Scolaris Content Display Scolaris Content Display

Cochrane Database of Systematic Reviews Protocol - Intervention

Antiepileptic drugs for the primary and secondary prevention of seizures after intracranial venous thrombosis

This is not the most recent version

Collapse all Expand all

Abstract

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

We aim to assess the effects of AEDs for the primary and secondary prevention of seizures related to ICVT.

  • For the question of primary prevention, we aim to examine whether AEDs reduce the likelihood of seizures in patients who have had an ICVT but have not had a seizure.

  • For the question of secondary prevention, we aim to examine whether AEDs reduce the likelihood of further seizures in patients who have had an ICVT and at least one seizure.

Background

Intracranial venous thrombosis (ICVT) is a rare condition, accounting for less than one per cent of all strokes (Masuhr 2004). It was first described by MF Ribes in 1825, and at that time the condition was largely regarded as fatal, with the majority of diagnoses being made at postmortem (Benamer 2000). More recently, the diagnosis of ICVT is becoming easier to confirm with newer and less invasive neuroimaging techniques, such as magnetic resonance imaging (Connor 2002). This has resulted in earlier treatment and thus much better prognosis than previously thought possible. Treatments of ICVT with anticoagulation, thrombolysis, and corticosteroids have been subjects of Cochrane reviews (Canhao 2001; Ciccone 2004; Stam 2002).

ICVT is a rare condition that occurs in all age groups, with highest incidence amongst neonates and adults in their third decade. ICVT is more common amongst females, with a female to male ratio of 1.5 to 5. Due to the wide spectrum of clinical symptoms and gradual onset of symptoms the diagnosis is often missed or delayed. Important causes and predisposing factors include intracranial or systemic infections; coagulation disorders (eg. protein C or S deficiency); vascular trauma (eg. neurosurgery, head injury); space‐occupying lesions (eg. brain tumours and other malignancies); hormonal factors (eg. oral contraceptive pill, pregnancy, puerperium); vasculitis (eg. lupus erythematosus, Behçet's disease); and metabolic disorders (eg. homocystinuria, hyperhomocysteinaemia). However, there may be no identifiable cause in up to a third of patients (Allroggen 2000; Heller 2003; Masuhr 2004).

There are several key pathophysiological differences between arterial and venous thrombosis in the brain. Firstly, ICVT is widely regarded as a continuing process in which the balance of pro‐thrombotic and thrombolytic processes is disturbed, leading to progression of the venous thrombus with time. This slow growth of the thrombus, together with good collateralisation of venous vessels, could explain the gradual onset of symptoms (often over days or weeks, but more abrupt onset has been reported). Secondly, haemorrhagic transformation occurs in a significant proportion of patients, probably as a result of raised venous and capillary pressure at and around the site of occlusion (Allroggen 2000).

The clinical presentation of ICVT depends on the extent, site, and progression of the thrombotic process, as well as the existence of venous collaterals (Masuhr 2004). Occlusion of a large venous sinus may lead to more generalised neurological sequelae such as headache, intracranial hypertension, epileptic seizures, and altered consciousness. Involvement of isolated cortical veins may present with more focal neurological symptoms such as motor or sensory deficits, and focal seizures (Masuhr 2004).

Compared with patients with strokes caused by arterial occlusion, those with ICVT are much more likely to experience seizures at the initial presentation and during follow up (de Bruijn 2001; Buccino 2003; Ferro 2003; Masuhr 2004). In one series of 59 patients with ICVT, 47% experienced seizures on admission (de Bruijn 2001). In another series of 142 patients with ICVT, 34% experienced seizures within the first two weeks of the event, and 10% experienced seizures after the first two weeks (Ferro 2003). In another series of 77 patients, 36% experienced seizures in the 'acute period' (undefined) but only 5% developed recurrent seizures (Preter 1996). The prevalence of seizures may be even higher amongst children with ICVT; in a series of 58 children with ICVT, 58% experienced seizures on admission, and those presenting with seizures were more likely to have a bad outcome (de Veber 2001). In Ferro 2003, early seizures were found to be more frequent in patients with motor and sensory deficits and in those with CT/MR evidence of focal brain oedema, venous infarction, or intracerebral haemorrhage on admission. Furthermore, late seizures were more frequent in patients with early seizures and CT/MR evidence of haemorrhage. However, the relationship between ICVT‐related seizures and outcome remains unclear; some studies have identified seizures as a poor prognostic indicator (Benamer 2000; de Veber 2001), whilst others have not found such a relationship (Ferro 2003).

The prophylactic use of antiepileptic drugs (AEDs) for the management of ICVT‐related seizures is controversial. In Ferro 2003, of the 31 patients who experienced early seizures after ICVT, 18 (58%) were prescribed AEDs and of the 60 patients who did not experience early seizures, 12 (20%) were prescribed AEDs. There is currently no consensus for the clinical management of ICVT‐related seizures. Whilst some experts recommend prophylactic treatment with AEDs for all patients with ICVT, because of the high risk of seizures and their potential adverse physiological effects (Einhaupl 1994), others have more recently recommended reserving prophylactic treatment for those who have already had a seizure, ie. for secondary prevention only (Buccino 2003; Masuhr 2004).

On the other hand, Ferro 2003 was more specific in recommending that prophylactic treatment should be used in those with proven risk factors for seizures (eg. those who have already experienced seizures, or with CT/MR evidence of haemorrhage). Overall, it remains unclear which patients with ICVT should receive prophylactic AEDs, which drug should be used, at what dosage, and for how long (Masuhr 2004).

Any potential benefits of using AEDs should also be balanced with their potential side effects. This systematic review aims to assess the potential benefits and risks of AEDs for the prevention of seizures related to ICVT.

Objectives

We aim to assess the effects of AEDs for the primary and secondary prevention of seizures related to ICVT.

  • For the question of primary prevention, we aim to examine whether AEDs reduce the likelihood of seizures in patients who have had an ICVT but have not had a seizure.

  • For the question of secondary prevention, we aim to examine whether AEDs reduce the likelihood of further seizures in patients who have had an ICVT and at least one seizure.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all randomised and quasi‐randomised controlled trials in which patients were assigned to a treatment group (ie. receiving at least one AED) or a control group (ie. receiving placebo or no drug).

Types of participants

We will consider all studies that recruited patients with a diagnosis of ICVT (including cerebral venous thrombosis and dural sinus thrombosis) regardless of aetiology or method of diagnosis. Patients may have or have not had seizures post‐ICVT. For studies which have reported the results for a mixture of patient groups (eg. arterial and venous thromboses), attempts will be made to separate the groups and identify those which are relevant to the patient groups of interest; if this is not possible, despite contacting the investigators, the studies will be subjected to a sensitivity analysis to determine the effects of including and excluding these studies. Children or adults with generalised, focal seizures, or both will be included.

Types of interventions

AEDs were any of those listed in the Cochrane Epilepsy Group information page, including carbamazepine, clobazam, clonazepam, diazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenytoin, phenobarbitone, primidone, sodium valproate, tiagabine, topiramate, vigabatrin, and zonisamide. We will consider all trials in which the intervention was compared with a placebo or with no drug. Studies will be included if they incorporate a control group; studies that compare two AED regimens will also be considered for indirect comparisons.

Types of outcome measures

Primary outcome measures
Proportion of patients who experienced symptomatic (clinical or overt) seizures in the scheduled follow‐up period. In cases where seizures have occurred, their nature (generalised or focal), timings, and method of diagnosis (clinical or using electroencephalography) will be noted; the investigators will be contacted if the outcome data are not readily available in the published report. As described in the Background section, seizures occurring within the first week of ICVT will be defined as early seizures, and those occurring after the first week will be defined as late seizures (ILAE 1981). Occurrence of recurrent late seizures will then be defined as post‐ICVT epilepsy.

Secondary outcome measures
(1) Proportion of patients who achieved remission for a pre‐defined period of time (eg. 12 or 24 months).
(2) Proportion of patients who suffered status epilepticus.
(3) Proportion of patients 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 are particularly interested in the occurrence of side effects for the different AEDs, which may be physical or neurobehavioural (eg. problems with memory, attention and performance skills).
(4) Proportion of patients who were dead or dependent at the end of the scheduled follow‐up period. Independent individuals will be 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 will be those who failed to meet one or more of these criteria.

Other outcomes of interest
(1) Quality of life (eg. using a recognised scoring system such as SF36 and EuroQol).
(2) Duration of hospital stay for the acute phase of recovery after ICVT.
(3) 'Optimal' duration of treatment (ie. the length of time that the intervention should be continued for).

Search methods for identification of studies

This review will draw on the search strategies developed for the Cochrane Epilepsy Group andCochrane Stroke Group as a whole. Relevant trials will be identified in the Cochrane Epilepsy Group and Cochrane Stroke Group Specialised Registers. In addition, we will undertake specialised searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE. We will also check the reference lists of articles retrieved from the above searches. Where clarification of information is needed, we will attempt to contact the investigators of the relevant studies.

We received guidance from the Cochrane Stroke Group for the stroke section of the search strategy (MEDLINE):

1. "INTRACRANIAL EMBOLISM and THROMBOSIS"/
2. INTRACRANIAL THROMBOSIS/
3. explode SINUS THROMBOSIS, INTRACRANIAL/
4. INTRACRANIAL EMBOLISM/
5. CEREBRAL VEINS/ or CAVERNOUS SINUS/ or CRANIAL SINUSES/ or explode DURA MATER/
6. VENOUS THROMBOSIS/ or THROMBOSIS/ or THROMBOEMBOLISM/
7. 5 and 6
8. ((SINUS$ or SINOVENOUS or CEREBRAL VENOUS or CEREBRAL VEIN$ or CAVERNOUS or SAGITTAL VENOUS or SAGITTAL VEIN$ or SINUS) adj5 THROMBO$).tw
9. (CVDST or CVT).tw.
10. 1 or 2 or 3 or 4 or 7 or 8 or 9

The epilepsy and intervention sections of the search will be identical to the Cochrane Epilepsy Group's main search strategy, which can be seen by clicking on the link above and selecting 'Specialized Register'.

Data collection and analysis

Selection of trials
One review author (JK) will screen all the titles, abstracts, and keywords of publications identified by the searches to assess their eligibility. Publications that clearly do not meet the inclusion criteria will be excluded at this stage. A paper copy of the full publication of every study that may possibly be relevant will be obtained. Three review authors (JK, LK, and AG) will assess them according to pre‐specified selection criteria. Any disagreement will be resolved by discussion.

Assessment of methodological quality
Three review authors (JK, LK, and AG) will independently assess the methodological quality of all the included studies and record the findings. We will note the important aspects of methodology: study design, type of control, method of allocation concealment, completeness of follow up, and the presence of blinding for assessments of non‐fatal outcomes. We will not use pre‐printed selection forms or an overall scoring system to evaluate methodological quality.

Data extraction
One review author (JK) will extract the data onto a data extraction form, and the other two review authors (LK and AG) will independently check the extracted data. Data reported by the published sources will be used for analyses in this review but, where additional outcome data are needed, we shall attempt to contact the investigator(s) of the studies. Apart from the methodology and outcome data we shall also extract demographic data (eg. total number of participants randomised, number of participants per group, age, and sex distribution) and possible confounding factors (eg. certainty of diagnosis of ICVT, location and aetiology of venous thrombosis, severity of condition, presence of venous infarct, previous history of epilepsy, other co‐morbid disorders, method and duration of treatment such as anticoagulation, number of patients who withdrew from the study or were lost during follow up, and duration of follow up). Pilot testing of the data collection forms will be done on a sample of studies to improve reliability. Disagreement will be resolved by discussion and a consensus decision made.

Data analysis
Data analysis will abide by the guidelines set out by The Cochrane Collaboration regarding statistical methods. Primary analysis will be by intention to treat. For dichotomous data, we will express relative treatment effects as odds or risk ratios (as appropriate) with 95% confidence intervals. For continuous data, we will use weighted mean difference with 95% confidence intervals. A P value of less than 0.05 will be taken as statistically significant. Clinical heterogeneity will be assessed by the distribution of demographic and prognostic variables across the treatment and control groups. Statistical heterogeneity between studies will be tested using the I2 heterogeneity test. Where there is no significant clinical or statistical heterogeneity, and if it appears sensible to combine the results, a meta‐analysis will be undertaken using a random‐effects model. Sensitivity analysis will be undertaken (to test the robustness of meta‐analysis) by excluding the study with the smallest or largest sample size, or the study with the smallest or largest effects, or by analysing the studies based on methodological quality.