancer Research UK (average yearly incidence 2015 to 2017). Approximately 1 in 65 females and 1 in 69 males in the UK will be diagnosed with a brain, CNS or other intracranial tumours in their lifetime. The average age of onset is 30 to 45 years old (CRUK 2023). Exposure to ionising radiation increases the risk of brain tumour development (Bondy 2008). In one large study of 1930 people with glioma, the mean age at time of diagnosis increased with the grade of glioma (Rasmussen 2017).

Brain tumours are classified from grade I to IV according to the World Health Organization (WHO) grading system, with grades I and II considered ‘low‐grade’ and grades III to IV ‘high‐grade’ tumours (Louis 2016). Even within individual grades, a wide range of heterogeneous tumour entities exist. Some, such as dysembryoplastic neuroepithelial tumours (DNET, grade I), are benign and frequently demonstrate little to no growth over many years of follow‐up. In contrast, glioblastoma multiforme (GBM) is a highly malignant grade IV tumour that often displays rapid growth and confers a poor prognosis with a median survival time from diagnosis of 15 months (Thakkar 2014).

Seizures and epilepsy are a common symptom of brain tumours. Low‐grade tumours can be up to three times more likely to cause seizures than tumours of a high grade, and are often more resistant to treatment with medication. It is thought that up to 100% of DNETs cause focal seizures (Kerkhof 2013). Other low‐grade entities, such as diffuse astrocytomas and oligodendrogliomas (both grade II), cause seizures in 60% to 90% of cases. Seizure frequency in people with high‐grade lesions is significantly lower, with estimates of between 30% to 62% of cases (Armstrong 2016). Seizures can be focal in onset, with or without impaired awareness, or focal to bilateral generalised tonic‐clonic in nature. The mechanisms determining seizure generation in people with brain tumours are poorly understood. It is thought that neurotransmitter derangement at the margin of the tumour and in the peritumoral zone could be a factor that promotes seizure generation in some gliomas, as well as local deafferentation and hypoperfusion injury (Pallud 2013). In many brain tumours the isocitrate dehydrogenase 1 (IDH‐1) gene is found to be mutated, resulting in the aberrant production of the compound 2‐hydroxyglutarate (2‐HG). 2‐HG is structurally similar to glutamate, the major excitatory neurotransmitter in the brain. It is possible that it is able to mimic its excitatory action, potentially inducing seizures (Chen 2017).

Tumour location does not appear to have a major impact on the risk of seizures occurring, as tumours in most supratentorial brain regions display similar seizure incidence. Involvement of particular regions may influence whether the seizures are refractory to treatment. Tumours within the insula, for example, may present with seizures that are poorly responsive to first‐line anticonvulsant medications (Pallud 2014).

Currently, management of brain tumours comprises either regular surveillance via frequent imaging or surgical resection of as much of the lesion as is safe to resect without causing significant disability. In addition, chemotherapy or radiotherapy, or both may be used as an adjunct if appropriate. For grade II to IV tumours, surgical resection is not curative and treatment is aimed at slowing progression and subsequently treating symptoms and complications if and when they arise. Surgical resection may also be considered in order to improve seizure frequency should anticonvulsants fail to achieve satisfactory improvements in seizure frequency.

At present, use of anticonvulsants in people with brain tumours is largely based on knowledge of anticonvulsant efficacy in the general population who have epilepsy. As most seizures seen in brain tumour‐related epilepsy are focal in nature, it follows that treatment is currently guided by best practice in treating focal seizures in the wider population. For example, studies such as the SANAD II trial found lamotrigine to be superior as a first‐line treatment in newly diagnosed focal epilepsy in the general population (Marson 2021). Other first‐line drugs for focal epilepsy generally include levetiracetam, topiramate and zonisamide. However, there is limited evidence to inform treatment policy specifically in people with tumour‐related epilepsy. Given the potentially novel mechanisms by which tumours may induce seizures, noted above, there is no guarantee that treatment effective in generic focal epilepsies will be as efficacious in people with brain tumour‐related epilepsy.

Description of the intervention

For the treatment of focal seizures and focal to bilateral tonic‐clonic seizures as monotherapy or add‐on therapy in brain tumours, we aim to include the following 16 antiepileptic drugs (AEDs) in this review, which are currently licenced and commonly used in clinical practice as monotherapy or add‐on therapy in at least one country (EMC 2023; FDA 2023):

1. brivaracetam;

2. carbamazepine;

3. phenobarbitone;

4. clobazam;

5. eslicarbazepine;

6. gabapentin;

7. lacosamide;

8. lamotrigine;

9. levetiracetam;

10. oxcarbazepine;

11. perampanel;

12. phenytoin;

13. pregabalin;

14. sodium valproate;

15. topiramate;

16. zonisamide.

Carbamazepine, sodium valproate, phenytoin and phenobarbitone are amongst the earliest drugs licenced for treating epileptic seizures (Gruber 1962; Shakir 1980). These traditionally‐used drugs are no longer considered first‐line agents in the USA and Europe due to emerging adverse event profiles (Wallace 1997; Wilder 1995), and unfavourable teratogenicity risks. Phenytoin is associated with foetal hydantoin syndrome (Scheinfeld 2003). Sodium valproate is associated with the highest incidence of major congenital malformation risk of around 10% including; spina bifida, cardiac, craniofacial, skeletal and limb defects, and 30% to 40% risk of neurodevelopmental disorders (Bromley 2013; Weston 2016). Prescribing policy has since changed with sodium valproate no longer used in women of childbearing age unless all other treatment options have been exhausted.

In the last 20 years, second‐generation AEDs have been licenced as monotherapy or add‐on therapy, or both; these include lamotrigine, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam and zonisamide and, most recently, perampanel, brivaracetam and cenobamate. These AEDs have demonstrated monotherapy efficacy or non‐inferiority when compared to traditional AEDs and efficacy as add‐on therapy when compared to placebo in randomised controlled clinical trials (RCTs) (Perucca 2020).

A network meta‐analysis review using individual patient data from randomised controlled trials of AED monotherapy concluded that carbamazepine, lamotrigine and levetiracetam were suitable first‐line treatments for focal seizures; and sodium valproate, lamotrigine and levetiracetam as the first‐line treatment for generalised tonic‐clonic seizures (with or without other generalised seizure types) (Nevitt 2022). A similar network meta‐analysis review is currently underway using RCTs of AEDs used as add‐on treatment in epilepsy (Gianatsi 2021). These monotherapy and add‐on RCTs however are likely to have excluded patients with brain tumours, and it is therefore unclear whether these generic results are valid in this population.

At this stage there is therefore no robust evidence to inform on the best add‐on AED therapy in focal seizures, and decisions around treatment rely on careful consideration of both individual clinical factors alongside an AED's adverse event profile.

How the intervention might work

Antiepileptic drugs often have multiple possible modes of action. Locations for their action include voltage‐gated sodium channels, calcium channels, glutamate receptors and parts of the gamma‐aminobutyric acid (GABA) system. Targeting these areas of action is thought to rebalance the overexcitation or reduced inhibition which leads to seizures.

The proposed mechanism of action of phenytoin, sodium valproate, carbamazepine, oxcarbazepine, eslicarbazepine and lamotrigine is via blocking of sodium channels (Brodie 1996; Faigle 1990; Granger 1995; Grant 1992; Lees 1993; McLean 1986; Pinder 1977; Ragsdale 1991; Willow 1985), while phenobarbitone binds with GABA‐A receptors (Rho 1996). Clobazam is also thought to potentiate GABAergic neurotransmission by binding at the benzodiazepine site at the GABA‐A receptor. Lacosamide enhances the inactivation of slow sodium channels (Doty 2007). 

Zonisamide is thought to have multiple mechanisms of action (Endoh 1994; Kawai 1994; Okada 1998; Sackellares 2004; Schauf 1987; Suzuki 1992; Zhu 1999), while the mechanisms of action of gabapentin and topiramate are not fully understood (Brodie 1996; Coulter 1993; Hill 1993; McLean 1995; McLean 1999; White 1997). Levetiracetam and brivaracetam have a novel mode of action, which is different to that of other AEDs (Cho 2011); it is thought to exhibit its antiepileptic effect by binding to synaptic vesicle protein 2A (encoded within the SV2A gene), influencing excitatory neurotransmitter release (Gillard 2006; Lynch 2004).

Perampanel is a highly selective, non‐competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist that may exert its antiepileptic effect through selective inhibition of AMPA receptors (Ceolin 2012; Hanada 2011).

Pregabalin acts by binding to an auxiliary protein (alpha 2 delta) of the voltage‐gated calcium channels. It reduces calcium influx into nerve terminals, resulting in reduced presynaptic release of glutamate (Ben‐Menachem 2004).

Why it is important to do this review

Seizures are very common in people with brain tumours and can contribute to significant psychosocial issues experienced in this patient population including mental health problems, an inability to drive, and effects on employment leading to poorer quality of life (Boele 2014). There is a high incidence of epilepsy in people with brain tumours, particularly low grade gliomas, which may reflect the underlying pathophysiology underpinning seizure generation. With up to one‐third of brain tumour‐related epilepsy under current practice being treatment resistant, it is important to further refine anti‐epileptic drug (AED) selection in this patient group (Vecht 2014). With poor seizure control, people are more at risk of status epilepticus, serious injury and sudden unexpected death in epilepsy.

Current treatment policy of seizures in brain tumours is with AEDs used in focal epilepsy. Decisions around which AED to choose are based on RCT monotherapy and add‐on trial data in focal epilepsy where patients with structural brain lesions are likely to have been excluded as participants.

Further factors when considering AEDs in brain tumour epilepsy include the possibility of interactions with chemotherapeutic agents and corticosteroids via changes in hepatic enzymes (induction or non‐induction), thus making decisions around drug selection more challenging.

At present there is no robust evidence and little guidance or consensus on the effectiveness of current AEDs in the treatment of seizures in brain tumours. This Cochrane Review aims to address this important question.

Objectives

To compare the efficacy and tolerability of antiepileptic drugs (AEDs) taken as monotherapy or add‐on therapy for seizures in people with brain tumours.

Methods

Criteria for considering studies for this review

Types of studies

1. RCT

2. Prospective non‐randomised cohort controlled studies with a control group

Types of participants

We will consider participants who satisfy all the following criteria:

1. Any age

2. Diagnosis of a primary or secondary brain tumour (any type) according to the WHO Classification of Tumours of the Central Nervous System (Louis 2016)

3. Treated with antiepileptic drugs for co‐existing epilepsy as monotherapy or add‐on therapy to a co‐existing antiepileptic drug regime

Types of interventions

Control group(s)

Patients who received a placebo, comparative antiepileptic drug or no treatment as monotherapy or as add‐on therapy to a co‐existing antiepileptic drug regime.

Intervention group

Patients who received an antiepileptic drug. We will include the following antiepileptic drugs.

Inducers of hepatic enzymes

1. Eslicarbazepine

2. Oxcarbazepine

3. Phenobarbital

4. Phenytoin

5. Topiramate

Non‐inducers of hepatic enzymes

1. Brivaracetam

2. Clobazam

3. Ethosuxmide

4. Gabapentin

5. Lacosamide

6. Lamotrigine

7. Levetiracetam

8. Perampanel

9. Pregabalin

10. Sodium valproate

11. Zonisamide

Types of outcome measures

Primary outcomes

1. Seizure outcomes ‐ monotherapy:

   1. retention rate (proportion who remained in the study)

2. Seizure outcomes ‐ add‐on therapy:

   1. the proportion of people with a greater than 50% reduction in seizure frequency (defined as a 'responder')

   2. treatment withdrawal

3. Tumour outcomes

4. Overall survival (OS) rate during or after antiepileptic drug treatment

5. Progression‐free survival (PFS) rate (the percentage of people who did not have new tumour growth or cancer spread during or after antiepileptic drug treatment)

Secondary outcomes

1. Seizure outcomes ‐ monotherapy:

   1. remission rate (proportion seizure free)

2. Seizure outcomes ‐ add‐on therapy:

   1. the proportion of people achieving seizure freedom

   2. mean difference in seizure frequency between baseline and treatment periods

3. Cognitive functioning:

   1. clinically important change in overall cognitive functioning

   2. overall cognitive functioning score (endpoint and average)

   3. clinically important change in specific cognitive functioning (attention, concentration, memory, language, executive functioning)

   4. specific cognitive score (average and endpoint)

4. Quality of life:

   1. clinically important change in quality of life

   2. any change in quality of life score (average and endpoint)

5. Adverse effects:

   1. death

   2. any non‐serious general adverse effects (sedation, dizziness, mood or anxiety disorder, weight changes, hyponatraemia, gastrointestinal symptoms)

   3. any serious, specific adverse effects (hypersensitivity reaction)

   4. any change in general adverse effect score (average and endpoint)

   5. clinically important change in specific adverse effects

   6. any change in specific adverse effects score (average and endpoint)

Search methods for identification of studies

Electronic searches

We will search the following databases:

1. Cochrane Register of Studies (CRS Web) using the search strategy in Appendix 1

2. MEDLINE (Ovid, 1946 onwards) using the search strategy in Appendix 2

3. SCOPUS (1823 onwards) using the search strategy in Appendix 3

4. ClinicalTrials.gov using the search strategy in Appendix 4

5. WHO International Clinical Trials Registry Platform (ICTRP) using the search strategy in Appendix 5

CRS Web includes randomised or quasi‐randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the WHO ICTRP, the Cochrane Central Register of Controlled Trials (CENTRAL) and the Specialised Registers of Cochrane Review Groups including Cochrane Epilepsy.

There will be no language restrictions.

Searching other resources

1. We will check conference proceedings and the reference lists of retrieved studies for additional reports of relevant studies

2. We will contact lead authors for any relevant unpublished material

3. We will omit any duplicate studies identified according to title, authors names, location and medical institute

Data collection and analysis

Selection of studies

Two review authors (MJM and SF) will independently assess all citations generated from the searches for inclusion. Where disputes arose, we will acquire the full report for more detailed scrutiny.

Data extraction and management

Two review authors (MJM and SF) will undertake data extraction separately for each included study. We will then cross‐check the data extraction. We will extract data using pre‐standardised data extraction forms. We will resolve any disagreements by discussion, document decisions and, if necessary, contact trial authors for clarification.

We will extract the following information from the included studies.

Methodological and trial design

1. Year of publication

2. Number of study centres

3. Language

4. Industry funding

5. Study design (RCT, prospective cohort study, retrospective cohort study)

6. Blinding

7. Type of control group (placebo, comparative antiepileptic drug, no treatment)

8. Sample size

9. Follow‐up period

10. Dose range of intervention

11. Inclusion and exclusion criteria

Patient demographic information

1. Age range

2. Number of male/female participants

3. Type of brain tumour

4. Previous number of antiepileptic drugs

5. Epilepsy type (focal, generalised, unclassified)

6. Location of epilepsy (temporal, extra‐temporal)

7. Baseline mean seizure frequency/month

Outcomes

1. The number of patients experiencing each outcome recorded per treatment group

2. Number of dropouts

Assessment of risk of bias in included studies

Two review authors (MJM and SF) will independently assess the risk of bias for the included studies.

Due to the observational design of some studies, we will assess risk of bias for non‐randomised studies using the ROBINS‐I tool (Sterne 2016). This tool considers seven domains of bias: two domains of bias pre‐intervention (bias due to confounding and bias in selection of participants into the study); one domain of bias at intervention (bias in the measurement of interventions); and four domains of bias post intervention (bias due to departures from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result). We plan to perform a separate 'Risk of bias' assessment for each outcome of interest in the study.

For RCTs, we will assess all domains of the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011).

We will make an overall summary judgement of risk of bias for each study per outcome, followed by an overall judgement per outcome across studies. We will aim to incorporate the risk of bias judgements into the analysis using sensitivity analysis; we will perform a secondary analysis of the data by only including studies rated as low risk of bias. 

Measures of treatment effect

For binary outcomes (50% or greater improvement in seizure, seizure freedom, treatment withdrawal, OS and PFS rate), we will present results as risk ratios (RRs) with 95% confidence intervals (CIs).

For continuous outcomes (mean change in seizure frequency), we will present results as mean differences (MDs) or standardised mean differences (SMDs) with 95% CIs.

Unit of analysis issues

We will deal with any unit of analysis issues according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Dealing with missing data

We will seek missing statistics from studies by contacting the study authors. We will seek reasons for missing data to determine whether the data were missing at random or not. 

Assessment of heterogeneity

We will assess clinical heterogeneity by comparing the distribution of important patient factors between studies (mean age, seizure type, duration of epilepsy, location of tumour, tumour type, baseline seizure frequency) and trial factors (study design, type of control group, enzyme versus non‐enzyme inducing AEDs). 

We will assess statistical heterogeneity by using the I² statistic, with an I² value of 75% to 100% indicating considerable heterogeneity, 50% to 90% indicating substantial heterogeneity, 30% to 60% indicating moderate heterogeneity, and 0% to 40% indicating possibly not being important. If the I² value is 75% or more, we will make an a priori decision not to carry out meta‐analysis; the review will then take a narrative form, and we will discuss all comparisons according to the findings presented within the studies. We plan to use meta‐regression techniques where possible to investigate possible sources of heterogeneity.

Assessment of reporting biases

We will investigate outcome reporting bias using the ORBIT classification system, allocating studies a letter from A‐I if selective outcome reporting bias is suspected to be present (Kirkham 2010).

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Higgins 2021; Sterne 2000). Funnel plots can be used in investigating reporting biases, but are of limited power to detect small‐study effects. 

Data synthesis

We will synthesise data using the RR, the MD or the SMD value depending on the measures used in both the controlled and uncontrolled studies. We will perform a sensitivity analysis to check for differences between a random‐effects model and fixed‐effect model in influencing conclusions. If differences between the models exist, we intend to report outcomes based on the random‐effects model, which incorporates an assumption that the different studies are estimating different, yet related, intervention effects.

For controlled studies we intend to undertake meta‐analysis using the Mantel‐Haenszel method for dichotomous outcomes and the inverse variance method for continuous outcomes. For before‐and‐after studies, we will use the inverse variance methods for continuous outcomes in meta‐analysis.

We aim to combine data for outcomes using both randomised and non‐randomised studies. 

Comparisons we expect to undertake include the following. Intervention group versus controls:

1. For change in mean seizure frequency;

2. On achieving a 50% reduction in seizures;

3. On achieving seizure freedom;

4. For overall survival rate;

5. For progression free survival rate;

6. On % of patients withdrawing from treatment.

We will stratify each comparison by type of control group, study design or study characteristics, or both to ensure appropriate combination of study data.

Subgroup analysis and investigation of heterogeneity

We will stratify subgroup analysis by enzyme inducing versus non‐enzyme inducing AED, tumour type and seizure type. For investigation of heterogeneity, please see the Assessment of heterogeneity section.

Sensitivity analysis

We intend to undertake sensitivity analysis if we identify peculiarities in study quality (see Assessment of risk of bias in included studies).

Summary of findings and assessment of the certainty of the evidence

We will create summary of findings tables for outcomes, and will assess the certainty of the evidence for each outcome accordingly using the GRADE approach (Guyatt 2008). We will report the following outcomes in the summary of findings tables, as these outcomes are most likely to be measured and reported: seizure frequency, withdrawals, general functioning, cognitive functioning, quality of life and adverse effects.

Notes

This protocol supercedes a published Cochrane Review (Kerrigan 2011).

Appendices

Appendix 1. CRS Web search strategy

1. MeSH DESCRIPTOR Brain Neoplasms Explode All AND CENTRAL:TARGET

2. MeSH DESCRIPTOR Glioma Explode All AND CENTRAL:TARGET

3. MeSH DESCRIPTOR Astrocytoma Explode All AND CENTRAL:TARGET

4. MeSH DESCRIPTOR Oligodendroglioma Explode All AND CENTRAL:TARGET

5. MeSH DESCRIPTOR Ependymoma Explode All AND CENTRAL:TARGET

6. MeSH DESCRIPTOR Meningioma Explode All AND CENTRAL:TARGET

7. MeSH DESCRIPTOR Skull Base Neoplasms Explode All AND CENTRAL:TARGET

8. (glioma* or astrocytoma* or oligodendroglioma* or ependymoma* or meningioma* or "skull base neoplasm*"):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

9. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 AND CENTRAL:TARGET

10. (brain or cerebra* or astrocyte* or oligodendrog* or ependym* or glial or skull base or choroid plexus or neuroepithel* or neuronal or neuronal‐glial or pineal* or embryonal or haemopoietic or hemopoietic or germ cell* or mening* or sella* or "central nervous system" or CNS):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

11. (cancer* or tumor* or tumour* or malignan* or carcinoma* or neoplasm* or metasta*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

12. #10 and #11 AND CENTRAL:TARGET

13. #9 or #12 AND CENTRAL:TARGET

14. MeSH DESCRIPTOR Epilepsy Explode All WITH QUALIFIER DT AND CENTRAL:TARGET

15. MESH DESCRIPTOR Seizures EXPLODE ALL WITH QUALIFIER DT AND CENTRAL:TARGET

16. MeSH DESCRIPTOR Anticonvulsants Explode All AND CENTRAL:TARGET

17. (antiepilep* or anti‐epilep* or anticonvulsant* or anti‐convulsant* or antiseizure* or anti‐seizure* or AED or AEDs):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

18. #14 OR #15 OR #16 OR #17 AND CENTRAL:TARGET

19. MeSH DESCRIPTOR Midazolam Explode All AND CENTRAL:TARGET

20. (Dalam OR Dormicum OR Dormire OR Epistatus OR Fulsed OR Garen OR Hypnovel OR Ipnovel OR Midazolam* OR Nocturna OR Setam OR Terap OR Versed):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

21. #19 OR #20 AND CENTRAL:TARGET

22. MeSH DESCRIPTOR Methazolamide Explode All AND CENTRAL:TARGET

23. (Methazolamid* OR Methylacetazolamide OR Neptazane):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

24. #22 OR #23 AND CENTRAL:TARGET

25. MeSH DESCRIPTOR Propofol Explode All AND CENTRAL:TARGET

26. (Anepol OR Diprivan OR Disoprivan OR Disoprofol OR Fresofol OR Hypro OR Lipuro OR Plofed OR Profol OR Propofil OR Propofol* OR Propolipid OR Propovan OR Propoven OR Provive OR Recofol):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

27. #25 OR #26 AND CENTRAL:TARGET

28. MeSH DESCRIPTOR Temazepam Explode All AND CENTRAL:TARGET

29. (Dasuen OR Euhypnos OR Hydroxydiazepam OR Levanxol OR Methyloxazepam OR Nocturne OR Norkotral OR Normison OR Normitab OR Nortem OR Oxydiazepam OR Planum OR Pronervon OR Remestan OR Restoril OR Signopam OR Temaze OR Temazep* OR Temtabs OR Tenox):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

30. #28 OR #29 AND CENTRAL:TARGET

31. MeSH DESCRIPTOR Thiopental Explode All AND CENTRAL:TARGET

32. (Bomathal OR Farmotal OR Nesdonal OR Penthiobarbit* OR Pentothal OR Sodipental OR Thiomebumal OR Thionembutal OR Thiopent* OR Tiobarbital OR Tiopental* OR Trapanal):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

33. #31 OR #32 AND CENTRAL:TARGET

34. #18 OR #21 OR #24 OR #27 OR #30 OR #33 AND CENTRAL:TARGET

35. (Acemit OR Acetamide OR Acetazolamid* OR Avva OR Azm OR Azol OR Diacarb OR Diamox OR Diazomid OR Diluran OR Edemox OR Glaupax):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

36. (Barbexaclon*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

37. (Beclamid* OR Chloracon OR Hibicon OR Posedrine OR Nydrane OR Seclar):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

38. (Brivaracetam*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

39. (Bromide*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

40. (Carbamazepin* OR Carbamazepen* OR Carbamezepin* OR CBZ OR SPD417 OR "Apo‐Carbamazepine" OR Atretol OR Biston OR Calepsin OR Carbagen OR Carbatrol OR Carbazepin* OR Carbelan OR Epitol OR Equetro OR Finlepsin OR Karbamazepin OR Lexin OR Neurotop OR "Novo‐Carbamaz" OR "Nu‐Carbamazepine" OR Sirtal OR Stazepin* OR "Taro‐Carbamazepine" OR Tegretal OR Tegretol OR Telesmin OR Teril OR Timonil):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

41. (Carisbamat* OR Comfyde OR "RWJ‐333369" OR "YKP 509"):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

42. (Cenobamat* OR Xcopri OR YKP3089):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

43. (Chlormethiazol* OR Distraneurin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

44. (Aedon OR Anxirloc OR Castilium OR Chlorepin OR Clarmyl OR Clobam OR Clobamax OR Clobator OR Clobazam* OR Clofritis OR Clopax OR Clorepin OR Frisium OR Grifoclobam OR Karidium OR Lucium OR Mystan OR Noiafren OR Onfi OR Sederlona OR Sentil OR Urbadan OR Urbanil OR Urbanol OR Urbanyl):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

45. (Antelepsin OR Antilepsin OR Chlonazepam OR Cloazepam OR Clonazepam* OR Clonex OR Clonopin OR Iktorivil OR Klonopin OR Kriadex OR Landsen OR Paxam OR Petril OR Ravotril OR Rivatril OR Rivotril OR “ro 5‐4023” OR “ro 54023”):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

46. (Calner OR Clorazepat* OR Justum OR Mendon OR "Novo‐Clopate" OR Tranxene OR Tranxilium):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

47. (Diapam OR Diastat OR Diazemuls OR Diazepam* OR Nervium OR Relanium OR Valium):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

48. (Dimethadion* OR Dimethyloxazolidinedione):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

49. (Eslicarbazepin* OR Exalief OR Stedesa OR Zebinix):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

50. (Esilgan OR Estazolam* OR Eurodin OR Nuctalon OR Prosom OR Tasedan):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

51. (Ethadion*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

52. (Aethosuximid* OR Emeside OR Ethosucci* OR Ethosuxide OR Ethosuximid* OR Etosuximid* OR Zarontin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

53. (Ethotoin* OR Peganone):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

54. (Felbamat* OR Felbatol OR Felbamyl OR Taloxa):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

55. (Flunarizin* OR Sibelium):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

56. (Cerebyx OR Fosphenytoin* OR Prodilantin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

57. (Gabapentin* OR Aclonium OR Fanatrex OR Gabapetin OR Gabarone OR GBP OR Gralise OR Neogab OR Neurontin OR "Novo‐Gabapentin" OR Nupentin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

58. ("CCD‐1042" OR Ganaxolon*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

59. (Erlosamide OR Harkoseride OR Lacosamid* OR Vimpat):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

60. (Lamotrigin* OR Elmendos OR Epilepax OR "GW 273293" OR Lamictal OR Lamictin OR Lamitor OR Lamitrin OR Lamogine OR Lamotrine OR LTG):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

61. (Levetiracetam* OR Keppra OR LEV OR Levitiracetam):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

62. (Ativan OR Intensl OR Loraz OR Lorazepam* OR Lormetazepam* OR Temesta):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

63. (Losigamon*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

64. ("Magnesium sulfat*" OR "Magnesium sulphat*"):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

65. (Medazepam* OR Nobrium OR Rudotel OR Rusedal):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

66. (Mephenytoin* OR Mesantoin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

67. (Dapaz OR Equanil OR Meprobamat* OR Meprospan OR Miltown OR Tranmep OR Visano):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

68. (Celontin OR Mesuximid* OR Methsuximide OR Petinutin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

69. (Mephobarbit* OR Mebaral OR Mephyltaletten OR Methylphenobarbit* OR Metilfenobarbital OR Phemiton OR Prominal):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

70. (Erimin OR Nimetazepam*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

71. (Alodorm OR Arem OR Insoma OR Mogadon OR Nitrados OR Nitrazadon OR Nitrazepam* OR Ormodon OR Paxadorm OR Remnos OR Somnite OR Pacisyn):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

72. (Oxcarbazepin* OR Actinium OR Barzepin OR Carbox OR Deprectal OR "GP 47680" OR Lonazet OR OCBZ OR Oxalepsy OR OXC OR Oxcarbamazepine OR Oxetol OR Oxpin OR Oxrate OR Oxtellar OR Oxypine OR Pharozepine OR Prolepsi OR Timox OR Trexapin OR Trileptal OR Trileptin):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

73. (Paraldehyd*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

74. (Paramethadion*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

75. (E2007 OR Fycompa OR Perampanel*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

76. (Phenacemid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

77. (Ethylphenacemid* OR Pheneturid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

78. (Adonal OR Aephenal OR Agrypnal OR Amylofene OR Aphenylbarbit OR Aphenyletten OR Barbenyl OR Barbinal OR Barbiphen* OR Barbipil OR Barbita OR Barbivis OR Barbonal OR Barbophen OR Bardorm OR Bartol OR Bialminal OR "Blu‐Phen" OR Cabronal OR Calmetten OR Calminal OR Cardenal OR Chinoin OR Codibarbita OR Coronaletta OR Cratecil OR Damoral OR Dezibarbitur OR Dormina OR Dormiral OR Dormital OR Doscalun OR Duneryl OR Ensobarb OR Ensodorm OR Epanal OR Epidorm OR Epilol OR Episedal OR Epsylone OR Eskabarb OR Etilfen OR Euneryl OR Fenbital OR Fenemal OR Fenobarbital OR Fenosed OR Fenylettae OR Gardenal OR Gardepanyl OR Glysoletten OR Haplopan OR Haplos OR Helional OR Hennoletten OR Henotal OR Hypnaletten OR Hypnette OR "Hypno‐Tablinetten" OR Hypnogen OR Hypnolone OR Hypnoltol OR Hysteps OR Lefebar OR Leonal OR Lephebar OR Lepinal OR Lepinaletten OR Linasen OR Liquital OR Lixophen OR Lubergal OR Lubrokal OR Lumen OR Lumesettes OR Lumesyn OR Luminal OR Lumofridetten OR Luphenil OR Luramin OR Molinal OR Neurobarb OR Nirvonal OR Noptil OR "Nova‐Pheno" OR Nunol OR Parkotal OR PB OR Pharmetten OR "Phen‐Bar" OR Phenaemal OR Phenemal* OR Phenobal OR Phenobarbit* OR Phenobarbyl OR Phenoluric OR Phenolurio OR Phenomet OR Phenonyl OR Phenoturic OR Phenylethylbarbit* OR Phenylethylmalonylurea OR Phenyletten OR Phenyral OR Phob OR Polcominal OR Prominal OR Promptonal OR "Seda‐Tablinen" OR Sedabar OR Sedicat OR Sedizorin OR Sedlyn OR Sedofen OR Sedonal OR Sedonettes OR Sevenal OR Sinoratox OR Solfoton OR "Solu‐Barb" OR Sombutol OR Somnolens OR Somnoletten OR Somnosan OR Somonal OR Spasepilin OR Starifen OR Starilettae OR Stental OR Talpheno OR Teolaxin OR Teoloxin OR Thenobarbital OR Theoloxin OR Triabarb OR Tridezibarbitur OR Triphenatol OR Versomnal OR Zadoletten OR Zadonal):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

79. (Phensuximid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

80. (Aleviatin OR Antisacer OR Auranile OR Causoin OR Citrullamon OR Citrulliamon OR Comital OR Comitoina OR Convul OR Danten OR Dantinal OR Dantoin* OR Denyl OR "Di‐Hydan" OR "Di‐Lan" OR "Di‐Phetine" OR Didan OR Difenilhidantoin* OR Difenin OR Difetoin OR Difhydan OR Dihycon OR Dihydantoin OR Dilabid OR Dilantin* OR Dillantin OR Dintoin* OR Diphantoin OR Diphedal OR Diphedan OR Diphenat OR Diphenin* OR Diphentoin OR Diphentyn OR Diphenylan OR Diphenylhydantoin* OR Diphenylhydatanoin OR Ditoinate OR Ekko OR Elepsindon OR Enkelfel OR Epamin OR Epanutin OR Epasmir OR Epdantoin* OR Epelin OR Epifenyl OR Epihydan OR Epilan OR Epilantin OR Epinat OR Epised OR Eptal OR Eptoin OR Fenantoin OR Fenidantoin OR Fenitoin* OR Fentoin OR Fenylepsin OR Fenytoin* OR "Gerot‐epilan‐D" OR Hidan OR Hidant* OR Hindatal OR Hydant* OR Ictalis OR Idantoi* OR Iphenylhydantoin OR Kessodanten OR Labopal OR Lehydan OR Lepitoin OR Lepsin OR Mesantoin OR Minetoin OR "Neos‐Hidantoina" OR Neosidantoina OR Novantoina OR Novophenytoin OR "Om‐hidantoina" OR "Om‐Hydantoine" OR Oxylan OR Phanantin* OR Phenatine OR Phenatoine OR Phenhydan* OR Phenitoin OR Phentoin OR Phentytoin OR Phenytek OR Phenytex OR Phenytoin* OR PHT OR Ritmenal OR Saceril OR Sanepil OR Silantin OR Sinergina OR Sodanthon OR Sodanto* OR Solantin OR Solantoin OR Solantyl OR Sylantoic OR Tacosal OR Thilophenyl OR TOIN OR Zentronal OR Zentropil):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

81. (Lyrica OR Pregabalin*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

82. (Mysoline OR Primidon* OR Sertan):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

83. (Gabrene OR Garene OR Halogabide OR Halogenide OR Progabid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

84. (Ecovia OR Remacemid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

85. ("D‐23129" OR "D23129" OR EZG OR Ezogabin* OR Retigabin* OR RTG OR Trobalt OR Potiga):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

86. (Rilutek OR Riluzol* OR Trifluoromethoxybenzothiazol*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

87. (Inovelon OR Rufinamid* OR Xilep):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

88. (Seletracetam*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

89. (Diacomit OR Stiripentol*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

90. (Sulthiam* OR Sultiam* OR Ospolot):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

91. (Talampanel*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

92. (Tiagabin* OR Gabitril):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

93. (Tiletamin*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

94. (Topiramat* OR Qudexy OR Tipiramate OR Topamax OR "Topiramic acid" OR TPM):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

95. (Tridione OR Trimethadion*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

96. (Valnoctamid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

97. (Avugane OR Baceca OR Convulex OR Delepsine OR Depacon OR Depakene OR Depakine OR Depakote OR Deproic OR Divalprax OR Divalproex* OR DPA OR Encorate OR Epiject OR Epilex OR Epilim OR Episenta OR Epival OR Ergenyl OR Mylproin OR Orfiril OR Orlept OR Selenica OR Stavzor OR Valance OR Valcote OR Valparin OR Valpro* OR VPA OR Zalkote):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

98. (Depamide OR Valpromid*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

99. (GVG OR Sabril OR Vigabatrin*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

100. (Zonisamid* OR Exceglan OR Excegram OR Excegran OR ZNS OR Zonegran):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

101. #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 OR #80 OR #81 OR #82 OR #83 OR #84 OR #85 OR #86 OR #87 OR #88 OR #89 OR #90 OR #91 OR #92 OR #93 OR #94 OR #95 OR #96 OR #97 OR #98 OR #99 OR #100

102. #13 AND #101

103. MeSH DESCRIPTOR Brain Neoplasms Explode All AND INSEGMENT

104. MeSH DESCRIPTOR Glioma Explode All AND INSEGMENT

105. MeSH DESCRIPTOR Astrocytoma Explode All AND INSEGMENT

106. MeSH DESCRIPTOR Oligodendroglioma Explode All AND INSEGMENT

107. MeSH DESCRIPTOR Ependymoma Explode All AND INSEGMENT

108. MeSH DESCRIPTOR Meningioma Explode All AND INSEGMENT

109. MeSH DESCRIPTOR Skull Base Neoplasms Explode All AND INSEGMENT

110. (glioma* or astrocytoma* or oligodendroglioma* or ependymoma* or meningioma* or "skull base neoplasm*"):AB,KW,KY,MC,MH,TI AND INSEGMENT

111. #103 or #104 or #105 or #106 or #107 or #108 or #109 or #110 AND INSEGMENT

112. (brain or astrocyte* or oligodendrog* or ependym* or glial or skull base or choroid plexus or neuroepithel* or neuronal or neuronal‐glial or pineal* or embryonal or haemopoietic or hemopoietic or germ cell* or mening* or sella* or "central nervous system" or CNS):AB,KW,KY,MC,MH,TI AND INSEGMENT

113. (cancer* or tumor* or tumour* or malignan* or carcinoma* or neoplasm* or metasta*):AB,KW,KY,MC,MH,TI AND INSEGMENT

114. #112 and #113 AND INSEGMENT

115. #111 or #114 AND INSEGMENT

116. MeSH DESCRIPTOR Epilepsy Explode All WITH QUALIFIER DT AND INSEGMENT

117. MESH DESCRIPTOR Seizures EXPLODE ALL WITH QUALIFIER DT AND INSEGMENT

118. MeSH DESCRIPTOR Anticonvulsants Explode All AND INSEGMENT

119. (antiepilep* or anti‐epilep* or anticonvulsant* or anti‐convulsant* or antiseizure* or anti‐seizure* or AED or AEDs):AB,KW,KY,MC,MH,TI AND INSEGMENT

120. #116 OR #117 OR #118 OR #119 AND INSEGMENT

121. MeSH DESCRIPTOR Midazolam Explode All AND INSEGMENT

122. (Dalam OR Dormicum OR Dormire OR Epistatus OR Fulsed OR Garen OR Hypnovel OR Ipnovel OR Midazolam* OR Nocturna OR Setam OR Terap OR Versed):AB,KW,KY,MC,MH,TI AND INSEGMENT

123. #121 OR #122 AND INSEGMENT

124. MeSH DESCRIPTOR Methazolamide Explode All AND INSEGMENT

125. (Methazolamid* OR Methylacetazolamide OR Neptazane):AB,KW,KY,MC,MH,TI AND INSEGMENT

126. #124 OR #125 AND INSEGMENT

127. MeSH DESCRIPTOR Propofol Explode All AND INSEGMENT

128. (Anepol OR Diprivan OR Disoprivan OR Disoprofol OR Fresofol OR Hypro OR Lipuro OR Plofed OR Profol OR Propofil OR Propofol* OR Propolipid OR Propovan OR Propoven OR Provive OR Recofol):AB,KW,KY,MC,MH,TI AND INSEGMENT

129. #127 OR #128 AND INSEGMENT

130. MeSH DESCRIPTOR Temazepam Explode All AND INSEGMENT

131. (Dasuen OR Euhypnos OR Hydroxydiazepam OR Levanxol OR Methyloxazepam OR Nocturne OR Norkotral OR Normison OR Normitab OR Nortem OR Oxydiazepam OR Planum OR Pronervon OR Remestan OR Restoril OR Signopam OR Temaze OR Temazep* OR Temtabs OR Tenox):AB,KW,KY,MC,MH,TI AND INSEGMENT

132. #130 OR #131 AND INSEGMENT

133. MeSH DESCRIPTOR Thiopental Explode All AND INSEGMENT

134. (Bomathal OR Farmotal OR Nesdonal OR Penthiobarbit* OR Pentothal OR Sodipental OR Thiomebumal OR Thionembutal OR Thiopent* OR Tiobarbital OR Tiopental* OR Trapanal):AB,KW,KY,MC,MH,TI AND INSEGMENT

135. #133 OR #134 AND INSEGMENT

136. #120 OR #123 OR #126 OR #129 OR #132 OR #135 AND INSEGMENT

137. (Acemit OR Acetamide OR Acetazolamid* OR Avva OR Azm OR Azol OR Diacarb OR Diamox OR Diazomid OR Diluran OR Edemox OR Glaupax):AB,KW,KY,MC,MH,TI AND INSEGMENT

138. (Barbexaclon*):AB,KW,KY,MC,MH,TI AND INSEGMENT

139. (Beclamid* OR Chloracon OR Hibicon OR Posedrine OR Nydrane OR Seclar):AB,KW,KY,MC,MH,TI AND INSEGMENT

140. (Brivaracetam*):AB,KW,KY,MC,MH,TI AND INSEGMENT

141. (Bromide*):AB,KW,KY,MC,MH,TI AND INSEGMENT

142. (Carbamazepin* OR Carbamazepen* OR Carbamezepin* OR CBZ OR SPD417 OR "Apo‐Carbamazepine" OR Atretol OR Biston OR Calepsin OR Carbagen OR Carbatrol OR Carbazepin* OR Carbelan OR Epitol OR Equetro OR Finlepsin OR Karbamazepin OR Lexin OR Neurotop OR "Novo‐Carbamaz" OR "Nu‐Carbamazepine" OR Sirtal OR Stazepin* OR "Taro‐Carbamazepine" OR Tegretal OR Tegretol OR Telesmin OR Teril OR Timonil):AB,KW,KY,MC,MH,TI AND INSEGMENT

143. (Carisbamat* OR Comfyde OR "RWJ‐333369" OR "YKP 509"):AB,KW,KY,MC,MH,TI AND INSEGMENT

144. (Cenobamat* OR Xcopri OR YKP3089):AB,KW,KY,MC,MH,TI AND INSEGMENT

145. (Chlormethiazol* OR Distraneurin):AB,KW,KY,MC,MH,TI AND INSEGMENT

146. (Aedon OR Anxirloc OR Castilium OR Chlorepin OR Clarmyl OR Clobam OR Clobamax OR Clobator OR Clobazam* OR Clofritis OR Clopax OR Clorepin OR Frisium OR Grifoclobam OR Karidium OR Lucium OR Mystan OR Noiafren OR Onfi OR Sederlona OR Sentil OR Urbadan OR Urbanil OR Urbanol OR Urbanyl):AB,KW,KY,MC,MH,TI AND INSEGMENT

147. (Antelepsin OR Antilepsin OR Chlonazepam OR Cloazepam OR Clonazepam* OR Clonex OR Clonopin OR Iktorivil OR Klonopin OR Kriadex OR Landsen OR Paxam OR Petril OR Ravotril OR Rivatril OR Rivotril OR “ro 5‐4023” OR “ro 54023”):AB,KW,KY,MC,MH,TI AND INSEGMENT

148. (Calner OR Clorazepat* OR Justum OR Mendon OR "Novo‐Clopate" OR Tranxene OR Tranxilium):AB,KW,KY,MC,MH,TI AND INSEGMENT

149. (Diapam OR Diastat OR Diazemuls OR Diazepam* OR Nervium OR Relanium OR Valium):AB,KW,KY,MC,MH,TI AND INSEGMENT

150. (Dimethadion* OR Dimethyloxazolidinedione):AB,KW,KY,MC,MH,TI AND INSEGMENT

151. (Eslicarbazepin* OR Exalief OR Stedesa OR Zebinix):AB,KW,KY,MC,MH,TI AND INSEGMENT

152. (Esilgan OR Estazolam* OR Eurodin OR Nuctalon OR Prosom OR Tasedan):AB,KW,KY,MC,MH,TI AND INSEGMENT

153. (Ethadion*):AB,KW,KY,MC,MH,TI AND INSEGMENT

154. (Aethosuximid* OR Emeside OR Ethosucci* OR Ethosuxide OR Ethosuximid* OR Etosuximid* OR Zarontin):AB,KW,KY,MC,MH,TI AND INSEGMENT

155. (Ethotoin* OR Peganone):AB,KW,KY,MC,MH,TI AND INSEGMENT

156. (Felbamat* OR Felbatol OR Felbamyl OR Taloxa):AB,KW,KY,MC,MH,TI AND INSEGMENT

157. (Flunarizin* OR Sibelium):AB,KW,KY,MC,MH,TI AND INSEGMENT

158. (Cerebyx OR Fosphenytoin* OR Prodilantin):AB,KW,KY,MC,MH,TI AND INSEGMENT

159. (Gabapentin* OR Aclonium OR Fanatrex OR Gabapetin OR Gabarone OR GBP OR Gralise OR Neogab OR Neurontin OR "Novo‐Gabapentin" OR Nupentin):AB,KW,KY,MC,MH,TI AND INSEGMENT

160. ("CCD‐1042" OR Ganaxolon*):AB,KW,KY,MC,MH,TI AND INSEGMENT

161. (Erlosamide OR Harkoseride OR Lacosamid* OR Vimpat):AB,KW,KY,MC,MH,TI AND INSEGMENT

162. (Lamotrigin* OR Elmendos OR Epilepax OR "GW 273293" OR Lamictal OR Lamictin OR Lamitor OR Lamitrin OR Lamogine OR Lamotrine OR LTG):AB,KW,KY,MC,MH,TI AND INSEGMENT

163. (Levetiracetam* OR Keppra OR LEV OR Levitiracetam):AB,KW,KY,MC,MH,TI AND INSEGMENT

164. (Ativan OR Intensl OR Loraz OR Lorazepam* OR Lormetazepam* OR Temesta):AB,KW,KY,MC,MH,TI AND INSEGMENT

165. (Losigamon*):AB,KW,KY,MC,MH,TI AND INSEGMENT

166. ("Magnesium sulfat*" OR "Magnesium sulphat*"):AB,KW,KY,MC,MH,TI AND INSEGMENT

167. (Medazepam* OR Nobrium OR Rudotel OR Rusedal):AB,KW,KY,MC,MH,TI AND INSEGMENT

168. (Mephenytoin* OR Mesantoin):AB,KW,KY,MC,MH,TI AND INSEGMENT

169. (Dapaz OR Equanil OR Meprobamat* OR Meprospan OR Miltown OR Tranmep OR Visano):AB,KW,KY,MC,MH,TI AND INSEGMENT

170. (Celontin OR Mesuximid* OR Methsuximide OR Petinutin):AB,KW,KY,MC,MH,TI AND INSEGMENT

171. (Mephobarbit* OR Mebaral OR Mephyltaletten OR Methylphenobarbit* OR Metilfenobarbital OR Phemiton OR Prominal):AB,KW,KY,MC,MH,TI AND INSEGMENT

172. (Erimin OR Nimetazepam*):AB,KW,KY,MC,MH,TI AND INSEGMENT

173. (Alodorm OR Arem OR Insoma OR Mogadon OR Nitrados OR Nitrazadon OR Nitrazepam* OR Ormodon OR Paxadorm OR Remnos OR Somnite OR Pacisyn):AB,KW,KY,MC,MH,TI AND INSEGMENT

174. (Oxcarbazepin* OR Actinium OR Barzepin OR Carbox OR Deprectal OR "GP 47680" OR Lonazet OR OCBZ OR Oxalepsy OR OXC OR Oxcarbamazepine OR Oxetol OR Oxpin OR Oxrate OR Oxtellar OR Oxypine OR Pharozepine OR Prolepsi OR Timox OR Trexapin OR Trileptal OR Trileptin):AB,KW,KY,MC,MH,TI AND INSEGMENT

175. (Paraldehyd*):AB,KW,KY,MC,MH,TI AND INSEGMENT

176. (Paramethadion*):AB,KW,KY,MC,MH,TI AND INSEGMENT

177. (E2007 OR Fycompa OR Perampanel*):AB,KW,KY,MC,MH,TI AND INSEGMENT

178. (Phenacemid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

179. (Ethylphenacemid* OR Pheneturid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

180. (Adonal OR Aephenal OR Agrypnal OR Amylofene OR Aphenylbarbit OR Aphenyletten OR Barbenyl OR Barbinal OR Barbiphen* OR Barbipil OR Barbita OR Barbivis OR Barbonal OR Barbophen OR Bardorm OR Bartol OR Bialminal OR "Blu‐Phen" OR Cabronal OR Calmetten OR Calminal OR Cardenal OR Chinoin OR Codibarbita OR Coronaletta OR Cratecil OR Damoral OR Dezibarbitur OR Dormina OR Dormiral OR Dormital OR Doscalun OR Duneryl OR Ensobarb OR Ensodorm OR Epanal OR Epidorm OR Epilol OR Episedal OR Epsylone OR Eskabarb OR Etilfen OR Euneryl OR Fenbital OR Fenemal OR Fenobarbital OR Fenosed OR Fenylettae OR Gardenal OR Gardepanyl OR Glysoletten OR Haplopan OR Haplos OR Helional OR Hennoletten OR Henotal OR Hypnaletten OR Hypnette OR "Hypno‐Tablinetten" OR Hypnogen OR Hypnolone OR Hypnoltol OR Hysteps OR Lefebar OR Leonal OR Lephebar OR Lepinal OR Lepinaletten OR Linasen OR Liquital OR Lixophen OR Lubergal OR Lubrokal OR Lumen OR Lumesettes OR Lumesyn OR Luminal OR Lumofridetten OR Luphenil OR Luramin OR Molinal OR Neurobarb OR Nirvonal OR Noptil OR "Nova‐Pheno" OR Nunol OR Parkotal OR PB OR Pharmetten OR "Phen‐Bar" OR Phenaemal OR Phenemal* OR Phenobal OR Phenobarbit* OR Phenobarbyl OR Phenoluric OR Phenolurio OR Phenomet OR Phenonyl OR Phenoturic OR Phenylethylbarbit* OR Phenylethylmalonylurea OR Phenyletten OR Phenyral OR Phob OR Polcominal OR Prominal OR Promptonal OR "Seda‐Tablinen" OR Sedabar OR Sedicat OR Sedizorin OR Sedlyn OR Sedofen OR Sedonal OR Sedonettes OR Sevenal OR Sinoratox OR Solfoton OR "Solu‐Barb" OR Sombutol OR Somnolens OR Somnoletten OR Somnosan OR Somonal OR Spasepilin OR Starifen OR Starilettae OR Stental OR Talpheno OR Teolaxin OR Teoloxin OR Thenobarbital OR Theoloxin OR Triabarb OR Tridezibarbitur OR Triphenatol OR Versomnal OR Zadoletten OR Zadonal):AB,KW,KY,MC,MH,TI AND INSEGMENT

181. (Phensuximid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

182. (Aleviatin OR Antisacer OR Auranile OR Causoin OR Citrullamon OR Citrulliamon OR Comital OR Comitoina OR Convul OR Danten OR Dantinal OR Dantoin* OR Denyl OR "Di‐Hydan" OR "Di‐Lan" OR "Di‐Phetine" OR Didan OR Difenilhidantoin* OR Difenin OR Difetoin OR Difhydan OR Dihycon OR Dihydantoin OR Dilabid OR Dilantin* OR Dillantin OR Dintoin* OR Diphantoin OR Diphedal OR Diphedan OR Diphenat OR Diphenin* OR Diphentoin OR Diphentyn OR Diphenylan OR Diphenylhydantoin* OR Diphenylhydatanoin OR Ditoinate OR Ekko OR Elepsindon OR Enkelfel OR Epamin OR Epanutin OR Epasmir OR Epdantoin* OR Epelin OR Epifenyl OR Epihydan OR Epilan OR Epilantin OR Epinat OR Epised OR Eptal OR Eptoin OR Fenantoin OR Fenidantoin OR Fenitoin* OR Fentoin OR Fenylepsin OR Fenytoin* OR "Gerot‐epilan‐D" OR Hidan OR Hidant* OR Hindatal OR Hydant* OR Ictalis OR Idantoi* OR Iphenylhydantoin OR Kessodanten OR Labopal OR Lehydan OR Lepitoin OR Lepsin OR Mesantoin OR Minetoin OR "Neos‐Hidantoina" OR Neosidantoina OR Novantoina OR Novophenytoin OR "Om‐hidantoina" OR "Om‐Hydantoine" OR Oxylan OR Phanantin* OR Phenatine OR Phenatoine OR Phenhydan* OR Phenitoin OR Phentoin OR Phentytoin OR Phenytek OR Phenytex OR Phenytoin* OR PHT OR Ritmenal OR Saceril OR Sanepil OR Silantin OR Sinergina OR Sodanthon OR Sodanto* OR Solantin OR Solantoin OR Solantyl OR Sylantoic OR Tacosal OR Thilophenyl OR TOIN OR Zentronal OR Zentropil):AB,KW,KY,MC,MH,TI AND INSEGMENT

183. (Lyrica OR Pregabalin*):AB,KW,KY,MC,MH,TI AND INSEGMENT

184. (Mysoline OR Primidon* OR Sertan):AB,KW,KY,MC,MH,TI AND INSEGMENT

185. (Gabrene OR Garene OR Halogabide OR Halogenide OR Progabid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

186. (Ecovia OR Remacemid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

187. ("D‐23129" OR "D23129" OR EZG OR Ezogabin* OR Retigabin* OR RTG OR Trobalt OR Potiga):AB,KW,KY,MC,MH,TI AND INSEGMENT

188. (Rilutek OR Riluzol* OR Trifluoromethoxybenzothiazol*):AB,KW,KY,MC,MH,TI AND INSEGMENT

189. (Inovelon OR Rufinamid* OR Xilep):AB,KW,KY,MC,MH,TI AND INSEGMENT

190. (Seletracetam*):AB,KW,KY,MC,MH,TI AND INSEGMENT

191. (Diacomit OR Stiripentol*):AB,KW,KY,MC,MH,TI AND INSEGMENT

192. (Sulthiam* OR Sultiam* OR Ospolot):AB,KW,KY,MC,MH,TI AND INSEGMENT

193. (Talampanel*):AB,KW,KY,MC,MH,TI AND INSEGMENT

194. (Tiagabin* OR Gabitril):AB,KW,KY,MC,MH,TI AND INSEGMENT

195. (Tiletamin*):AB,KW,KY,MC,MH,TI AND INSEGMENT

196. (Topiramat* OR Qudexy OR Tipiramate OR Topamax OR "Topiramic acid" OR TPM):AB,KW,KY,MC,MH,TI AND INSEGMENT

197. (Tridione OR Trimethadion*):AB,KW,KY,MC,MH,TI AND INSEGMENT

198. (Valnoctamid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

199. (Avugane OR Baceca OR Convulex OR Delepsine OR Depacon OR Depakene OR Depakine OR Depakote OR Deproic OR Divalprax OR Divalproex* OR DPA OR Encorate OR Epiject OR Epilex OR Epilim OR Episenta OR Epival OR Ergenyl OR Mylproin OR Orfiril OR Orlept OR Selenica OR Stavzor OR Valance OR Valcote OR Valparin OR Valpro* OR VPA OR Zalkote):AB,KW,KY,MC,MH,TI AND INSEGMENT

200. (Depamide OR Valpromid*):AB,KW,KY,MC,MH,TI AND INSEGMENT

201. (GVG OR Sabril OR Vigabatrin*):AB,KW,KY,MC,MH,TI AND INSEGMENT

202. (Zonisamid* OR Exceglan OR Excegram OR Excegran OR ZNS OR Zonegran):AB,KW,KY,MC,MH,TI AND INSEGMENT

203. #136 OR #137 OR #138 OR #139 OR #140 OR #141 OR #142 OR #143 OR #144 OR #145 OR #146 OR #147 OR #148 OR #149 OR #150 OR #151 OR #152 OR #153 OR #154 OR #155 OR #156 OR #157 OR #158 OR #159 OR #160 OR #161 OR #162 OR #163 OR #164 OR #165 OR #166 OR #167 OR #168 OR #169 OR #170 OR #171 OR #172 OR #173 OR #174 OR #175 OR #176 OR #177 OR #178 OR #179 OR #180 OR #181 OR #182 OR #183 OR #184 OR #185 OR #186 OR #187 OR #188 OR #189 OR #190 OR #191 OR #192 OR #193 OR #194 OR #195 OR #196 OR #197 OR #198 OR #199 OR #200 OR #201 OR #202 AND INSEGMENT

204. #115 AND #203 AND INSEGMENT

205. #102 OR #204

Appendix 2. MEDLINE search strategy

This strategy includes a modification of the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2021).

1. exp Brain Neoplasms/

2. exp Glioma/

3. exp Astrocytoma/

4. exp Oligodendroglioma/

5. exp Ependymoma/

6. exp Meningioma/

7. exp Skull Base Neoplasms/

8. (glioma$ or astrocytoma$ or oligodendroglioma$ or ependymoma$ or meningioma$ or skull base neoplasm$).mp.

9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10. (brain or cerebra$ or astrocyte$ or oligodendrog$ or ependym$ or glial or skull base or choroid plexus or neuroepithel$ or neuronal or neuronal‐glial or pineal$ or embryonal or haemopoietic or hemopoietic or germ cell$ or mening$ or sella$ or central nervous system or CNS).mp.

11. (cancer$ or tumor$ or tumour$ or malignan$ or carcinoma$ or neoplasm$ or metasta$).mp.

12. 10 and 11

13. 9 or 12

14. exp *Epilepsy/dt [Drug Therapy]

15. exp Seizures/dt [Drug Therapy]

16. exp Anticonvulsants/

17. (antiepilep$ or anti‐epilep$ or anticonvulsant$ or anti‐convulsant$ or antiseizure$ or anti‐seizure$ or AED or AEDs).mp.

18. exp Midazolam/

19. (Dalam or Dormicum or Dormire or Epistatus or Fulsed or Garen or Hypnovel or Ipnovel or Midazolam* or Nocturna or Setam or Terap or Versed).mp.

20. exp Methazolamide/

21. (Methazolamid* or Methylacetazolamide or Neptazane).mp.

22. exp Propofol/

23. (Anepol or Diprivan or Disoprivan or Disoprofol or Fresofol or Hypro or Lipuro or Plofed or Profol or Propofil or Propofol* or Propolipid or Propovan or Propoven or Provive or Recofol).mp.

24. exp Temazepam/

25. (Dasuen or Euhypnos or Hydroxydiazepam or Levanxol or Methyloxazepam or Nocturne or Norkotral or Normison or Normitab or Nortem or Oxydiazepam or Planum or Pronervon or Remestan or Restoril or Signopam or Temaze or Temazep* or Temtabs or Tenox).mp.

26. exp Thiopental/

27. (Bomathal or Farmotal or Nesdonal or Penthiobarbit* or Pentothal or Sodipental or Thiomebumal or Thionembutal or Thiopent* or Tiobarbital or Tiopental* or Trapanal).mp.

28. (Acemit or Acetamide or Acetazolamid* or Avva or Azm or Azol or Diacarb or Diamox or Diazomid or Diluran or Edemox or Glaupax).mp.

29. Barbexaclon*.mp.

30. (Beclamid* or Chloracon or Hibicon or Posedrine or Nydrane or Seclar).mp.

31. Brivaracetam*.mp.

32. Bromide*.mp.

33. (Carbamazepin* or Carbamazepen* or Carbamezepin* or CBZ or SPD417 or "Apo‐Carbamazepine" or Atretol or Biston or Calepsin or Carbagen or Carbatrol or Carbazepin* or Carbelan or Epitol or Equetro or Finlepsin or Karbamazepin or Lexin or Neurotop or "Novo‐Carbamaz" or "Nu‐Carbamazepine" or Sirtal or Stazepin* or "Taro‐Carbamazepine" or Tegretal or Tegretol or Telesmin or Teril or Timonil).mp.

34. (Carisbamat* or Comfyde or "RWJ‐333369" or "YKP 509").mp.

35. (cenobamat* or Xcopri or YKP3089).mp.

36. (Chlormethiazol* or Distraneurin).mp.

37. (Aedon or Anxirloc or Castilium or Chlorepin or Clarmyl or Clobam or Clobamax or Clobator or Clobazam* or Clofritis or Clopax or Clorepin or Frisium or Grifoclobam or Karidium or Lucium or Mystan or Noiafren or Onfi or Sederlona or Sentil or Urbadan or Urbanil or Urbanol or Urbanyl).mp.

38. (Antelepsin or Antilepsin or Chlonazepam or Cloazepam or Clonazepam* or Clonex or Clonopin or Iktorivil or Klonopin or Kriadex or Landsen or Paxam or Petril or Ravotril or Rivatril or Rivotril or "ro 5‐4023" or "ro 54023").mp.

39. (Calner or Clorazepat* or Justum or Mendon or "Novo‐Clopate" or Tranxene or Tranxilium).mp.

40. (Diapam or Diastat or Diazemuls or Diazepam* or Nervium or Relanium or Valium).mp.

41. (Dimethadion* or Dimethyloxazolidinedione).mp.

42. (Eslicarbazepin* or Exalief or Stedesa or Zebinix).mp.

43. (Esilgan or Estazolam* or Eurodin or Nuctalon or Prosom or Tasedan).mp.

44. Ethadion*.mp.

45. (Aethosuximid* or Emeside or Ethosucci* or Ethosuxide or Ethosuximid* or Etosuximid* or Zarontin).mp.

46. (Ethotoin* or Peganone).mp.

47. (Felbamat* or Felbatol or Felbamyl or Taloxa).mp.

48. (Flunarizin* or Sibelium).mp.

49. (Cerebyx or Fosphenytoin* or Prodilantin).mp.

50. (Gabapentin* or Aclonium or Fanatrex or Gabapetin or Gabarone or GBP or Gralise or Neogab or Neurontin or "Novo‐Gabapentin" or Nupentin).mp.

51. ("CCD‐1042" or Ganaxolon*).mp.

52. (Erlosamide or Harkoseride or Lacosamid* or Vimpat).mp.

53. (Lamotrigin* or Elmendos or Epilepax or "GW 273293" or Lamictal or Lamictin or Lamitor or Lamitrin or Lamogine or Lamotrine or LTG).mp.

54. (Levetiracetam* or Keppra or LEV or Levitiracetam).mp.

55. (Ativan or Intensl or Loraz or Lorazepam* or Lormetazepam* or Temesta).mp.

56. Losigamon*.mp.

57. ("Magnesium sulfat*" or "Magnesium sulphat*").mp.

58. (Medazepam* or Nobrium or Rudotel or Rusedal).mp.

59. (Mephenytoin* or Mesantoin).mp.

60. (Dapaz or Equanil or Meprobamat* or Meprospan or Miltown or Tranmep or Visano).mp.

61. (Celontin or Mesuximid* or Methsuximide or Petinutin).mp.

62. (Mephobarbit* or Mebaral or Mephyltaletten or Methylphenobarbit* or Metilfenobarbital or Phemiton or Prominal).mp.

63. (Erimin or Nimetazepam*).mp.

64. (Alodorm or Arem or Insoma or Mogadon or Nitrados or Nitrazadon or Nitrazepam* or Ormodon or Paxadorm or Remnos or Somnite or Pacisyn).mp.

65. (Oxcarbazepin* or Actinium or Barzepin or Carbox or Deprectal or "GP 47680" or Lonazet or OCBZ or Oxalepsy or OXC or Oxcarbamazepine or Oxetol or Oxpin or Oxrate or Oxtellar or Oxypine or Pharozepine or Prolepsi or Timox or Trexapin or Trileptal or Trileptin).mp.

66. Paraldehyd*.mp.

67. Paramethadion*.mp.

68. (E2007 or Fycompa or Perampanel*).mp.

69. Phenacemid*.mp.

70. (Ethylphenacemid* or Pheneturid*).mp.

71. (Adonal or Aephenal or Agrypnal or Amylofene or Aphenylbarbit or Aphenyletten or Barbenyl or Barbinal or Barbiphen* or Barbipil or Barbita or Barbivis or Barbonal or Barbophen or Bardorm or Bartol or Bialminal or "Blu‐Phen" or Cabronal or Calmetten or Calminal or Cardenal or Chinoin or Codibarbita or Coronaletta or Cratecil or Damoral or Dezibarbitur or Dormina or Dormiral or Dormital or Doscalun or Duneryl or Ensobarb or Ensodorm or Epanal or Epidorm or Epilol or Episedal or Epsylone or Eskabarb or Etilfen or Euneryl or Fenbital or Fenemal or Fenobarbital or Fenosed or Fenylettae or Gardenal or Gardepanyl or Glysoletten or Haplopan or Haplos or Helional or Hennoletten or Henotal or Hypnaletten or Hypnette or "Hypno‐Tablinetten" or Hypnogen or Hypnolone or Hypnoltol or Hysteps or Lefebar or Leonal or Lephebar or Lepinal or Lepinaletten or Linasen or Liquital or Lixophen or Lubergal or Lubrokal or Lumen or Lumesettes or Lumesyn or Luminal or Lumofridetten or Luphenil or Luramin or Molinal or Neurobarb or Nirvonal or Noptil or "Nova‐Pheno" or Nunol or Parkotal or PB or Pharmetten or "Phen‐Bar" or Phenaemal or Phenemal* or Phenobal or Phenobarbit* or Phenobarbyl or Phenoluric or Phenolurio or Phenomet or Phenonyl or Phenoturic or Phenylethylbarbit* or Phenylethylmalonylurea or Phenyletten or Phenyral or Phob or Polcominal or Prominal or Promptonal or "Seda‐Tablinen" or Sedabar or Sedicat or Sedizorin or Sedlyn or Sedofen or Sedonal or Sedonettes or Sevenal or Sinoratox or Solfoton or "Solu‐Barb" or Sombutol or Somnolens or Somnoletten or Somnosan or Somonal or Spasepilin or Starifen or Starilettae or Stental or Talpheno or Teolaxin or Teoloxin or Thenobarbital or Theoloxin or Triabarb or Tridezibarbitur or Triphenatol or Versomnal or Zadoletten or Zadonal).mp.

72. Phensuximid*.mp.

73. (Aleviatin or Antisacer or Auranile or Causoin or Citrullamon or Citrulliamon or Comital or Comitoina or Convul or Danten or Dantinal or Dantoin* or Denyl or "Di‐Hydan" or "Di‐Lan" or "Di‐Phetine" or Didan or Difenilhidantoin* or Difenin or Difetoin or Difhydan or Dihycon or Dihydantoin or Dilabid or Dilantin* or Dillantin or Dintoin* or Diphantoin or Diphedal or Diphedan or Diphenat or Diphenin* or Diphentoin or Diphentyn or Diphenylan or Diphenylhydantoin* or Diphenylhydatanoin or Ditoinate or Ekko or Elepsindon or Enkelfel or Epamin or Epanutin or Epasmir or Epdantoin* or Epelin or Epifenyl or Epihydan or Epilan or Epilantin or Epinat or Epised or Eptal or Eptoin or Fenantoin or Fenidantoin or Fenitoin* or Fentoin or Fenylepsin or Fenytoin* or "Gerot‐epilan‐D" or Hidan or Hidant* or Hindatal or Hydant* or Ictalis or Idantoi* or Iphenylhydantoin or Kessodanten or Labopal or Lehydan or Lepitoin or Lepsin or Mesantoin or Minetoin or "Neos‐Hidantoina" or Neosidantoina or Novantoina or Novophenytoin or "Om‐hidantoina" or "Om‐Hydantoine" or Oxylan or Phanantin* or Phenatine or Phenatoine or Phenhydan* or Phenitoin or Phentoin or Phentytoin or Phenytek or Phenytex or Phenytoin* or PHT or Ritmenal or Saceril or Sanepil or Silantin or Sinergina or Sodanthon or Sodanto* or Solantin or Solantoin or Solantyl or Sylantoic or Tacosal or Thilophenyl or TOIN or Zentronal or Zentropil).mp.

74. (Lyrica or Pregabalin*).mp.

75. (Mysoline or Primidon* or Sertan).mp.

76. (Gabrene or Garene or Halogabide or Halogenide or Progabid*).mp.

77. (Ecovia or Remacemid*).mp.

78. ("D‐23129" or "D23129" or EZG or Ezogabin* or Retigabin* or RTG or Trobalt or Potiga).mp.

79. (Rilutek or Riluzol* or Trifluoromethoxybenzothiazol*).mp.

80. (Inovelon or Rufinamid* or Xilep).mp.

81. Seletracetam*.mp.

82. (Diacomit or Stiripentol*).mp.

83. (Sulthiam* or Sultiam* or Ospolot).mp.

84. Talampanel*.mp.

85. (Tiagabin* or Gabitril).mp.

86. Tiletamin*.mp.

87. (Topiramat* or Qudexy or Tipiramate or Topamax or "Topiramic acid" or TPM).mp.

88. (Tridione or Trimethadion*).mp.

89. Valnoctamid*.mp.

90. (Avugane or Baceca or Convulex or Delepsine or Depacon or Depakene or Depakine or Depakote or Deproic or Divalprax or Divalproex$ or DPA or Encorate or Epiject or Epilex or Epilim or Episenta or Epival or Ergenyl or Mylproin or Orfiril or Orlept or Selenica or Stavzor or Valance or Valcote or Valparin or Valpro$ or VPA or Zalkote).mp.

91. (Depamide or Valpromid*).mp.

92. (GVG or Sabril or Vigabatrin*).mp.

93. (Zonisamid* or Exceglan or Excegram or Excegran or ZNS or Zonegran).mp.

94. or/14‐93

95. (randomi?ed or placebo or randomly).mp.

96. exp controlled clinical trial/

97. (control$ adj3 (analy$ or area or cohort? or compar$ or condition or design or evaluat$ or group? or intervention? or investigat$ or method or participant? or procedure or study or trial?)).mp.

98. exp double‐blind method/ or exp single‐blind method/

99. ((single or doubl$ or tripl$ or treb$) adj3 (blind$ or mask$)).mp.

100. unblinded.mp.

101. 95 or 96 or 97 or 98 or 99 or 100

102. exp animals/ not humans.sh.

103. 101 not 102

104. (case adj (report? or study or studies)).ti.

105. 103 not 104

106. 13 and 94 and 105

107. remove duplicates from 106

Appendix 3. SCOPUS search strategy

((TITLE‐ABS‐KEY(glioma* OR astrocytoma* OR oligodendroglioma* OR ependymoma* OR meningioma* OR "skull base neoplasm*")) OR ((TITLE‐ABS‐KEY(brain OR cerebra* OR astrocyte* OR oligodendrog* OR ependym* OR glial OR skull base OR "choroid plexus" OR neuroepithel* OR neuronal OR "neuronal‐glial" OR pineal* OR embryonal OR haemopoietic OR hemopoietic OR "germ cell*" OR mening* OR sella* OR "central nervous system" OR CNS)) AND (TITLE‐ABS‐KEY(cancer* OR tumor* OR tumour* OR malignan* OR carcinoma* OR neoplasm* OR metasta*)))) AND (TITLE‐ABS‐KEY(antiepilep* or anti‐epilep* or anticonvuls* or anti‐convuls* or antiseizure* or anti‐seizure* or AED or AEDs or Acetazolamid* or Alodorm or Antilepsin or Arem or Ativan or Avugane or Baceca or Barbexaclon* or Beclamid* or Biston or Brivaracetam* or Bromide* or Carbagen or Carbamazepen* or Carbamazepin* or Carbatrol or Carisbamat* or CBZ or Celontin or Cenobamat* or Cerebyx or Chlonazepam or Chloracon or Chlormethiazol* or Cloazepam or Clobazam* or Clonazepam* or Clonex or Clonopin or Clorazepat* or Convulex or Delepsine or Depacon or Depak* or Depamide or Deproic or Desitin or Diacomit or Diamox or Diastat or Diazepam* or Dilantin* or Dimethadion* or Diphenin* or Diphenylhydantoin* or Divalpr* or Dormicum or DPA or Ecovia or Emeside or Encorate or Epanutin or Epiject or Epilepax or Epilex or Epilim or Episenta or Epitol or Epival or Eptoin or Equetro or Ergenyl or Erimin or Eslicarbazepin* or Estazolam* or Ethadion* or Ethosuximid* or Ethotoin* or Ethylphenacemide or Exalief or Exceglan or Excegram or Excegran or Ezogabin* or Fanatrex or Felbamat* or Felbatol or Fenitoin* or Fenytoin* or Flunarizin* or Fosphenytoin* or Frisium or Fycompa or Gabapentin* or Gabarone or Gabitril or Gabrene or Ganaxolon* or Garene or GBP or Gralise or GVG or Halogabide or Halogenide or Hibicon or Hypnovel or Iktorivil or Inovelon or Insoma or Intensl or Keppra or Klonopin or Kriadex or Lacosamid* or Lamict* or Lamitor or Lamitrin or Lamogine or Lamotrigin* or Lamotrine or Landsen or LEV or Levetiracetam* or Liskantin or Loraz or Lorazepam* or Losigamon* or LTG or Luminal or Lyrica or "Magnesium sulfat*" or "Magnesium sulphat*"or Mebaral or Medazepam* or Mephenytoin* or Mephobarbit* or Mephyltaletten or Meprobamat* or Mesantoin or Mesuximide or Methazolamid* or Methsuximid* or Methylphenobarbit* or Midazolam* or Mogadon or Mylepsinum or Mylproin or Mysoline or Neogab or Neptazane or Neurontin or Neurotop or Nimetazepam* or Nitrados or Nitrazadon or Nitrazepam* or Normison or Novo‐Clopate or Nupentin or Nydrane or Onfi or Orfiril or Orlept or Ormodon or Ospolot or OXC or Oxcarbazepin* or Pacisyn or Paraldehyd* or Paramethadion* or Paxadorm or Paxam or PB or Peganone or Pentothal or Perampanel* or Petinutin or Petril or Phemiton or Phenacemid* or Pheneturid* or Phenobarbit* or Phensuximid* or Phenytek or Phenytoin* or PHT or Posedrine or Potiga or Pregabalin* or Primidon* or Prodilantin or Progabid* or Prominal or Propofol* or Prysoline or Qudexy or Ravotril or Remacemid* or Remnos or Resimatil or Restoril or Retigabin* or Rilutek or Riluzol* or Riv?tril or Rufinamid* or Sabril or Seclar or Selenica or Seletracetam* or Sertan or Somnite or Stavzor or Stedesa or Stiripentol* or Sulthiam* or Sultiam* or Talampanel* or Tegret?l or Temazep* or Temesta or Teril or Thiopent* or Tiagabin* or Tiletamin* or Timonil or Topamax or Topiramat* or Topiramic or TPM or Tranxene or Tridione or Trileptal or Trileptin or Trimethadion* or Trobalt or Urban?l or Valance or Valcote or Valium or Valnoctamid* or Valparin or Valpro* or Versed or Vigabatrin* or Vimpat or VPA or Xcopri or Xilep or YKP3089 or Zalkote or Zarontin or Zebinix or ZNS or Zonegran or Zonisamid*)) AND (((TITLE‐ABS(randomiz* OR randomis* OR placebo OR randomly) OR TITLE‐ABS(control* W/4 (analy* or area or cohort or compar* or condition or design or evaluat* or group or intervention or investigat* or method or participant or procedure or study or trial)) OR TITLE‐ABS(unblinded) OR TITLE‐ABS((single OR doubl* OR tripl* OR treb*) W/3 (blind* OR mask*))) AND NOT (TITLE(animal OR mouse OR mice OR murine OR rat OR rodent OR dog OR canine OR zebrafish) AND NOT TITLE(human* OR patient OR child* OR infant* OR adolescen* OR adult OR elderly OR man OR men OR male OR wom?n OR female))) AND NOT (TITLE(case PRE/0 (report OR series OR study OR studies)) OR TITLE("expert opinion" OR "self report")))

Appendix 4. ClinicalTrials.gov search strategy

Interventional Studies | Brain Tumor | Antiepileptic

Appendix 5. WHO ICTRP search strategy

Condition: ((brain OR skull base) AND (tumour OR tumor OR cancer OR neoplasm)) OR glioma OR astrocytoma OR oligodendroglioma OR ependymoma OR meningioma

Intervention: antiepileptic OR anti‐epileptic OR anticonvulsant OR anti‐convulsant OR antiseizure OR anti‐seizure

Contributions of authors

All protocol authors contributed equally in writing the protocol. All authors approved the final protocol version for publication.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health and Care Research (NIHR), UK

Declarations of interest

MJM: none known.
SF: none known.
SJN: none known.

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