Treatments for the idiopathic occipital lobe epilepsies

Abstract

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

To evaluate the effectiveness and tolerability of treatments for the idiopathic occipital lobe epilepsies.

Background

Description of the condition

Idiopathic occipital lobe epilepsy (IOLE), initially described by Gastaut (Gastaut 1982), has been classified under the idiopathic focal epilepsy syndromes, which has two types: early onset childhood epilepsy with occipital spikes (Panayiotopoulos type or Panayiotopoulos syndrome) and late onset childhood epilepsy with occipital spikes (Gastaut type) (Engel 2001; Panayiotopoulos 2008). Idiopathic photosensitive occipital epilepsy, as a reflex epilepsy syndrome, has also been considered as a type of IOLE (Panayiotopoulos 2008; Taylor 2003). IOLE is a benign epilepsy syndrome with EEG features of occipital sharp and slow wave complexes. Compared to benign rolandic epilepsy, IOLE is less common and accounts for 20% to 30% of the benign childhood partial epilepsies (Panayiotopoulos 1989). Panayiotopoulos type was reported to range from 6.7% to 13% of childhood focal epilepsies (Lada 2003; Oguni 2001). In Panayiotopoulos type, children present at a mean of five years (range one to 14 years) with prolonged nocturnal seizures. Seizures usually start with prominent autonomic and behavioural symptoms such as vomiting, pallor and irritability (Panayiotopoulos 2008). The prognosis of Panayiotopoulos type is excellent, with seizure remission usually occurring within one to two years (Berg 2000; Caraballo 2000). The Gastaut type is a relatively rare form of pure occipital epilepsy accounting for 2% to 7% of benign childhood focal seizures. In Gastaut type, children present at a mean of eight years (range three to 16 years) with frequent, brief and diurnal seizures. Seizures characterised by initial visual hallucinations such as phosphenes and/or ictal blindness and illusions (Gastaut 1982; Wakamoto 2011). Seizures remit in 50% to 60% cases within two to five years from onset in Gastaut type. Idiopathic photosensitive occipital lobe epilepsy has been clarified as a syndrome of reflex epilepsy with age‐related onset (Engel 2001), which was previously considered as part of the Gastaut type. It begins between five and 17 years and is more common in girls. Seizures are classically induced by television and video games and stopped by removing the photic stimulus (Guerrini 1995). Although an increasing number of partial epilepsy syndromes with a genetic basis are being recognised, the aetiology of IOLE currently remains unknown (Grosso 2007; Taylor 2008). Most patients with IOLE follow a truly benign course, but 40% to 50% of patients of Gastaut type may continue to have visual seizures and infrequent secondarily tonic‐clonic seizures (Wakamoto 2011). Furthermore, some children with IOLE may present atypical evolutions and/or persistent neuropsychological deficits (Gülgönen 2000).

Description of the intervention

Antiepileptic drugs (AEDs) are the most common methods used to treat IOLE. It seems that people with IOLE respond well to AEDs and the prognosis is good (Taylor 2008). Carbamazepine has been the most commonly used AED and valproate is often considered in the first instance if photosensitivity is present (Glauser 2006). It is unclear whether there is any difference in efficacy with the AEDs used in IOLE. Because of negative laboratory and neuroimaging of IOLE, surgery may not be considered as general therapy. However, for those with medically refractory occipital epilepsy, surgery is increasingly being considered and people may benefit from it (Aykut‐Bingol 1998).

How the intervention might work

So far, the detailed mechanism of the epilepsy has not been completely understood. Different AEDs have an antiepileptic effect on voltage‐dependent sodium, calcium, potassium channels, GABA receptors, excitatory amino acid receptors, some enzymes and synaptic proteins. For example, carbamazepine is dominated by the blockage of voltage dependent sodium channels, making fewer of these channels available to subsequently open. Also, surgery by removing the abnormal epileptic zone may be able to stop the seizure.

Why it is important to do this review

Although there are many drugs and surgical methods to treat IOLE, the best way to manage it and improve the prognosis is still unknown. By conducting this review, we will systematically evaluate the effectiveness and safety of treatments for the IOLE.

Objectives

To evaluate the effectiveness and tolerability of treatments for the idiopathic occipital lobe epilepsies.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (blinded and unblinded) are eligible for this review, irrespective of any language restrictions.

Types of participants

Participants of all ages with idiopathic occipital lobe epilepsy (early‐onset childhood epilepsy with occipital spikes, late‐onset childhood epilepsy with occipital spikes and idiopathic photosensitive occipital lobe epilepsy).

Types of interventions

Surgery and antiepileptic drugs are the two main treatments of the idiopathic occipital lobe epilepsies. We will investigate the following treatment comparisons.

1. Antiepileptic drugs or surgery alone compared with no treatment or placebo.

2. Antiepileptic drugs and surgery together compared with no treatment or placebo.

3. One antiepileptic drug compared with another antiepileptic drug( two groups on the same drug, one group with a drug added and one with no treatment or placebo).

4. Two antiepileptic drugs compared with one antiepileptic drug.

5. Antiepileptic drugs compared with surgery.

Types of outcome measures

Primary outcomes

1. Seizure freedom for at least 48 weeks (Glauser 2006).

2. Satisfactory seizure control: 50% or greater reduction in seizure frequency.

3. Absolute or percentage reduction in seizure frequency and duration.

Secondary outcomes

1. Neuropsychological functioning including attention, memory, visuomotor ability and executive functioning.

2. Incidence of adverse or harmful effects:

   1. organ damage: irreversible end organ damage;

   2. cognitive side effects;

   3. allergic reactions (e.g. skin rashes, Steven Johnson syndrome).

3. Withdrawals due to adverse events.

4. Withdrawals due to lack of efficacy.

Search methods for identification of studies

We will search for all RCTs and quasi‐RCTs about the treatments for the idiopathic occipital lobe epilepsies, irrespective of any language restrictions.

Electronic searches

We will search the following databases:

1. Cochrane Epilepsy Group Specialised Register;

2. the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library);

3. MEDLINE on Ovid, using the search strategy set out in Appendix 1;

4. Embase, using the search strategy set out in Appendix 2;

5. the China Biological Medicine Database (CBM‐disc).

The proposed search strategies for MEDLINE and Embase will be adapted for use with the other databases.

Searching other resources

We will check the references of published studies to identify additional trials. We will also review the bibliographies of the randomised and quasi‐randomised trials identified, and contact the authors and known experts in the field to identify additional published or unpublished data. We will impose no language restrictions either in the search or in the inclusion of studies.

Data collection and analysis

Selection of studies

To determine the studies to be assessed further, two review authors (ZX Chen and YJ Hu) will scan the titles, abstract sections and keywords of every record. The two authors will retrieve full‐text articles for further assessment if the information given suggests that the study:

1. includes participants with idiopathic lobe epilepsies;

2. compares the interventions listed above in Types of interventions;

3. uses random or quasi‐random allocation to the comparison groups.

If there is any doubt regarding these criteria from the information given in the title and abstract, we will retrieve the full‐text article for clarification. Two review authors (ZX Chen and YJ Hu) will assess each of these studies for inclusion. A third author (QF Li) will help to arbitrate when necessary. We will exclude studies that do not meet the inclusion criteria and state the reasons in the 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (ZX Chen and YJ Hu) will assess the included studies for quality. When there are disagreements about inclusion criteria, the two authors will discuss the discrepancy carefully. A third review author (QF Li) will help to arbitrate when necessary. The following data will be extracted, if available.

1. General information

i) Published/unpublished; title; authors; reference/source; contact address; country; urban/rural etc.; language of publication; year of publication; duplicate publications; sponsor; setting.

2. Study methods

i) Method of generation of random list. ii) Method of concealment of randomisation. iii) Stratification factors. iv) Blinding methods.

3. Participants

i) Number (total and per group). ii) Sex and age distribution. iii) Seizure types and idiopathic occipital lobe epilepsy syndrome. iv) Time between first seizure and randomisation. v) Aetiology of epilepsy. vi) Presence of neurological signs. vii) Number and types of antiepileptic drugs (AEDs) taken. viii) Number and types of surgery taken.

4. Intervention and control

i) Type of AEDs. ii) Details of treatment regime (dose, route, timing). iii) Type of control. iv) Details of control treatment (dose, route, timing). v) Type of surgery. vi) Details of surgical treatment (method, route, timing).

5. Follow‐up data

i) Duration of follow‐up. ii) Dates of treatment withdrawal and reasons for treatment withdrawal. iii) Withdrawal rates. iv) Dates of surgery outcomes.

6. Outcome data

i) As described in the types of outcome measures

7. Analysis data

i) Methods of analysis (intention‐to‐treat (ITT) and per‐protocol analysis). ii) Comparability of groups at baseline (yes or no).

Assessment of risk of bias in included studies

Two review authors (ZX Chen and YJ Hu) will independently assess the risk of bias of the included studies using the Cochrane 'Risk of bias' tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The Cochrane 'Risk of bias' tool mainly comprises seven specific parameters: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessors, (5) incomplete outcome data, (6) selective outcome reporting, and (7) other bias. For each entry, the judgement ('low' risk of bias, 'high' risk of bias or 'unclear' risk of bias) is followed by a description. We will resolve any disagreement through discussion or by referral to a third review author.

Measures of treatment effect

We will analyse the data by using Cochrane RevMan 5.3 software (RevMan 2014) and reporting results according to Cochrane criteria, following the Cochrane Epilepsy Group's guidelines. We will calculate a pooled treatment effect using a fixed‐effect model across trials with RevMan 5.3. Results will be expressed as risk ratios (RRs) with 95% confidence intervals (CIs) or risk differences (RDs) with 95% CIs for dichotomous outcomes (all of the primary outcomes and secondary outcomes two to four). We will use mean differences (MDs) for continuous outcomes for the secondary outcome "Neuropsychological functioning including attention, memory, visuomotor ability and executive functioning", which is assessed by scales or scores. If standard errors are available for differences in effect, but the standard deviations of the individual study groups are not, we will use the RevMan Generic Inverse Variance (GIV) facility to pool studies.

Unit of analysis issues

Cluster‐randomised studies or cross‐over trials could be conducted, but they are not appropriate for the assessment of long‐term outcomes of interest in this review. In studies that compare more than two intervention groups, we will select the relevant pair of intervention groups to include in the analyses.

Dealing with missing data

We will analyse data on an intention‐to‐treat basis. Therefore, all participants with available data will be included in the analysis in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants are not analysed in the group to which they were randomised, and there are sufficient information in the trial report, we will attempt to restore them to the correct group. We will obtain missing data from the study authors whenever possible.

Assessment of heterogeneity

We will assess heterogeneity amongst trials by using the Chi² test with a 10% level of statistical significance (P < 0.1) and an I² greater than 50% (Higgins 2002; Higgins 2003). If significant heterogeneity is present, we plan to re‐check the data and determine the causes of heterogeneity and then undertake sensitivity analyses. If there is still unexplained heterogeneity, we will combine the study results using a random‐effects model. For trials that are clinically heterogeneous or present insufficient information for pooling, we will provide a descriptive analysis (Higgins 2011).

Assessment of reporting biases

If we include more than ten studies, we plan to assess reporting biases by looking for funnel plot asymmetry. Reasons for asymmetry include publication bias, outcome reporting bias, language bias, citation bias, poor methodological design and heterogeneity. We will assess these for each trial. If there are less than ten studies, we will use a descriptive analysis to evaluate possible reporting biases.

Data synthesis

We will use RevMan 5.3 to perform meta‐analyses of the studies that report on the efficacy of the treatments for idiopathic occipital lobe epilepsies, and display the results as a forest plot. Only trials that provide a measure of effect size will be included. Descriptive analyses of other included trials will also be undertaken. When comparing interventions in a study or meta‐analysis, a simplifying assumption is often made that the hazard ratio is constant across the follow‐up period.

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses will be carried out.

1. Sex:

   1. Treatments for males with idiopathic occipital lobe epilepsies.

   2. Treatments for females with idiopathic occipital lobe epilepsies.

2. Dose:

   1. Low‐dose AEDs treatments for idiopathic occipital lobe epilepsies.

   2. Conventional‐dose AEDs treatments for idiopathic occipital lobe epilepsies.

   3. High‐dose AEDs treatments for idiopathic occipital lobe epilepsies.

Sensitivity analysis

We will also undertake a sensitivity analysis on the basis of methodological quality by repeating the calculation after omitting the trials which have high risk of bias on individual quality items.

Summarising and interpreting results

We will use the GRADE approach to interpret findings (Schunemann 2011). We will use GRADE Profiler Software (GRADEPro 2004), and import data from Review Manager 5.3, to create 'Summary of findings’ tables for each comparison included in the review for all the primary outcomes and all the secondary outcomes.

The 'Summary of findings' table for each comparison will include information on overall quality of the evidence from the trials and information of importance for healthcare decision making. The GRADE approach determines the quality of evidence on the basis of an evaluation of eight criteria (risk of bias, inconsistency, indirectness, imprecision, publication bias, effect size, presence of plausible confounding that will change effect and dose‐response gradient). We will use these to guide our conclusions.

Appendices

Appendix 1. MEDLINE search strategy

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials.

1. randomized controlled trial.pt. 2. controlled clinical trial.pt. 3. randomized.ab. 4. placebo.ab. 5. clinical trials as topic.sh. 6. randomly.ab. 7. trial.ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. exp animals/ not humans.sh. 10. 8 not 9 11. occipital epilep$.tw. 12. occipital lobe epilep$.tw. 13. 11 or 12 14. 10 and 13

Appendix 2. OVID Embase strategy

1 Randomized Controlled Trial/ 2 Clinical Trial/ 3 Multicenter Study/ 4 Controlled Study/ 5 Crossover Procedure/ 6 Double Blind Procedure/ 7 Single Blind Procedure/ 8 exp RANDOMIZATION/ 9 Major Clinical Study/ 10 PLACEBO/ 11 Meta Analysis/ 12 phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/ 13 (clin$ adj25 trial$).tw. 14 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw. 15 placebo$.tw. 16 random$.tw. 17 control$.tw. 18 (meta?analys$ or systematic review$).tw. 19 (cross?over or factorial or sham? or dummy).tw. 20 ABAB design$.tw. 21 or/1‐20 22 human/ 23 nonhuman/ 24 22 or 23 25 21 not 24 26 21 and 22 27 25 or 26 28 Idiopathic occipital lobe epilepsies/ 29 Benign childhood occipital epilepsy/ 30 Idiopathic occipital lobe epilep$.tw. 31 Benign childhood occipital epilep$.tw. 34 or/28‐31 35 Drug therapy/ 36 Surgery/ 37 Drug therap$.tw. 38 Surger$.tw. 39 or/35‐38

Contributions of authors

Shengmei Chen drafted the protocol and will perform the bibliographic searches, identify the studies and extract the data. Dr Qifu Li, the contact author, developed the proposal, revised the protocol and will be responsible for developing the review. Dr Taixiang Wu will assess the methodological quality of the studies. Dr.Zhibin Chen, Dr. Shurong Wang and Dr.Dong Zhou will check the extracted data, and along with Jennifer Cotton, comment on all the draft manuscripts.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research (NIHR), UK.

  This protocol was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Epilepsy Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Declarations of interest

None known.

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