Antiepileptic drugs for the primary and secondary prevention of seizures after stroke

Abstract

Background

Seizures after stroke are an important clinical problem and may result in poor outcomes. The indications of antiepileptic drugs (AEDs) for seizure prophylaxis after stroke remain unclear.

This is an updated version of the Cochrane Review previously published in 2014.

Objectives

To assess the effects of AEDs for the primary and secondary prevention of seizures after stroke. For primary prevention, we aimed to assess whether AEDs reduce the likelihood of seizures in people who have a stroke but do not have a seizure. For secondary prevention, we aimed to assess whether AEDs reduce the likelihood of further seizures in people who have a stroke and at least one post‐stroke seizure.

Search methods

We searched the following databases on 9 March 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 08, 2021). CRS Web includes randomised or quasi‐randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy and Stroke. We also checked the reference lists of articles retrieved from these searches.

Selection criteria

We selected randomised and quasi‐randomised controlled studies that recruited participants with a clinical diagnosis of stroke, either ischaemic or haemorrhagic. We excluded studies that only recruited participants with subarachnoid haemorrhage, subdural haemorrhage, extradural haemorrhage, or other non‐stroke diagnoses such as tumour‐ or infection‐related infarction or haemorrhage. We also excluded studies that recruited only participants who had undergone neurosurgery. We included participants of all ages suffering any seizure type who were assigned to AEDs or placebo groups.

Data collection and analysis

In accordance with standard methodological procedures expected by The Cochrane Collaboration, two review authors independently assessed trials for inclusion before evaluating trial risk of bias and extracting relevant data. The primary outcome assessed was the proportion of participants who experienced seizures in the follow‐up period. We presented results as summary risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with 95% CIs for continuous outcomes. Where we had sufficient data, we calculated random‐effects (Mantel‐Haenszel) meta‐analyses for dichotomous outcomes; otherwise, we reported results narratively. We used the I² statistic to analyse statistical heterogeneity. We planned to use funnel plots to assess publication bias in meta‐analyses with at least 10 included studies. We used the GRADE approach to assess the certainty of the evidence.

Main results

Two studies with a total of 856 subjects were included. AEDs were not shown to be effective in primary prophylaxis of post‐stroke seizure (RR 0.65, 95% CI 0.34 to 1.26; 2 studies, 856 participants; moderate‐certainty evidence).

The first study was a randomised double‐blind study comparing valproic acid with placebo for primary seizure prevention up to one year after stroke. The study included 72 adults with intracerebral haemorrhage. There was no difference in the risk of post‐stroke seizures (RR 0.88, 95% CI 0.35 to 2.16) or of death (RR 1.20, 95% CI 0.40 to 3.58).

The second study was a substudy on the use of diazepam in acute stroke. It was a randomised double‐blind study, comparing a three‐day diazepam treatment versus placebo for primary seizure prevention up to three months after stroke in 784 adults with acute stroke. There was no evidence of a difference in the risk of post‐stroke seizures for all stroke or subgroups of haemorrhagic or ischaemic stroke (RR for all stroke 0.47, 95% CI 0.18 to 1.22). In a subgroup analysis of anterior circulation cortical infarcts, primary prophylaxis with diazepam was associated with a reduced risk of post‐stroke seizures (RR 0.21, 95% CI 0.05 to 0.95). Risks of mortality did not differ between the diazepam and the placebo group at two weeks (RR 0.84, 95% CI 0.56 to 1.26) and three months follow‐up (RR 0.95, 95% CI 0.72 to 1.26).

We assessed both studies to be at a low overall risk of bias. Using the GRADE approach, we assessed the overall certainty of the evidence as low to moderate.

Authors' conclusions

There is insufficient evidence to support the routine use of AEDs on the primary and secondary prevention of seizures after stroke. Further well‐conducted studies are warranted for this important clinical problem.

Plain language summary

Effects of antiepileptic drugs for the primary and secondary prevention of seizures after stroke

Review question

Is there evidence to support the routine use of antiepileptic drugs (AEDs) for the primary and secondary prevention of seizures after stroke?

Background

Seizures after a stroke are clinically important. It is unclear whether AEDs are effective in preventing seizures after a stroke in adults.

Results

We found two prospective randomised, double‐blind, placebo‐controlled trials, assessing the effect of AEDs on primary seizure prevention after stroke. The first study included 72 adults, comparing valproic acid with placebo, and it showed no difference in post‐stroke seizure between the intervention and controlled group. The second study included 784 adults, comparing diazepam with placebo, and it showed no difference in post‐stroke seizure between the diazepam group and placebo group. However, a subgroup analysis of the anterior circulation cortical infarcts showed a possible benefit with prophylactic diazepam within the first three months after stroke. Overall, there is insufficient evidence to support the routine use of AEDs to prevent seizures after stroke. Further research on whether AED prophylaxis is indicated in all strokes or in strokes with specific characteristics is warranted.

Quality of the evidence

We assessed the included studies to be at an overall low risk of bias and the certainty of the evidence to be low to moderate. This means that further research is likely to have an important impact on our confidence in estimation of effect and may change the conclusions.

The evidence is current to 9 March 2021.

Summary of findings

Summary of findings 1. Summary of findings.

AEDs compared with placebo for post‐stroke seizure prophylaxis
Patient or population: patients with stroke Settings: clinical Intervention: AEDs Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
Primary outcomes
Primary seizure prophylaxis after stroke	49 per 1000	31 per 1000	RR 0.65 (0.34 to 1.26)	856 (2 studies)	⊕⊕⊕⊝a MODERATE	In subgroup analysis of van Tuijl 2021, 408 ischaemic stroke patients with a total or partial anterior circulation infarction, the risk of post‐stroke was lower in the diazepam group (2 out of 211) than the placebo group (9 out of 197) (RR 0.21, 95% CI 0.05 to 0.95).
Secondary seizure prophylaxis after stroke	No evidence identified
Secondary outcomes
Proportion of participants who had died or become dependent at the end of the scheduled follow‐up period	195 per 1000 (mortality)	188 per 1000 (mortality)	RR 0.97 (0.73 to 1.27)	856 (2 studies)	⊕⊕⊕⊝a MODERATE
NIHSS from admission for SICH to 12 months follow‐up	mean 4.4 (+/‐ 4.1) out of 42 (30 participants)	mean 8.6 (+/‐ 6.1) out of 42 (31 participants)		72 (1 study)	⊕⊕⊝⊝b, c LOW	6 patients in the VPA group and 5 patients in the placebo group died before 12 months follow‐up
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AEDs: Antiepileptic drugs; CI: Confidence interval; NIHSS: National Institutes of Health Stroke Scale; RR: Risk ratio; SICH: Spontaneous intracerebral haemorrhage. GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect a Downgraded one level: impression for wide confidence interval bDowngraded one level: information from one study. c Downgraded one level: small number of participants included in this study.

Background

Description of the condition

Stroke is a major global health problem. In industrialised countries, it is the third most common cause of death, just after ischaemic heart disease and cancers. Almost half of all stroke survivors are left with permanent disabilities (Bamford 1991). Although stroke mainly affects the elderly population, it is worth noting that about 30% of all strokes occur in people aged under 65 (Kelly‐Hayes 2010).

Cerebrovascular disease is one of the most common structural etiologies of epilepsy. Post‐stroke seizures account for 11% of all epilepsy, 22% of all cases of status epilepticus, and 55% of newly‐diagnosed seizures amongst older people (Camilo 2004; DeLorenzo 1996; Herman 2002). The reported incidences of post‐stroke seizures vary widely between epidemiological studies, ranging from 2% to 33% for early‐onset seizures and 3% to 67% for late‐onset seizures (Camilo 2004). This is mainly due to the varying methods of case ascertainment and definitions used in relation to the timing of post‐stroke seizures. According to epidemiological guidelines developed by the International League Against Epilepsy (ILAE), seizures occurring within the first week of stroke are defined as 'early post‐stroke seizures', and those occurring after the first week are defined as 'late post‐stroke seizures' (ILAE 1981). Using this definition, approximately 2% to 6% of people with stroke suffer early seizures (Lamy 2003; So 1996), and 3% to 5% suffer late seizures (Lamy 2003; So 1996). In the longer term, one community‐based study found that the cumulative actuarial risk of having a post‐stroke seizure was 4.2% at one year and 11.5% at five years (Burn 1997).

Possible risk factors for post‐stroke seizures include: 1. stroke subtype: cerebral haemorrhage (especially subarachnoid haemorrhage); 2. location of the lesion: cortical involvement, stroke occurring within the carotid artery territory; 3. stroke severity (but correlation may be weaker after adjusting for stroke subtype and location); 4. occurrence of post‐stroke bacterial infections (Burn 1997; Camilo 2004; Kwan 2007; Lamy 2003; Shinton 1988).

The pathophysiology of early‐ and late‐onset seizures after stroke is believed to be different. In the first few days following an ischaemic brain lesion, cellular biochemical dysfunction can lead to cortical excitability and seizure activity (Kessler 2002). Acute ischaemia leads to the massive release of glutamate, causing excessive activation of glutamate receptors. This process is believed to be responsible for secondary neuronal injury and epileptogenesis in ischaemic stroke (Sun 2001; Sun 2002). Within the ischaemic penumbra, a mixed population of dead, dying, and surviving neurons can become the underlying substrate for ischaemia‐induced epileptogenesis (Kessler 2002). In contrast, late‐onset seizures may be caused by the development of gliosis and meningocerebral cicatrices, with changes in membrane properties, deafferentation, selective neuronal loss, and collateral sprouting (Camilo 2004). This can result in cortical hyperexcitability and neuronal synchrony sufficient to cause seizures (Kessler 2002).

After a stroke, seizures and later development of epilepsy can have a devastating impact on patient outcome and quality of life. Predicting the risk of developing post‐stroke epilepsy is currently an inexact science, and improving the accuracy of this process could lead to more‐targeted use of prophylactic antiepileptic drugs for a defined period of time (Kwan 2010a). Several studies have found that post‐stroke seizures may predict worse functional outcome (Menon 2009), but many of these studies have not adjusted for important covariates, such as stroke severity (Camilo 2004). One large study showed that before adjusting for stroke severity, the occurrence of early post‐stroke seizures increased the risk of 30‐day mortality (odds ratio (OR) 4.3, 95% confidence interval (CI) 1.5 to 12.5; (Labovitz 2001)). However, after adjusting for stroke severity using the US National Institutes of Health Stroke Scale (NIHSS) score, this association was not statistically significant (OR 2.1, 95% CI 0.6 to 7.1). In another large community‐based study, early post‐stroke seizures actually predicted a better neurological outcome (Reith 1997). There is also some evidence that post‐stroke seizures may significantly affect health‐related quality of life (Leidy 1999), but a large prospective study did not find any adverse effect on rehabilitation outcomes, as measured by the Barthel Index or the Rivermead Mobility Index (Paolucci 1997).

Description of the intervention

AEDs are the mainstay therapy for seizure prevention in epilepsy. They work by various mechanisms including sodium channel blockade (e.g. phenytoin, carbamazepine, oxcarbazepine, lacosamide and rufinamide), gamma‐aminobutyric acid (GABA) analogue (e.g. gabapentin and pregabalin), and synaptic vesicle glycoprotein 2A (SV2A) binding (e.g. levetiracetam and brivaracetam). The antiepileptic drugs could be divided into old‐generation and new‐generation AEDs. In general, the old‐generation AEDs have more adverse effects and drug interactions. The number of new‐generation AEDs has increased exponentially in recent decades.

AEDs can result in adverse effects including drowsiness, dizziness, tremor, etc. Some AEDs (e.g. topiramate) can cause cognitive impairment, while some (e.g. levetiracetam and perampanel) may lead to psychiatric side effects. Ultimately, these potential side effects may hinder stroke rehabilitation progress and lead to significant morbidity. Drug interaction is another concern, as many of the AEDs are involved in cytochrome P450‐mediated metabolism, including many of the old‐generation AEDs and some new‐generation AEDs at high doses. This may have potential implications on many drugs that are often concomitantly prescribed for stroke patients, including anticoagulants.

How the intervention might work

More than 70% of all epilepsy patients will achieve complete seizure control with AEDs (Kwan 2000). Some evidence suggests that the number of seizures before commencing the AED may affect the chance of long‐term remission, though this has not been demonstrated in randomised controlled trial. Stroke involves neuronal damage in both acute and delayed phases resulting in epileptogenesis, AEDs may have a theoretical role in antagonise the process. Timing may be crucial in the above hypothesis. AEDs may have a role to halt or attenuate the neuronal network damage resulted from stroke. It may be beneficial to use AEDs as primary prophylaxis, that is even before the occurrence of first seizure after stroke.

Why it is important to do this review

Indications of AEDs as both primary and secondary seizure prophylaxis after stroke are debatable. The benefit of AED prophylaxis is uncertain in the post‐stroke population. Also, the medications are potentially harmful due to their adverse effects or drug interactions. Over‐treatment may therefore cause unnecessary morbidity. Hence, it is meaningful to have a systematic review on the current evidence on the indications of AEDs for seizure prophylaxis after stroke.

Objectives

To assess the effects of AEDs for the primary and secondary prevention of seizures after stroke. For primary prevention, we aimed to assess whether AEDs reduce the likelihood of seizures in people who have a stroke but do not have a seizure. For secondary prevention, we aimed to assess whether AEDs reduce the likelihood of further seizures in people who have a stroke and at least one post‐stroke seizure.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised and quasi‐randomised controlled trials in which participants were assigned to either treatment or control groups. By control groups, we mean those in which participants received placebo or no drug. We did not consider studies with head‐to‐head drug comparisons (i.e. drug A versus drug B), or those comparing combinations of different drugs. The main reason for this decision was that the conclusion from such a comparison would not answer our objective, which was to assess whether the use of any AED (compared to no AED) was effective for the primary or secondary prevention of seizures after stroke.

Types of participants

We used the World Health Organisation's definition of stroke in this review (WHO 1989). We considered all studies that recruited participants with a new neurological deficit consistent with a clinical diagnosis of stroke. We considered studies that included participants with either ischaemic or haemorrhagic stroke, but we excluded studies that only recruited participants with subarachnoid haemorrhage, subdural haemorrhage, extradural haemorrhage, or other non‐stroke diagnoses such as tumour‐ or infection‐related infarction or haemorrhage. We also excluded studies that recruited only participants who had undergone any type of neurosurgery. The management of these excluded patient groups is likely to be substantially different from the generality of people with stroke. For studies that reported the results for a mixture of participant groups, we attempted to separate them, and identify those which were relevant to the participant groups of interest. When we found that this was not possible, we excluded the studies. We included participants of all ages suffering any seizure type.

Types of interventions

The AEDs included were: acetazolamide, barbexaclone, beclamide, brivaracetam, carbamazepine, carisbamate, chlormethiazole, clobazam, clonazepam, clorazepate, diazepam, dimethadione, divaproex, esclicarbazepine, extazolam, ethadione, ethosuximide, ethotoin, felbamate, flunarizine, fosphenytoin, gabapentin, ganaxolone, lacosamide, lamotrigine, levetiracetam, lorazepam, losigamone, magnesium sulphate, medazepam, mephenytoin, meprobamate, mesuximide, methazolamide, methylphenobarbital, midazolam, nimetazepam, nitrazepam, oxcarbazepine, paraldehyde, paramethadione, perampanel, phenacemide, pheneturide, phenobarbitone, phensuximide, phenytoin, pregabalin, primidone, progabide, propofol, remacemide, retigabine, riluzole, rufinamide, seletracetam, stiripentol, sulthiame, talampanel, temazepam, thiopental, tiagabine, tiletamine, topiramate, trimethadione, valnoctamide, valproic acid, valpromide, vigabatrin and zonisamide.

We excluded studies comparing two AEDs.

Types of outcome measures

We included the following primary and secondary outcomes.

Primary outcomes

1. Proportion of participants who experienced seizures in the scheduled follow‐up period. In cases where seizures had occurred, we noted their nature (generalised or focal) and timing, if reported.

Secondary outcomes

1. Proportion of participants who achieved remission for a predefined period of time (e.g. 12 or 24 months).

2. Proportion of participants who withdrew from the allocated treatment within the scheduled follow‐up period. This is a composite outcome, which takes into account several factors, including adverse events, compliance, and effectiveness of treatment. We were particularly interested in the occurrence of side effects for the different AEDs, which might be physical or neurobehavioural (e.g. problems with memory, attention, and performance skills).

3. Proportion of participants who had died or become dependent at the end of the scheduled follow‐up period. 'Independent' individuals were defined as those who did not require regular physical assistance from another person for activities of daily living, such as mobility, dressing, transfers, and feeding. 'Dependent' individuals were those who failed to meet one or more of these criteria.

4. NIHSS upon follow‐up.

5. Quality of life (e.g. using a recognised scoring system such as SF36 and EuroQol).

6. Duration of stay for the acute phase of stroke recovery.

7. Optimal duration of treatment (i.e. length of time that the intervention should be continued).

Search methods for identification of studies

We used the following search methods to identify studies.

Electronic searches

Searches were run for the original review in July 2009. Subsequent update searches were run in May 2011, August 2012, August 2013, June 2016, November 2017, and October 2019. For the latest update, we searched the following databases on 9 March 2021:

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

2. MEDLINE (Ovid, 1946 to March 08, 2021), using the search strategy shown in Appendix 2.

CRS Web includes randomised or quasi‐randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups, including the Epilepsy and Stroke Review Groups.

Searching other resources

We also checked the reference lists of articles retrieved from the above searches. Where clarification of information was needed, we attempted to contact the investigators of the relevant studies.

Data collection and analysis

Selection of studies

Two review authors (JK and RC) independently screened all the titles, abstracts, and keywords of publications identified by the searches, to assess their eligibility. The review authors were blinded to the names of study authors, institutions where the work had been carried out, and the journals (i.e. by printing out the titles, abstracts and keywords without the author names, etc). Publications that clearly did not meet the inclusion criteria were excluded at this stage. We obtained a paper copy of the full publication of every study that appeared to be relevant. Both review authors independently assessed their suitability for inclusion according to prespecified selection criteria, resolving any disagreements by discussion.

Data extraction and management

Two review authors (JK and RC) independently extracted data directly from the two studies that fulfilled our inclusion criteria.

Assessment of risk of bias in included studies

Two review authors (JC and RC) independently assessed the risk of bias for each trial using the Cochrane 'Risk of bias' tool as described in the Cochrane Handbook (Higgins 2011). We rated included studies to be at high, low or unclear risk of bias on six domains applicable to RCTs: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting and other sources of bias.

Measures of treatment effect

We undertook data analyses according to the methods described in Chapter 9 of the Cochrane Handbook (Deeks 2017). We presented results as summary risk ratios (RRs) with 95% confidence intervals (CIs) (if available) for dichotomous outcomes. We reported mean differences (MDs) with 95% CIs (if available) for continuous outcomes.

Unit of analysis issues

The unit of analysis was the study participant. We ensured that it was the number of participants with post‐stroke seizures that was analysed rather than repeated seizure episodes within the same participant. We did not identify cross‐over trials or cluster‐randomised trials.

Dealing with missing data

We contacted study authors to obtain missing outcome data if necessary.

Assessment of heterogeneity

We visually assessed clinical heterogeneity by comparing the characteristics of the participants and interventions, and methodological heterogeneity by comparing methodological factors (such as study designs, concealment of allocation, blinding, etc.) between studies that met our inclusion criteria. We assessed statistical heterogeneity using the I² statistic. We assessed the percentage ranges of I² statistic as follows (Higgins 2011):

1. 0% to 40%: may not be important;

2. 30% to 60%: represents moderate heterogeneity;

3. 50% to 90%: represents substantial heterogeneity;

4. 75% to 100%: represents considerable heterogeneity.

Visual inspection of the forest plots also helped us to assess whether or not heterogeneity was present.

Assessment of reporting biases

Had we identified more than 10 studies, we would have visually inspected funnel plots for asymmetry. We would have investigated reasons for asymmetry (if any) including publication bias, outcome reporting bias, language bias, citation bias, poor methodological design, and heterogeneity.

Data synthesis

Only two studies were included; hence we performed no data analysis beyond that performed and reported in the study itself.

Subgroup analysis and investigation of heterogeneity

We did not carry out any subgroup analyses.

Sensitivity analysis

We did not perform a sensitivity analysis, as the number of studies was small.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach to interpret findings (Schünemann 2011). We used GRADEpro GDT software (GRADEPro GDT 2020), and imported data from Review Manager 5 (Review Manager 2020), to create a 'Summary of findings' table.

The 'Summary of findings' table includes information on certainty of the evidence from the trials and information of importance for healthcare decision‐making. The GRADE approach determines the certainty of evidence for each outcome across studies on the basis of an evaluation of eight criteria (risk of bias, inconsistency, indirectness, imprecision, risk of publication bias, large magnitude of effect, the presence of plausible confounding that could have influenced the effect, and the dose‐response gradient). We used our GRADE assessments of evidence certainty to guide our conclusions.

Results

Description of studies

Two studies met the inclusion criteria. We describe them below. Please see Table 2 for a detailed description of the excluded studies, and Figure 1 for the PRISMA study flow diagram.

1. Detailed description of the excluded studies.

Study	Participants randomised/ analysed	Experimental treatment	Control treatment	Primary outcomes	Secondary outcomes
Alvarez‐Sabin 2002	71 adults with late post‐stroke seizures	Gabapentin	Nil	Efficacy as measured by seizure recurrence average and the recurrence rate (estimated recurrence per year) of seizures after the start of medication and after completing the dose titration period	Tolerability as measured by incidence of side effects and withdrawal
Angriman 2019	Meta‐analytic narrative review
Capone 2009	35 patients with post‐stroke seizures	Levetiracetam	Sustained‐release carbamazepine	Compare time to second seizure	Cognitive function and quality of life, EEG changes, seizure frequency and safety of the drugs
Consoli 2012	128 adults with post‐stroke seizures	Levetiracetam	Sustained‐release carbamazepine	Efficacy as measured by seizure freedom	Time recurrence to the first seizure, EEG tracings, cognitive functions and side effects
Daniele 2005	54 patients with early post‐stroke seizures	Levetiracetam	Control (details not mentioned)	Efficacy as measured by seizure recurrence	Nil
EUCTR2004‐004053‐26‐SE 2005	Nil (ongoing trial)	Levetiracetam	Valproic acid	Efficacy as measured by seizure freedom during the 12 months
Gilad 2007	64 patients with post‐stroke seizures	Lamotrigine	Sustained‐release carbamazepine	Efficacy as measured by secure freedom	Tolerability as measured by withdrawal due to side effects
Johnson 2009	97 with TBI or stroke, 32 patients in the phenytoin arm and 65 patients in the levetiracetam arm	Levetiracetam	Phenytoin	Seizure frequency	Cost, adverse drug reactions
Kaur 2019	Nil (Review, not a study)
Khor 2018	522 patients with TBI were included, 272 patients in study arm and 250 patients in control arm	Levetiracetam	No treatment	Incidence of early seizures	Nil
Liu 2016	60 adults with late post‐stroke seizures after cerebral haemorrhage	Traditional Chinese medicine combined with valproic acid	Valproic acid	TCM syndrome efficacy as defined by Guiding Principles for Clinical Research of Treatment of Epilepsy Using New TCM; seizure frequency	EEG performance; Quality of life measured by Minnesota life quality scale; cognitive function as measured by Wechsler Adult Intelligence Scale revised; safety indicators as confirmed by routine laboratory blood, urine and stool tests, etc.
Messé 2009	295 patients with intracerebral haemorrhage	AEDs	No treatment	mRS on day 90	Nil
NCT01137110 2010	84 SAH patients	Extended levetiracetam	Brief levetiracetam	In‐hospital seizures	Nil
NCT01801072 2013	Nil (ongoing trial)	Levetiracetam	No treatment	Incidence of seizure	Nil
NCT01935908 2013	Nil (terminated trial), targeted patients with aneurysmal subarachnoid haemorrhage	Levetiracetam	No treatment	Randomisation yield	Protocol adherence yield
NCT01974700 2013	Nil (terminated trial), targeted patients undergoing surgical repair of unruptured intracranial aneurysms	Levetiracetam	No treatment	Incidence of seizure	Return to daily activities and return to work
Petiz 2010	178 patients with traumatic or spontaneous subarachnoid haemorrhage	Levetiracetam Phenytoin	No treatment	Seizure preceding and during hospitalisation	Hospital length of stay Mortality
Pulsinelli 1999	462 patients with acute ischaemic stroke	Fosphenytoin	Placebo	Stroke outcome assessed at months 1 and 3 by the mRS	Stroke outcome assessments at months 1 and 3 including the BI, Glasgow Outcome Scale, and NIHSS
Rosenow 2020	1. Initial monotherapy trial: 61 patients with post‐stroke epilepsy	Lacosamide	Carbamazepine	Treatment‐emergent adverse events (TEAEs) during treatment	Seizure free for 6 and 12 consecutive months
	2. Conversion to lacosamide monotherapy trial: 30 patients with post‐stroke epilepsy	Lacosamide	Nil	Treatment‐emergent adverse events (TEAEs) during treatment	50% and 75% seizure reduction and seizure freedom
	3. Lacosamide adjective to one baseline AED: 83 patients with post‐stroke epilepsy	Lacosamide in addition to one AED	Nil	Treatment‐emergent adverse events (TEAEs) during treatment	50% and 75% seizure reduction and seizure freedom
Rowan 2005	593 elderly patients of age 60 or above	Lamotrigine and gabapentin	Carbamazepine	Retention in the trial for 12 months	Seizure freedom at 12 months, time to first seizure, and drug toxicity
SANAD 2007	716 patients with epilepsy	Valproate, topiramate and lamotrigine	Nil	Time to treatment failure and time to 1‐year remission	Time from randomisation to a first seizure; time to achieve a 2‐year remission; and the frequency of clinically important adverse events and side effects emerging after randomisation; quality of life outcomes as measured by Newly Diagnosed Epilepsy Quality of Life battery; and cost‐effectiveness
SANAD 2007a	1721 patients with epilepsy	Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate	Nil	Time to treatment failure and time to 1‐year remission	Time from randomisation to a first seizure; time to achieve a 2‐year remission; and the frequency of clinically important adverse events and side effects emerging after randomisation; quality of life outcomes as measured by Newly Diagnosed Epilepsy Quality of Life battery; and cost‐effectiveness
Siniscalchi 2014	89 adult patients with late onset post‐stroke epilepsy	Phenobarbital or levetiracetam	No treatment	PR and QTc intervals in ECG	Nil
TCTR20180111004 2018	Nil (ongoing trial), targeted cerebrovascular disease patients	Antiepileptic drug	No treatment	Seizure	Nil
Tietjen 1996	Abstract or full text could not be retrieved	Unknown	Unknown	Unknown	Unknown
UMIN000013507 2014	Nil (ongoing trial), targeted 80 patients with poor‐grade subarachnoid haemorrhage	Levetiracetam	Placebo	Functional outcome using the mRS	1. Frequency of convulsion 2. Frequency of abnormal findings on electroencephalograph 3. Frequency of delayed cerebral ischaemia and occurrence of performing endovascular therapy against cerebral vasospasm 4. Rate of brain atrophy at 6 months after the onset 5. Functional improvement using Mini‐Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Barthel Index (BI) at 1 and 6 months after onset 6. Safety
Venturellia 2017	25 patients with non‐convulsive status epilepticus	Lacosamide	Nil	Time for Termination of non‐convulsive status epilepticus	Time to improvement in the EEG and in clinical observation Side effects of treatment
Zhou 2017	92 patients with epilepsy after stroke	Gastrodin in combination with folate and vitamin‐B12 in additional to regular antiepileptics	Regular antiepileptics	Frequency of epileptic seizure and Montreal cognitive assessment (MoCA) scores	Changes in serum high‐mobility group protein B1, interleukin‐2 and interleukin‐6
BI: Barthel scale; LDH: lactate dehydrogenase; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin Scale; PDH: Pirovate dehydrogenase; SAH: subarachnoid haemorrhage; TBI: traumatic brain injury

1.

Study flow diagram

Results of the search

References through database searching from 2011 to 2021 were combined with those included in the previous reviews in 2010 and 2014. After removal of duplicates, 349 references were screened and 316 were rejected. We obtained the full‐texts for 33 studies and assessed their eligibility. Twenty‐eight were excluded as they did not meet the inclusion criteria. Three were excluded as they were ongoing studies. Two studies were included in qualitative and quantitative data synthesis.

Included studies

Design and sample size

Two studies were included in this review (Gilad 2011 and van Tuijl 2021). Both were prospective, randomised, double‐blind, placebo‐controlled trials. Gilad 2011 was single‐centre while van Tuijl 2021 was multi‐centre. The van Tuijl 2021 study was a substudy of the Early GABA‐ergic Activation Study In Stroke (EGASIS) study (Lodder 2006). A total of 856 participants were included. Gilad 2011 recruited 72 participants while van Tuijl 2021 recruited 784. Gilad 2011 included spontaneous non‐traumatic and non‐aneurysmatic spontaneous intracerebral haemorrhage. All participants recruited in both trials were adults (over 18 years of age). In van Tuijl 2021, both ischaemic and haemorrhagic stroke were included. Patients with transient ischaemic attack or pre‐existing epilepsy were excluded. See 'Characteristics of included studies'.

Interventions

Gilad 2011 studied the efficacy of valproic acid versus placebo in the primary prevention of seizure. Oral valproic acid 400 mg twice daily or placebo was given for one month. In the van Tuijl 2021 study, the efficacy of primary seizure prevention within three months post‐stroke with diazepam was investigated. Rectal diazepam 10 mg or placebo was given within 12 hours after stroke onset, followed by oral 10 mg tablets twice daily for three days.

Outcomes

Gilad 2011 defined primary outcome as seizure occurrence at one year of follow‐up. Early seizures were defined as seizure attack within 14 days after stroke onset while late seizures were defined as seizure attack beyond 14 days. Secondary outcome was the mortality rate and NIHSS score at one year of follow‐up. The primary outcome measured by van Tuijl 2021 was any seizure occurred within 3 months of follow‐up period. Secondary outcome was the mortality rate in the follow‐up period. Refer to Table 3 for more details.

2. Outcomes.

	Gilad 2011	van Tuijl 2021
Setting	Hospital, Israel	Multi‐centre, International
Design	Prospective randomised placebo controlled trial	Prospective randomised placebo controlled trial
Total number of participants	72	784
Treatment group: placebo group participants	36:36	389:395
Mean age in treatment group	68.5	70.53
Mean age in placebo group	71	70.73
Gender in treatment group (male number (%))	24 (66.7)	205 (52.7)
Gender in placebo group (male number (%))	23 (63.9)	223(56.5)
Primary Outcome
Total number of seizures
Treatment group Placebo group	7 8	6a 13b
Number of early seizures
Treatment group Placebo group	1 4	NA NA
Number of late seizures
Treatment group Placebo group	6 4	NA NA
Secondary Outcome
NIHSS score
Treatment group Placebo group	4.4 8.6	NA NA
Mortality
Treatment group Placebo group	6 5	74c 79c
a 2 out of 43 ICH, 4 out of 346 IS, 2 out of 211 PACI/TACI b 3 out of 48 ICH, 10 out of 347 IS, 9 out of 197 PACI/TACI c upon 3 months follow‐up NA: Not available ICH: intracerebral haemorrhage IS: ischaemic stroke PACI: partial anterior circulation infarction TACI: total anterior circulation infarction

Excluded studies

We excluded 28 studies, and provide reasons for their exclusion (see Characteristics of excluded studies and Table 2 for details).

Ongoing studies

Hu 2014 is a published study protocol. The study is designed to investigate whether short‐duration valproate could prevent seizure onset or improve the survival and neurological outcome in adults after acute spontaneous supratentorial intracerebral haemorrhage. It is proposed to be a randomised, double‐blinded, placebo‐controlled trial. It aims to include 258 participants. In addition to standard care, participants are to be randomly assigned to receive a seven‐day prophylaxis of valproate 500 mg daily (alternatively 400 mg daily by intravenous infusion in 250 ml 0.9% normal saline) or matching placebo. Participants are aimed to be followed up at seven days, three months, six months, and twelve months. The primary outcomes include early‐ (up to seven days), and late‐onset seizures (later than seven days). Secondary outcomes include neuroimaging features (midline shift and enlargement of haematoma), all‐cause mortality, adverse effects, and functional outcome assessed by Glasgow Outcome Scale and modified Rankin Scale (mRS). No results have been reported yet.

CTRI/2018/02/011926 2018 is a randomised double‐blinded trial to study the prophylactic role of levetiracetam in prevention of post‐stroke seizures when compared to placebo. It recruits both arterial and venous stroke patients within one to two weeks of onset with a cortical syndrome. The patients are recruited into three groups (cortical ischaemic stroke, supratentorial, non‐aneurysmal, nontraumatic cortical intracerebral haemorrhage (ICH) and cortical venous thrombosis with a cortical syndrome). In each subgroup, the patients are randomised to two arms (three months levetiracetam versus three months placebo). In each group, it is supposed to have a sample size of 200 patients in each arm. Hence, the total sample size is 1200 patients. All patients satisfying the inclusion criteria are block‐randomised using a computer‐generated randomisation sequence into active and control arms. The primary outcome is the occurrence of first seizure. Diagnosis of seizure is established by a neurologist based on direct observation of seizures by hospital’s medical staff or on reliable description by patients, family members, caregivers, or other eyewitnesses. The secondary outcomes are time from stroke to occurrence of a late epileptic seizure, occurrence of early epileptic seizures after stroke, seizure severity, neurological function, midline shift, enlargement of haematoma, death (all cause), functional outcome and the occurrence of side effects of the trial medication. The characteristics of the recruited cohort have been recently published (Agarwal 2021), but the results of the trial are pending to be reported.

PEACH 2015 is a randomised controlled trial aiming at evaluating the impact of prophylactic antiepileptic treatment with levetiracetam versus placebo in acute supratentorial spontaneous intracerebral haemorrhage. The aim is to recruit 104 patients with acute supratentorial spontaneous intracerebral haemorrhage over two years. The intervention is levetiracetam. The primary endpoint is the occurrence of at least one clinical or electrical epileptic seizure recorded on continuous 48 hour Holter electroencephalogram (EEG). Secondary outcomes include the number of EEG seizures, the total duration of epileptic seizures continuously recorded on EEG, the occurrence of some paroxysmal EEG patterns, the number of clinical seizures occurred during 72 hours of diagnosis, the occurrence of early (day 0 to day 30) and late (from day 30 to 12 months) clinical seizures, and the functional prognosis evaluated by the mRS, the cerebral oedema and mass effect evaluated by comparing the admission brain CT scan with the control CT scan performed at 72 hours, the neurological status as assessed by the NIHSS and the quality of life measured by the Stroke Impact Scale. The frequency of side effects related to treatment with levetiracetam (anxiety and depression assessed by the Hospital Anxiety and Depression Scale) are also to be included among reported outcomes.

Risk of bias in included studies

See Figure 2 and Figure 3 for summaries of the risk of bias in each included study. We allocated each study an overall rating for risk of bias. All studies included in the review were individually rated as low risk of bias. Please see below for specific domain ratings.

2.

Risk of bias summary: review authors' judgements about each risk of bias domain for each included study

3.

Risk of bias graph: review authors' judgements about each risk of bias domain presented as percentages across all included studies

Allocation

Gilad 2011 used a computer‐generated randomisation scheme to randomise 72 consecutively admitted participants into the valproic acid treatment group and the placebo control group. van Tuijl 2021 included 784 out of 879 subjects from the EGASIS study (Lodder 2006). Participants were randomised by a computer‐generated randomisation scheme to receive a three‐day course of diazepam or placebo. Overall, the risk of selection biases in random sequence generation and allocation concealment were low in both studies.

Blinding

Gilad 2011 was a double‐blinded study. Participants and outcome assessors were blinded to the group allocation. The neurologist monitoring the valproic acid drug level was also blinded to the group allocation and medication adjustment. van Tuijl 2021, which was a subgroup analysis of EGASIS (Lodder 2006), was also a double‐blinded study. Participants, investigators, treating physicians, and nurses were blinded to trial medication. The risk of performance bias and detection bias were considered to be low in the two studies.

Incomplete outcome data

In Gilad 2011, the reasons for subject exclusion were reported in detail. The study had low attrition due to loss to follow‐up. In van Tuijl 2021, the authors had stated that the patients lost to follow‐up had been excluded. We considered the risk of attrition bias to be low in both studies.

Selective reporting

The outcomes stated in the method sections of the publications of both studies were reported. We considered the risk of reporting bias to be low.

Other potential sources of bias

We did not detect any other sources of bias.

Effects of interventions

See: Table 1

Primary outcomes

Primary prevention of post‐stroke seizure by AEDs

In Gilad 2011, the one‐month treatment with valproic acid with initial dose of 800 mg/d (400 mg twice daily, entirely oral) and then with maintenance dose to aim at mid therapeutic serum levels (50 to 100 g/dl), showed no difference in both early and late seizure prevention after one year, when compared with placebo. The authors defined any seizure within two weeks after stroke onset as early seizure, and after two weeks as late seizure. This study randomised 36 patients into the valproic acid group and 36 patients into the placebo group. The total number of patients with seizures in the valproic acid group was seven (19.4%) while that in the placebo group was eight (22.2%), (RR 0.88, 95% CI 0.35 to 2.16). The number of patients with early seizures in the valproic acid group was one (2.8%) while that in the placebo group was 4 (11.1%), (RR 0.25, 95% CI 0.03 to 2.13). The number of patients with late seizures in the valproic acid group was six (16.6%) while that in the placebo group was four (11.1%) (RR 1.5, 95% CI 0.46 to 4.87).

	Early and late seizure	No seizure	Total
Valproic acid group	7	29	36
Placebo group	8	28	36
Risk of early and late seizure in VPA group/risk of early and late seizure in placebo group= (7/29)/(8/28): RR 0.88, 95% CI 0.35 to 2.16

	Early seizure (seizure within 2 weeks)	No early seizure	Total
Valproic acid group	1	35	36
Placebo group	4	32	36
Risk of early seizure in VPA group/risk of early seizure in placebo group= (1/35)/(4/32): RR 0.25, 95% CI 0.03 to 2.13

	Late seizure (seizure beyond 2 weeks)	No late seizure	Total
Valproic acid group	6	30	36
Placebo group	4	32	36
Risk of late seizure in VPA group/risk of late seizure in placebo group= (6/30)/(4/32): RR 1.5, 95% CI 0.46 to 4.87

In van Tuijl 2021, 784 patients were randomised into diazepam or placebo groups. The diazepam group received 10 mg diazepam administered rectally within 12 hours after stroke onset, followed by 10 mg diazepam administered orally twice daily at 12‐hour intervals for the following three days (in total, six 10 mg doses) or until earlier discharge. There was no significant difference in primary post‐stroke seizure prevention in total stroke group nor in a subgroup of patients with an intracerebral haemorrhage or ischaemic stroke after three months follow‐up. Overall, the post‐stroke seizure rate was 1.5% (6 out of 389) in the diazepam group compared with 3.3% (13 out of 395) in the placebo group (RR 0.47, 95% CI 0.18 to 1.22). In the haemorrhagic stroke subgroup, post‐stroke seizure rate was 4.7% (2 out of 43) in the diazepam group compared with 6.3% (3 out of 48) in the placebo group (RR 0.74, 95% CI 0.13 to 4.25). In the ischaemic stroke subgroup, the post‐stroke seizure rate was 1.2% (4 out of 346) in the diazepam group compared with 2.9% (10 out of 347) in the placebo group (RR 0.40, 95% CI 0.13 to 1.27). There was no evidence of difference between these two groups.

However, in a subgroup analysis of 408 ischaemic stroke patients with anterior circulation infarction (including total and partial anterior circulation infarction), the risk of post‐stroke seizure was significantly lower in the diazepam group than in the placebo group. In the diazepam group, 2 patients out of 211 (0.9%) had at least one seizure while in the placebo group, 9 patients out of 197 (4.6%) had at least one seizure (RR 0.21, 95% CI 0.05 to 0.95).

Overall	Seizure	No seizure	Total
Diazepam group	6	383	389
Placebo group	13	382	395
RR = risk of seizure in diazepam group/risk of seizure in placebo group = (6/389)/(13/395) = RR 0.47, 95% CI 0.18 to 1.22

Intracerebral haemorrhage subgroup	Seizure	No seizure	Total
Diazepam group	2	41	43
Placebo group	3	45	48
Risk of seizure in diazepam group/risk of seizure in placebo group = (2/43)/(3/48): RR 0.74, 95% CI 0.13 to 4.25

Ischaemic stroke subgroup	Seizure	No seizure	Total
Diazepam group	4	342	346
Placebo group	10	337	347
Risk of seizure in diazepam group/risk of seizure in placebo group = (4/346)/(10/347): RR 0.40, 95% CI 0.13 to 1.27

Anterior circulation infarct subgroup	Seizure	No seizure	Total
Diazepam group	2	209	211
Placebo group	9	188	197
Risk of seizure in diazepam group/risk of seizure in placebo group = (2/211)/(9/197): RR 0.21, 95% CI 0.05 to 0.95

Pooled analysis of the two studies suggests a non‐significant trend towards a lower risk of post‐stroke seizure when AEDs were used for primary prevention of post‐stroke seizure compared to placebo (RR 0.65, 95% CI 0.34 to 1.26; 2 RCTs, 856 participants, moderate‐certainty evidence; Tau² = 0.00, I² = 0%, low heterogeneity). We downgraded the certainty of evidence from high to moderate because of imprecision of effect estimates in view of the wide confidence interval.

Secondary prevention of post‐stroke seizure by AEDs

Neither study reported data on this outcome.

Secondary outcomes

Proportion of participants who achieved remission

Neither study reported data on this outcome.

Proportion of participants who withdrew from the allocated treatment within the scheduled follow‐up period

Neither study reported data on this outcome.

Proportion of participants who had died or become dependent at the end of the scheduled follow‐up period

In Gilad 2011, 6 participants out of 36 in the valproic acid group died before the 12 months follow‐up while 5 out of 36 died in the placebo group (RR 1.2, 95% CI 0.40 to 3.58).

Intervention	Death	Survival	Total
Valproic acid group	6	30	36
Placebo group	5	31	36
Risk of death in diazepam group/risk of death in placebo group: RR 1.2, 95% CI 0.40 to 3.58

In van Tuijl 2021, mortality rates did not differ between the diazepam group and the placebo group at 2 weeks (RR 0.84, 95% CI 0.56 to 1.26) and 3 months follow‐up (RR 0.95, 95% CI 0.72 to 1.26). 

Intervention	Death within 2 weeks	Survival	Total
Diazepam group	39	350	389
Placebo group	47	348	395
Risk of death within 3 months in diazepam group/risk of death in placebo group: RR 0.84, 95% CI 0.56 to 1.26

Intervention	Death within 3 months	Survival	Total
Diazepam group	74	315	389
Placebo group	79	316	395
Risk of death within 2 weeks in diazepam group/risk of death in placebo group: RR 0.95, 95% CI 0.72 to 1.26

Pooled analysis of the two studies suggests AEDs did not alter the mortality rate after stroke ( RR 0.97, 95% CI 0.73 to 1.27; 2 RCTs, 856 participants, moderate‐certainty evidence; Tau² = 0.00, I² = 0%, low heterogeneity). We downgraded the certainty of evidence from high to moderate because of imprecision of effect estimates in view of the wide confidence interval.

NIHSS upon follow‐up

In Gilad 2011, the mean NIHSS of the valproic acid group was lower at 12 months after spontaneous intracerebral haemorrhage than in the placebo group. The mean NIHSS was 4.4 (+/‐ 4.1) in the treatment group, compared with 8.6 (+/‐ 6.1) In the placebo group (P = 0.002). In van Tuijl 2021, this outcome was not included.

Quality of life

Neither study reported data on this outcome.

Duration of stay for the acute phase of stroke recovery

Neither study reported data on this outcome.

Optimal duration of treatment

Neither study reported data on this outcome.

Discussion

Summary of main results

This review aimed to assess the effects of AEDs for the primary and secondary prevention of seizures after stroke. Using our review criteria, only two studies, with a total of 856 subjects, could be included for further analysis.

The first study (72 participants) did not produce a statistically significant result when comparing valproic acid with placebo for the primary prevention of seizures after spontaneous non‐aneurysmal, non‐traumatic intracerebral haemorrhage. However, the treatment group had a lower, non‐statistically significant incidence of early seizures (less than 14 days after onset of haemorrhage) compared to the placebo group. Notably, the time definition of early post‐stroke seizure was different from that of ILAE. Mortality rates were similar in both groups. The valproic acid treatment group also demonstrated a probable benefit in the secondary outcome of lower NIHSS score at one year compared to the placebo group. This supports the hypothesis that valproic acid might have a neuroprotective or neuro‐remodelling effect, but this requires further confirmation. Whether these results can be applied to other forms of stroke (e.g. ischaemic, subarachnoid haemorrhage) is not certain.

The second study (784 participants) demonstrated that primary prophylaxis with three‐day diazepam after acute stroke prevents seizures in the first three months but did not show evidence in prophylactic effect in post‐stroke seizure, in overall strokes and in the subgroup of haemorrhagic and ischaemic strokes. However, it was shown that diazepam had prophylactic effect for post‐stroke seizure in the subgroup of total or partial anterior circulation infarction. There was no difference in mortality between diazepam and placebo at two weeks and three months follow‐up.

In the meta‐analysis, AEDs were not shown to be effective in the primary prophylaxis of post‐stroke seizure (RR 0.65, 95% CI 0.34 to 1.26; 2 studies, 856 participants, moderate‐certainty evidence). AEDs did not affect the mortality rate of patients after stroke (RR 1.03, 95% CI 0.78 to 1.36; 2 RCTs, 856 participants, moderate‐certainty evidence).

Overall completeness and applicability of evidence

This is the second update of the original 2010 Cochrane Review on this topic (Kwan 2010; Sykes 2014). We have thoroughly searched for and critically analysed all available evidence. We identified only two eligible trials, one of which focused on intracerebral haemorrhagic stroke and the other on both haemorrhagic and ischaemic strokes. In view of the selective focus in these studies, the results may not be applicable to other settings or stroke subtypes. The included studies only reported on primary prevention of seizures after stroke. We found no evidence on secondary prevention.

The European Stroke Organisation does not recommend primary prophylactic therapy for haemorrhagic stroke (ESO 2014). The latest American Stroke Association guideline does not suggest any routine primary prophylaxis for post‐stroke seizures (ASA 2016). It recommends standard management approaches to any patient who develops a seizure after stroke. Some other experts go further and recommend that early and late post‐stroke seizures should receive long‐term prophylactic treatment with AEDs (Asconape 1991). In some countries, such as the United Kingdom, sodium valproate remains a very popular AED for the treatment of post‐stroke seizures (Stephen 2003), although according to previous trials, there is no conclusive evidence to support this practice (SANAD 2007).

Many clinicians would agree that repeated unprovoked post‐stroke seizures would require treatment with AEDs, but again there is no good evidence to inform which drug(s) should be initiated, at what dosage, and for how long. Furthermore, there is some evidence that there may be potential risks with using AEDs in the post‐stroke recovery period. For example, there are concerns that the use of phenytoin, phenobarbital, and benzodiazepines in the post‐stroke period may adversely affect motor recovery (Goldstein 1990). Therefore, the management of post‐stroke seizures remains controversial.

Quality of the evidence

We used the GRADE approach to assess the certainty of the evidence in the included studies, using the criteria outlined in the Cochrane Handbook (Higgins 2011). The certainty of evidence for the reported outcomes was low to moderate. The number of recruited participants was relatively large in the study of van Tuijl 2021 (n = 784), though the number of Gilad 2011 was relatively small (n = 72). We judged both studies to be at an overall low risk of bias. Both included studies had detailed descriptions on randomisation, sequence generation and blinding. However, the two studies only investigated the effectiveness of primary seizure prevention after stroke. No data were provided on secondary post‐stroke seizure prevention. We downgraded the evidence from high to moderate due to imprecision as the confidence interval of the relative effect of primary post‐stroke seizure prophylaxis by AEDs was wide. Overall, there was a paucity of data on the secondary outcomes. Both studies reported the mortality rates. Only Gilad 2011 included the outcome of change in NIHSS score.

Potential biases in the review process

We followed the guidance provided in the Cochrane Handbook to minimise potential biases in the review process (Higgins 2011). Multiple databases were covered in the literature searches. The search outputs were independently screened by two review authors to assess their eligibility. As only two trials were included in this review, we were unable to use funnel plots to assess the risk of publication bias. Three ongoing studies were identified that may be reported in further updates of this review.

Agreements and disagreements with other studies or reviews

One meta‐analytic narrative review evaluated the evidence on primary post‐stroke seizure prevention with AEDs (Angriman 2019). The authors focused on haemorrhagic stroke. They included seven studies in qualitative synthesis. Their selection criteria were different from those of this review, as they included observational studies and randomised controlled trials (including Gilad 2011), while we included only studies of the latter design. Angriman 2019 concluded that the use of AEDs as primary prophylaxis for post‐stroke seizure was not associated with improved neurological function or decreased seizure incidence. Although the scope of their review and study inclusion criteria were different from the current review, the conclusions of Angriman 2019 did not contradict with ours.

Another systematic review with a network meta‐analysis evaluated the evidence on secondary post‐stroke seizure prevention with AEDs (Brigo 2018). Adjusted indirect comparisons were made between each AED using controlled‐release carbamazepine (CR‐CBZ) as a common comparator. Two randomised controlled trials were included, one comparing levetiracetam with CR‐CBZ and the other comparing lamotrigine with CR‐CBZ. No significant difference was found in seizure freedom with either agent against CR‐CBZ. Our review did not include these two studies as they did not have a placebo comparison group, and thus failed to fulfil our inclusion criteria.

Authors' conclusions

Implications for practice.

Moderate‐certainty evidence from two trials suggests that there is no difference between AEDs and placebo in the primary prophylaxis of post‐stroke seizure.

Implications for research.

More research is needed to assess the efficacy and tolerability of AEDs for the primary and secondary prevention of seizures after stroke. Future studies should be randomised and double‐blinded, and should compare one or more AEDs with placebo. Such studies should aim to recruit large numbers of participants and assess clinically meaningful outcome measures, e.g. seizure‐free periods and withdrawal rates from the allocated AEDs within the scheduled follow‐up period. Other important aspects also need to be answered by future studies, including, for example, optimal timing and duration of treatment.

What's new

Date	Event	Description
9 March 2021	New search has been performed	Searches updated 9 March 2021; one new study (van Tuijl 2021) has been included in the review.
9 March 2021	New citation required but conclusions have not changed	Conclusions are unchanged.

History

Protocol first published: Issue 3, 2005
Review first published: Issue 1, 2010

Date	Event	Description
12 August 2013	New citation required but conclusions have not changed	One new study has been added (Liu 2016). Conclusions remain unchanged.
12 August 2013	New search has been performed	Searches updated 12 August 2013.

Appendices

Appendix 1. CRS Web search strategy

1. MeSH DESCRIPTOR Cerebrovascular Disorders Explode All AND CENTRAL:TARGET

2. MeSH DESCRIPTOR Basal Ganglia Cerebrovascular Disease Explode All AND CENTRAL:TARGET

3. MeSH DESCRIPTOR Brain Ischemia Explode All AND CENTRAL:TARGET

4. MeSH DESCRIPTOR Carotid Artery Diseases Explode All AND CENTRAL:TARGET

5. MeSH DESCRIPTOR Brain Infarction Explode All AND CENTRAL:TARGET

6. MeSH DESCRIPTOR Hypoxia‐Ischemia, Brain Explode All AND CENTRAL:TARGET

7. MeSH DESCRIPTOR Intracranial Arterial Diseases Explode All AND CENTRAL:TARGET

8. MeSH DESCRIPTOR Intracranial Arteriovenous Malformations Explode All AND CENTRAL:TARGET

9. MeSH DESCRIPTOR Intracranial Embolism Explode All AND CENTRAL:TARGET

10. MeSH DESCRIPTOR Intracranial Hemorrhages Explode All AND CENTRAL:TARGET

11. MeSH DESCRIPTOR Vasospasm, Intracranial Explode All AND CENTRAL:TARGET

12. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 AND CENTRAL:TARGET

13. stroke* OR poststroke* OR cva OR cerebrovascular* OR "cerebral vascular" AND CENTRAL:TARGET

14. cerebral or cerebellar or brainstem or vertebrobasilar AND CENTRAL:TARGET

15. infarct* or ischemi* or ischaemi* or thrombo* or apoplexy or emboli* AND CENTRAL:TARGET

16. #14 AND #15 AND CENTRAL:TARGET

17. cerebral or intracerebral or intracranial or parenchymal or brain or intraventricular or brainstem or cerebellar or infratentorial or supratentorial AND CENTRAL:TARGET

18. haemorrhage or hemorrhage or haematoma or hematoma or bleeding or aneurysm AND CENTRAL:TARGET

19. #17 AND #18 AND CENTRAL:TARGET

20. #12 OR #13 OR #16 OR #19 AND CENTRAL:TARGET

21. MESH DESCRIPTOR Seizures EXPLODE ALL AND CENTRAL:TARGET

22. (seizure* OR convuls*):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

23. #21 OR #22

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

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

26. MeSH DESCRIPTOR Anticonvulsants Explode All AND CENTRAL:TARGET

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

28. #24 OR #25 OR #26 OR #27 AND CENTRAL:TARGET

29. MeSH DESCRIPTOR Midazolam Explode All AND CENTRAL:TARGET

30. (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

31. #29 OR #30 AND CENTRAL:TARGET

32. MeSH DESCRIPTOR Methazolamide Explode All AND CENTRAL:TARGET

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

34. #32 OR #33 AND CENTRAL:TARGET

35. MeSH DESCRIPTOR Propofol Explode All AND CENTRAL:TARGET

36. (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

37. #35 OR #36 AND CENTRAL:TARGET

38. MeSH DESCRIPTOR Temazepam Explode All AND CENTRAL:TARGET

39. (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

40. #38 OR #39 AND CENTRAL:TARGET

41. MeSH DESCRIPTOR Thiopental Explode All AND CENTRAL:TARGET

42. (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

43. #41 OR #42 AND CENTRAL:TARGET

44. #28 OR #31 OR #34 OR #37 OR #40 OR #43 AND CENTRAL:TARGET

45. (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

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

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

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

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

50. (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

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

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

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

54. (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

55. (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

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

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

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

59. (Divalproex* OR Divalprax OR Ergenyl OR Valance OR Valcote OR Zalkote):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

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

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

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

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

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

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

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

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

68. (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

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

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

71. (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

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

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

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

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

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

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

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

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

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

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

82. (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

83. (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

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

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

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

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

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

89. (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

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

91. (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

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

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

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

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

96. ("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

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

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

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

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

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

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

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

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

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

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

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

108. (Avugane OR Baceca OR Convulex OR Delepsine OR Depacon OR Depakene OR Depakine OR Depakote OR Deproic 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 Valcote OR Valparin OR Valpro* OR VPA):AB,KW,KY,MC,MH,TI AND CENTRAL:TARGET

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

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

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

112. #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 OR #101 OR #102 OR #103 OR #104 OR #105 OR #106 OR #107 OR #108 OR #109 OR #110 OR #111

113. #20 AND #23 AND #112

114. #113 AND >28/10/2019:CRSCREATED

Appendix 2. MEDLINE search strategy

We received guidance from the Cochrane Stroke Group for the stroke section of this strategy. The filter to identify randomised controlled trials is a modification of the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2021).

1. Cerebrovascular Disorders/

2. exp Basal Ganglia Cerebrovascular Disease/

3. exp Brain Ischemia/

4. exp Carotid Artery Diseases/

5. exp Brain Infarction/

6. exp Hypoxia‐Ischemia, Brain/

7. exp Intracranial Arterial Diseases/

8. Intracranial Arteriovenous Malformations/

9. exp Intracranial Embolism/

10. exp Intracranial Hemorrhages/

11. Vasospasm, Intracranial/

12. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

13. (stroke$ or poststroke$ or cva).tw.

14. (cerebrovascular$ or cerebral vascular).tw.

15. (cerebral or cerebellar or brainstem or vertebrobasilar).tw.

16. (infarct$ or isch?emi$ or thrombo$ or apoplexy or emboli$).tw.

17. 15 and 16

18. (cerebral or intracerebral or intracranial or parenchymal).tw.

19. (brain or intraventricular or brainstem or cerebellar).tw.

20. (infratentorial or supratentorial).tw.

21. 18 or 19 or 20

22. (haemorrhage or hemorrhage or haematoma or hematoma or bleeding or aneurysm).tw.

23. 21 and 22

24. 12 or 13 or 14 or 17 or 23

25. exp Seizures/

26. (seizure$ or convuls$).tw.

27. 25 or 26

28. exp *Pre‐Eclampsia/ or exp *Eclampsia/

29. 27 not 28

30. exp *Epilepsy/dt [Drug Therapy]

31. exp Seizures/dt [Drug Therapy]

32. exp Anticonvulsants/

33. (antiepilep$ or anti‐epilep$ or anticonvulsant$ or anti‐convulsant$ or AED or AEDs).tw.

34. exp Midazolam/

35. (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).tw.

36. exp Methazolamide/

37. (Methazolamid* or Methylacetazolamide or Neptazane).tw.

38. exp Propofol/

39. (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).tw.

40. exp Temazepam/

41. (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).tw.

42. exp Thiopental/

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

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

45. Barbexaclon*.tw.

46. (Beclamid* or Chloracon or Hibicon or Posedrine or Nydrane or Seclar).tw.

47. Brivaracetam*.tw.

48. Bromide*.tw.

49. (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).tw.

50. (Carisbamat* or Comfyde or "RWJ‐333369" or "YKP 509").tw.

51. (cenobamat* or Xcopri or YKP3089).tw.

52. (Chlormethiazol* or Distraneurin).tw.

53. (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).tw.

54. (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").tw.

55. (Calner or Clorazepat* or Justum or Mendon or "Novo‐Clopate" or Tranxene or Tranxilium).tw.

56. (Diapam or Diastat or Diazemuls or Diazepam* or Nervium or Relanium or Valium).tw.

57. (Dimethadion* or Dimethyloxazolidinedione).tw.

58. (Divalproex* or Divalprax or Ergenyl or Valance or Valcote or Zalkote).tw.

59. (Eslicarbazepin* or Exalief or Stedesa or Zebinix).tw.

60. (Esilgan or Estazolam* or Eurodin or Nuctalon or Prosom or Tasedan).tw.

61. Ethadion*.tw.

62. (Aethosuximid* or Emeside or Ethosucci* or Ethosuxide or Ethosuximid* or Etosuximid* or Zarontin).tw.

63. (Ethotoin* or Peganone).tw.

64. (Felbamat* or Felbatol or Felbamyl or Taloxa).tw.

65. (Flunarizin* or Sibelium).tw.

66. (Cerebyx or Fosphenytoin* or Prodilantin).tw.

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

68. ("CCD‐1042" or Ganaxolon*).tw.

69. (Erlosamide or Harkoseride or Lacosamid* or Vimpat).tw.

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

71. (Levetiracetam* or Keppra or LEV or Levitiracetam).tw.

72. (Ativan or Intensl or Loraz or Lorazepam* or Lormetazepam* or Temesta).tw.

73. Losigamon*.tw.

74. ("Magnesium sulfat*" or "Magnesium sulphat*").tw.

75. (Medazepam* or Nobrium or Rudotel or Rusedal).tw.

76. (Mephenytoin* or Mesantoin).tw.

77. (Dapaz or Equanil or Meprobamat* or Meprospan or Miltown or Tranmep or Visano).tw.

78. (Celontin or Mesuximid* or Methsuximide or Petinutin).tw.

79. (Mephobarbit* or Mebaral or Mephyltaletten or Methylphenobarbit* or Metilfenobarbital or Phemiton or Prominal).tw.

80. (Erimin or Nimetazepam*).tw.

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

82. (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).tw.

83. Paraldehyd*.tw.

84. Paramethadion*.tw.

85. (E2007 or Fycompa or Perampanel*).tw.

86. Phenacemid*.tw.

87. (Ethylphenacemid* or Pheneturid*).tw.

88. (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).tw.

89. Phensuximid*.tw.

90. (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).tw.

91. (Lyrica or Pregabalin*).tw.

92. (Mysoline or Primidon* or Sertan).tw.

93. (Gabrene or Garene or Halogabide or Halogenide or Progabid*).tw.

94. (Ecovia or Remacemid*).tw.

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

96. (Rilutek or Riluzol* or Trifluoromethoxybenzothiazol*).tw.

97. (Inovelon or Rufinamid* or Xilep).tw.

98. Seletracetam*.tw.

99. (Diacomit or Stiripentol*).tw.

100. (Sulthiam* or Sultiam* or Ospolot).tw.

101. Talampanel*.tw.

102. (Tiagabin* or Gabitril).tw.

103. Tiletamin*.tw.

104. (Topiramat* or Qudexy or Tipiramate or Topamax or "Topiramic acid" or TPM).tw.

105. (Tridione or Trimethadion*).tw.

106. Valnoctamid*.tw.

107. (Avugane or Baceca or Convulex or Delepsine or Depacon or Depakene or Depakine or Depakote or Deproic 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 Valcote or Valparin or Valpro* or VPA).tw.

108. (Depamide or Valpromid*).tw.

109. (GVG or Sabril or Vigabatrin*).tw.

110. (Zonisamid* or Exceglan or Excegram or Excegran or ZNS or Zonegran).tw.

111. or/30‐110

112. exp controlled clinical trial/ or (randomi?ed or placebo or randomly).ab.

113. clinical trials as topic.sh.

114. trial.ti.

115. 112 or 113 or 114

116. exp animals/ not humans.sh.

117. 115 not 116

118. 24 and 29 and 111 and 117

119. remove duplicates from 118

120. limit 119 to ed=20191025‐20210309

121. 119 not (1$ or 2$).ed.

122. 121 and (2019$ or 2020$ or 2021$).dt.

123. 120 or 122

Data and analyses

Comparison 1. Effect of AEDs on primary prevention of post‐stroke seizure (for all types of stroke).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Post‐stroke seizure	2	856	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.34, 1.26]

1.1. Analysis.

Comparison 1: Effect of AEDs on primary prevention of post‐stroke seizure (for all types of stroke), Outcome 1: Post‐stroke seizure

Comparison 2. Effect of AEDs on mortality.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mortality	2	856	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.78, 1.36]

2.1. Analysis.

Comparison 2: Effect of AEDs on mortality, Outcome 1: Mortality

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Gilad 2011.

Study characteristics
Methods	Study design: prospective randomised, double‐blind, placebo‐controlled study. Purpose: to assess the occurrence of seizure and neurological outcome in spontaneous intracerebral haemorrhage patients who were treated with valproic acid or a placebo for 1 month and follow‐up of 1 year. Methods: CT brain scan at baseline, seizures diagnosed on the basis of eyewitness evidence from staff, relatives, or other eyewitnesses. NIHSS at baseline and at 1 year.
Participants	Sample size: 72 participants. Inclusion criteria: consecutive patients with spontaneous non‐aneurysmal, non‐traumatic intracerebral haemorrhage admitted to a neurological centre. They were then randomly allocated to either the treatment or placebo group. Exclusion criteria: patients with early (less than 24 hours after onset) seizures or those lost to follow‐up (due to other illness or withdrawal of consent for inclusion).
Interventions	Oral valproic acid 400 mg twice daily or placebo at a corresponding dosage for an active therapy period of one month.
Outcomes	Primary outcome: seizure occurrence at 1 year of follow‐up. Secondary outcomes: a. mortality; b. NIHSS score at 1 year of follow‐up.
Notes	No information provided regarding funding or conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated randomisation list was used, such that each consecutive patient recruited was assigned to treatment according to the list.
Allocation concealment (selection bias)	Low risk	No information provided.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinded participants
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Low risk	The attrition due to patients lost to follow‐up was clearly reported, and the proportion was low.
Selective reporting (reporting bias)	Low risk	All outcomes stated in the methods sections of the publications were reported.
Other bias	Low risk	The study appears to be free of other sources of bias.

van Tuijl 2021.

Study characteristics
Methods	Study design: prospective randomised, double‐blind, placebo‐controlled study. Purpose: to assess the occurrence of seizure in acute stroke patients who were treated with diazepam or a placebo for 3 days and follow‐up of 3 months. Methods: CT or MRI within 7 days was mandatory.
Participants	Sample size: 784 participants. Inclusion criteria: participants of EGASIS with acute stroke with 12 hours of onset. Exclusion criteria: Patients with a clear indication for or contraindication to benzodiazepines (at the discretion of the attending physician); patients with unresponsive coma patients another diagnosis than stroke; patients with transient ischaemic attack; patients lost to follow‐up; and patients with a prior history of seizures
Interventions	Diazepam 10 mg or placebo by rectal within 12 hours after stroke onset, followed by 10‐mg tablets twice daily for 3 days
Outcomes	Primary outcome: Occurrence of at least one seizure within 3 months after stroke Secondary outcome: Mortality rates at 2 weeks and 3 months
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated random listing of the two treatment assignments blocked in groups of four and stratified for centre, time from stroke onset to start of treatment and whether the patient was fully alert or not.
Allocation concealment (selection bias)	Low risk	Treatment or controlled group allocation were concealed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	A treatment pack number was provided that matched one of the treatment packs held in the centre. Trial medication was packed and labelled by a pharmacist of University Hospital Maastricht according to a medication code schedule generated before the trial, and sent to the participating centres in boxes of 20 treatment packs. All others involved (patients, investigators, treating physicians, nurses) were blinded to trial medication.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Patients, investigators, treating physicians and nurses were blinded to trial medication.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The attrition due to patients lost to follow‐up was clearly reported, and the proportion was low.
Selective reporting (reporting bias)	Low risk	All outcomes stated in the methods sections of the publications were reported.
Other bias	Low risk	The study appears to be free of other sources of bias.

CT: computed tomography
MRI: magnetic resonance Imaging
NIHSS: National Institutes of Health Stroke Scale

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Alvarez‐Sabin 2002	Not a randomised controlled trial; no placebo arm
Angriman 2019	Meta‐analysis, not a randomised controlled trial
Capone 2009	No placebo arm
Consoli 2012	No placebo arm
Daniele 2005	Not a randomised controlled trial; control group but no mention of placebo arm
EUCTR2004‐004053‐26‐SE 2005	No placebo arm
Gilad 2007	No placebo arm
Johnson 2009	No placebo arm
Kaur 2019	Review, not a randomised controlled trial
Khor 2018	Observational study, not a randomised controlled trial
Liu 2016	No placebo arm
Messé 2009	Not a randomised controlled trial; analysis of data from placebo arm only of a randomised controlled trial of an unproven neuroprotective medication
NCT01137110 2010	No placebo arm
NCT01801072 2013	No placebo arm
NCT01935908 2013	No placebo arm
NCT01974700 2013	No placebo arm
Petiz 2010	Not a randomised controlled trial
Pulsinelli 1999	Investigated the efficacy of fosphenytoin in the treatment of acute ischaemic stroke but not to prevent or treat post‐stroke seizures
Rosenow 2020	No placebo arm
Rowan 2005	Investigated the efficacy of AEDs in "geriatric epilepsy" ‐ data for people with stroke could not be extracted and analysed separately; no placebo arm
SANAD 2007	Data of stroke subgroup is not available for analysis
SANAD 2007a	Data of stroke subgroup is not available for analysis
Siniscalchi 2014	It studied the cardiac adverse effects of phenobarbital and levetiracetam in patients with post‐stroke seizure, but not the efficacy in prophylaxis against post‐stroke seizures
TCTR20180111004 2018	No placebo arm
Tietjen 1996	Investigates the safety of phenytoin for the treatment of acute ischaemic stroke, but prevention or treatment of post‐stroke seizures
UMIN000013507 2014	Investigates the effect of levetiracetam on non‐convulsive status epileptics or non‐convulsive seizure occurring after aneurysmal subarachnoid haemorrhage, but not primary or secondary prevention of seizure
Venturellia 2017	No placebo arm, data of stroke subgroup is not available for analysis
Zhou 2017	No placebo arm

Characteristics of ongoing studies [ordered by study ID]

CTRI/2018/02/011926 2018.

Study name	Role of anti‐seizure drugs in stroke patients to prevent post stroke seizures. 2018.
Methods	Randomised, double‐blind, placebo‐controlled trial
Participants	Arterial or venous stroke patients within 1‐2 weeks of onset and with a cortical syndrome
Interventions	3‐month levetiracetam vs 3‐month placebo
Outcomes	Primary outcome: occurrence of first seizure Secondary outcomes a. time from stroke to occurrence of a late epileptic seizure; b. occurrence of early epileptic seizures after stroke; c. seizure severity; d. neurological function; e. midline shift, enlargement of hematoma; f. death (all cause); g. functional outcome; and h. the occurrence of side effects of the trial medication.
Starting date	01/05/2018
Contact information	vishnuvy16@yahoo.com
Notes	www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19682

Hu 2014.

Study name	Seizure prophylaxis following intracerebral haemorrhage study (SPICH)
Methods	Randomised, double‐blind, placebo‐controlled trial
Participants	258 patients with acute spontaneous supratentorial intracerebral haemorrhage
Interventions	7‐day prophylaxis of valproate 500 mg daily (alternatively 400 mg daily by intravenous infusion in 250 ml 0.9% normal saline) or matching placebo
Outcomes	Primary outcomes: early (< 7 days) and late onset seizures (> 7 days). Secondary outcomes: a. neuroimaging features (midline shift and enlargement of hematoma); b. all cause mortality; c. adverse effects; and d. functional outcome assessed by Glasgow Outcome Scale and mRS.
Starting date	Not available
Contact information	youchao_nswc@163.com; wyplmh@hotmail.com
Notes

PEACH 2015.

Study name	Prevention of epileptic seizures in acute intracerebral haemorrhage (PEACH)
Methods	Randomised placebo‐controlled trial
Participants	Age greater than 18 years with spontaneous intracerebral haemorrhage
Interventions	1 month of Levetiracetam versus 1 month of placebo
Outcomes	Primary outcome: occurrence of at least one clinical or electrical epileptic seizure recorded on continuous 48‐hour Holter EEG Secondary outcome: 1. Occurrence of electroencephalographic signs 2. Number of EEG seizures 3. Total duration of epileptic seizures continuously recorded on EEG 4. Occurrence of some paroxysmal EEG patterns Other outcome measures: 1. Occurrence of early (day 0 to day 30) and late (from day 30 to 12 months) clinical seizures 2. Functional prognosis at 3, 6 and 12 months evaluated by the mRS 3. Cerebral oedema and mass effect evaluated by comparing the admission brain CT scan with the control CT scan performed at 72 hours 4. Neurological status as assessed by the National Institute of Health Stroke Scale at 72 hours, 1 month and 3 months 5. Quality of life measured by the Stroke Impact Scale at 3, 6 and 12 months 6. Frequency of side effects related to treatment with levetiracetam (anxiety and depression assessed by the Hospital Anxiety and Depression Scale at 1 and 3 months)
Starting date	October 2016
Contact information	laure.peter-derex@chu-lyon.fr anne.termoz@chu-lyon.fr
Notes	The principal investigator is Laure Peter‐Derex

CT: Computed Tomography

EEG: Electroencephalogram

mRS: modified Rankin Scale

Differences between protocol and review

We made a slight amendment to the search terms that were set out in the protocol, as 'Cerebrovascular Accident' is no longer used as an index term in MEDLINE. Please see Appendices for details.

We have also updated the assessment for risk of bias and overall certainty of the body of evidence for the outcomes of interest, in keeping with current standards.

Contributions of authors

Original review 2010 (Kwan 2010): Joseph Kwan and Emma Wood performed the original bibliographic searches, identified the studies, and assessed the methodological quality of the studies. Both review authors contributed to the writing of the manuscript, with Joseph Kwan being the lead review author. The review update in 2014 was performed by Lucy Sykes (Sykes 2014), and this latest review update was conducted by Richard Chang, William Leung and Michael Vassallo; Joseph Kwan was the lead review author for both of these two updates.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute of Health Research (NIHR), UK

Declarations of interest

RC: none known
WL: none known
MV: none known
LS: none known
BWE: none known
JK: has received honoraria from Bayer Ltd for invited lectures.

New search for studies and content updated (no change to conclusions)