Antiepileptic drugs versus no treatment or placebo for children with benign epilepsy with centro temporal spikes
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective is to evaluate whether or not treatment with AEDs changes the short or long term outcome of children with BECTS or both.
Background
Benign Epilepsy with Centro Temporal Spikes (BECTS), also called Benign Rolandic Epilepsy, is one of the most common epilepsy syndromes in children. Annual incidence is between 6.2 and 10.7 per 100,000 children. BECTS is a well recognised seizure syndrome, with onset generally between the ages of 4 and 10 years (Luders 1987).
Children have normal development, and no neurological deficits. However, as BECTS is very common, it can also coincidentally present in children with neurological problems. Seizures originate from the somatosensory and motor area in the lower rolandic region. Seizures tend to occur at night, and are brief.
An attack starts with a somatosensory aura around the mouth, with unilateral paraesthesia of the tongue and mouth, followed by unilateral twitching of face, mouth, pharynx and larynx (Loiseau 1973). These can be associated with drooling and dysarthria. The seizure can propagate and involve the upper arm, and Todds paralysis can follow. Consciousness is usually maintained, unless there is secondary generalisation. Secondary generalisation is rare in the day, but common at night (ILAE 1989). The focal onset of seizures during sleep can easily be missed. Seizures are generally brief, lasting from a few seconds to a few minutes. Seizure frequency is low. Although in general children do not have long term problems associated with the seizures, some children show subtle cognitive problems (Deonna 2000). The transient, cognitive impairment seems to correlate with epileptic activity on the electroencephalogram (EEG) (Massa 2001). Some people consider BECTS as a mild form of epileptic encephalopathy in the spectrum of Landau‐Kleffner syndrome, and Electrical Status Epilepticus in Slow Wave Sleep.
The EEG background is normal, though slower rhythms can be seen in the same areas as spikes. The characteristic EEG shows high voltage spikes in the centro temporal region on the left, right or bilaterally. These spikes can also be seen in non‐epileptic children, and tend to disappear spontaneously. A family history of epilepsy is common, and siblings and parents can show sharp waves or focal epileptiform activity on their EEGs, indicating a genetic predisposition in these children.
Treatment is controversial, as the prognosis is deemed to be good. Antiepileptic drugs (AEDs) may control generalised seizures, but do not always help with the focal seizures. In most children with BECTS the epilepsy will resolve, whether treated or not. By 12 years 92% of children are in remission, and by 18 years 99.8% (Bouma 1997). Many parents and children will choose not to start medication, especially if the seizures are infrequent or only occur at night. If treatment is required, most clinicians will choose carbamazepine as a first drug of choice, although several other AEDs have been found to be effective.
In this review, we plan to address the following questions. (1) Does AED treatment make a difference to the remission rate? (2) Which AED is the most effective in controlling seizures in children with BECTS?
Objectives
The objective is to evaluate whether or not treatment with AEDs changes the short or long term outcome of children with BECTS or both.
Methods
Criteria for considering studies for this review
Types of studies
All Randomised Controlled Trials (RCTs) that compare the use of different AEDs, or compare the use of AEDs with placebo or both will be included.
Types of participants
The meta‐analysis will include children up to the age of 12 years old who have presented with BECTS.
Studies will only be included if the case definition of participants includes a history suggestive of BECTS and an EEG showing centro temporal spikes.
Types of interventions
Trials will be included if they compare one treatment with another or with placebo. Specific drugs include carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbitone, phenytoin, sodium valproate, sulthiam, topiramate, and vigabatrin.
Types of outcome measures
The outcome measures will include.
(1) Short term outcome: (a) percentage of children that achieve three month remission (i.e. seizure freedom) after randomisation; (b) time to first seizure after randomisation.
(2) Medium term outcome: (c) time to 12 month seizure remission (i.e. seizure freedom) after randomisation.
(3) Long term outcome: (d) percentage of children who remain seizure free after cessation of medication.
(4) Adverse effects of medication: (e) percentage of children who discontinue medication because of adverse effects, (f) percentage of children with increased day time sleepiness, rash, or other adverse effects ascribed to the medication.
(5) Cognitive functioning: (g) in children with specific cognitive difficulties e.g. dysgraphia, resolution of these difficulties on medication.
Resolution of EEG abnormalities has not been included as an outcome because of the following reasons: (1) clinical manifestation of seizures is not related to persisting EEG abnormality; (2) cognitive functioning may correlate with resolution of EEG abnormalities, but main aim of treatment is to improve cognitive function, and not to improve the EEG.
Search methods for identification of studies
We will search the following databases using the comprehensive search strategy of the Cochrane Epilepsy Group (see epilepsy module): Cochrane Epilepsy Group's Specialised Register, MEDLINE, EMBASE, Pharmline, Micromedex. The identified articles will be obtained to look for further cross‐references.
Search criteria
A. A set of terms to search for randomized controlled trials (RCTs)
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. exp Randomized Controlled Trials/
4. exp Random Allocation/
5. exp Double‐Blind Method/
6. exp Single‐Blind Method/
1 or 2 or 3 or 4 or 5 or 6
8. (animals not human).sh.
9. 7 not 8
10. clinical trial.pt.
11. exp Clinical Trials/
12. (clin$ adj trial$).ab,ti.
13. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ab,ti.
14. exp PLACEBOS/
15. placebo$.ab,ti.
16. random$.ab,ti.
17. exp Research Design/
18. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17
19. (animals not human).sh.
20. 18 not 19
21. 9 or 20 (all RCTs)
B. A set of terms to search for BECTS
22. exp epilepsy, rolandic/all
23. benign rolandic epilep$
24. sylvian epilep$
25. centralopathic epilep$
26. centrotemporal epilep$
27. roland$ adj (epilep$ or seizure$)
28. 22 or 23 or 24 or 25 or 26 or 27 (all studies concerning BECTS)
Combining search A and B
29. 21 AND 28 (RCTs concerning BECTS)
Data collection and analysis
We will independently assess all trials that appear potentially relevant for inclusion. We will independently extract the data collected from the individual studies. We will compare results and resolve any disagreements by conference. If necessary, we will contact the original authors for clarification and to obtain individual patient data. We will extract the following data from the articles.
Methodology
(1) Case definition used in study.
(2) Method of randomisation and concealment.
(3) Method of (double) blinding.
(4) Whether or not patients have been excluded from the analysis, and if so the reasons for withdrawal. If data are missing, we will attempt to contact the original authors for this information.
Patient information
(1) Number of participants allocated to each treatment group.
(2) Mean age of participants when seizures started.
(3) Mean age of participants when randomised.
(4) Sex of participants.
(5) Average frequency of seizures on randomisation (severity).
(6) Proportion of participants that remain seizure free for 3 months, 12 months or other identifiable length of time after initiation of medication/placebo.
(7) Time to first seizure after randomisation.
(8) Proportion of children who remain seizure free after cessation of medication.
(9) Proportion of participants who discontinue medication because of adverse effects
(10) Proportion of participants with specific adverse effects, as day time sleepiness.
Data analysis plan
Comparison will be made for placebo controlled trials and for studies comparing different AEDs. The primary analysis is intention‐to‐treat, and will include all randomised participants, analysed in the treatment group to which they were allocated, irrespective of the treatment they actually received. The quality of the studies will be assessed according to their methodology. A sensitivity analysis will be performed, excluding studies of poor quality, and results of this will be compared to overall results. Clinical heterogeneity will be assessed by reviewing the differences across trials in characteristics of recruited participants and treatment. Possible heterogeneity of studies would include different age distribution, different sex distribution, differences in severity, recruitment of participants in a general paediatric setting versus children seen in a tertiary neurology clinic. Heterogeneity will also be assessed using a chi‐squared test for heterogeneity. Dichotomous outcomes will be expressed as relative risk with 95% confidence intervals. Continuous outcomes will be expressed as a weighted mean difference. Hazard ratios will be determined for time to event outcomes. Outcomes will be stratified by seizure type (generalised or partial), and data will be analysed separately as well as for the combined data.
