Polyunsaturated fatty acid supplementation for drug-resistant epilepsy

  • Protocol
  • Intervention


  • Vivian Sarmento Vasconcelos,

    1. UNCISAL (Universidade Estadual de Ciencias de Saude de Alagoas), Maceio, Alagoas, Brazil
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  • Cristiane R Macedo,

    Corresponding author
    1. Centro de Estudos de Medicina Baseada em Evidências e Avaliação Tecnológica em Saúde, Brazilian Cochrane Centre, São Paulo, São Paulo, Brazil
    • Cristiane R Macedo, Brazilian Cochrane Centre, Centro de Estudos de Medicina Baseada em Evidências e Avaliação Tecnológica em Saúde, Rua Borges Lagoa 564 cj 63, São Paulo, São Paulo, CEP 04038-000, Brazil. crisrufa@uol.com.br.

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  • Alexsandra Souza Pedrosa,

    1. University of Health Sciences of Alagoas - UNCISAL, Physiotherapy, Maceió, Brazil
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  • Edna Pereira Gomes Morais,

    1. Universidade Estadual de Ciências da Saúde Alagoas - UNCISAL, Propaedeutic and Therapeutic Sciences, Maceió, Alagoas, Brazil
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  • Maria R Torloni

    1. Centro de Estudos de Medicina Baseada em Evidências e Avaliação Tecnológica em Saúde, Brazilian Cochrane Centre, São Paulo, São Paulo, Brazil
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This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of PUFA supplementation compared to no supplementation, placebo or other treatments for controlling convulsions in patients with drug-resistant epilepsy.


Description of the condition

Epilepsy is a common neurological disorder characterised by recurrent convulsions. These are caused by spontaneous and rhythmic changes in the electrical activity of neurons, which are unrelated to toxic, metabolic or infectious factors (Berg 2010). An estimated 1% to 3% of people will receive a diagnosis of epilepsy during their lives, which corresponds to approximately 50 million affected patients worldwide (Kwan 2000). In developed countries, each year 50 new cases of epilepsy are diagnosed for every 100,000 persons while in developing countries there are 100 to 190 new cases per 100,000 persons per year (Sander 2003).

Although most patients achieve adequate control of their disease though the use of medication (Duncan 2006; Ranganathan 2009), approximately 25% to 30% of individuals with epilepsy are refractory to pharmacological treatment (Lefevre 2000). Drug-resistant epilepsy is defined as unsatisfactory control of seizures despite the use of at least two tolerated antiepileptic drugs at an adequate strength/dosage for a sufficient length of time, whether as monotherapy or in combination (Kwan 2010).

Drug-resistant epilepsy, also known as refractory, pharmacoresistant, intractable, incapacitating, disabling or severe epilepsy (Cardenas-Rodriguez 2013), can be distressing and affect the quality of life of patients and their families (Duncan 2006; Kwan 2000; Lefevre 2000). Drug-resistant epilepsy is also associated with an increased risk of sudden death (Surges 2009). Sudden unexpected death in epilepsy (SUDEP) is up to five times more common In the population with medically intractable seizures than in people with well-controlled epilepsy (Walczak 2001; Opeskin 2003; Surges 2009; DeGiorgio 2008).

Description of the intervention

Polyunsaturated fatty acids (PUFAs) are hydrocarbon chain molecules with multiple double bonds. PUFAs are divided into two major groups (omega-3 and omega-6), depending on the position of the double bonds (Taha 2010)

Eicosapentaenoic and docosahexaenoic acid are long-chain omega-3 (n-3) PUFAs derived from α-linolenic acid. These long-chain PUFAs can be synthesised in the body to a small extent but the main source is diet (Gao 2009; Gao 2010). n-3 PUFAs are found mainly in foods such as cold water fish (salmon, tuna and sardines), fish oils, some nuts and flaxseed (Clayton 2007).

PUFAs are abundant in the brain and regulate many brain functions (Musto 2011). Over the last decade, researchers have tested the use of PUFA supplements for the treatment of refractory epilepsy, with controversial results. While some studies have reported a significant reduction in the number of convulsions in patients receiving omega-3 (Schlanger 2002; Yuen 2005), this has not been confirmed by other investigators (Bromfield 2008).

Although high doses of eicosapentaenoic and docosahexaenoic acid are apparently safe, omega-3 PUFA compounds reduce platelet aggregation and could, in theory, cause bleeding (Phang 2013).

How the intervention might work

The beneficial effects of n-3 PUFAs for epilepsy are related to their anti-excitatory and neuroprotective mechanisms (Porta 2009; Schlanger 2002; Taha 2010). Studies from the 1980s and 1990s showing that PUFAs helped to control cardiac arrhythmias led to the hypothesis that they could also help to reduce convulsive activity (Schlanger 2002; Yehuda 1994). In animal models n-3 PUFAs have been shown to reduce the electrical activity of neurons, inhibit the repeated excitatory activity of these cells and modulate the propagation of epileptic crises (Freeman 2006; Voskuyl 1998; Xiao 1999; Yehuda 1994).

The anti-excitatory effect of n-3 PUFAs is thought to be related to the partial inhibition of ion channels on cell membranes, which reduces the influx of positive ions, such as sodium and calcium, into the cell (Börjesson 2011; Taha 2010; Xiao 1999). There is evidence to support the hypothesis that increased levels of PUFAs may contribute to the anticonvulsive effects of ketogenic diets (Fraser 2003; Freeman 2006). This diet was derived from historical observations that seizures ceased when patients with epilepsy were fasting (Guelpa 1911; Geyelin 1921). This was attributed to ketosis, which led to the creation of a diet high in fat and low in carbohydrates, usually with a ratio of 4:1, to produce the same effect (Wilder 1921). Although the exact mechanisms of action are still unclear, the increased production of ketone bodies and changes in energy metabolism induced by this diet can have a neuroprotective effect (Levy 2012).

PUFAs are important structural components of neuronal membranes and in their free form they are also involved in the regulation of neuronal function (Taha 2010). n-3 PUFAs reduce the production of reactive oxygen species, bio products of the energetic metabolism which can cause oxidative damage to membrane phospholipids, thus contributing to the inflammation and neurodegeneration present in patients with epilepsy (Chuang 2010; Freeman 2006). n-3 PUFAs also inhibit the synthesis of cyclooxygenase-2 (COX-2), an enzyme involved in the production of pro-inflammatory substances (Dahlin 2007).

Why it is important to do this review

Drug-resistant epilepsy affects millions of individuals worldwide and is associated with important adverse outcomes including an increased risk of death. The search for new and effective therapies for these patients is a priority for the neurology research agenda. Existing options for the treatment of drug-resistant epilepsy include surgery, which is not suitable for all cases and involves risks (Zhang 2013) and a ketogenic diet, which is difficult to tolerate and has a high rate of drop-out (Levy 2012). If PUFA supplements have a similar effect to a ketogenic diet, this would be a significantly easier option for most patients with drug-resistant epilepsy and their families. There are studies on the use of PUFAs in patients with drug-resistant epilepsy, but as yet they have not been critically appraised and synthesised though a systematic review of the literature.

If supplementation with PUFAs is effective in controlling drug-resistant epilepsy, this could be an important therapeutic alternative for patients with this condition. The findings of this review will help to inform patients and healthcare professionals on the effectiveness and safety of PUFAs for the treatment of drug-resistant epilepsy.


To assess the effectiveness and safety of PUFA supplementation compared to no supplementation, placebo or other treatments for controlling convulsions in patients with drug-resistant epilepsy.


Criteria for considering studies for this review

Types of studies

All randomised and quasi-randomised studies using PUFAs for the treatment of drug-resistant epilepsy.

Types of participants

All patients (adults and children) with a diagnosis of drug-resistant epilepsy, irrespective of their seizure type or epilepsy syndrome. A diagnosis of drug-resistant epilepsy will be defined as monthly spontaneous seizures despite the use of at least two antiepileptic drugs in adequate dosages. Patients under dietary treatments (e.g. ketogenic diet) or who have previously used PUFA supplements will not be included.

Types of interventions

Supplementation with PUFAs belonging to the omega-3 series (eicosapentaenoic and docosahexaenoic acid) at any dosage and over any period of time, as monotherapy or combined with antiepileptic drugs. The intervention will be compared to no supplementation, placebo treatment or other treatment.

Types of outcome measures

Primary outcomes
  1. Seizure freedom: proportion of participants with complete cessation of seizures during the treatment period.

  2. Seizure reduction: proportion of participants with at least 50% or greater reduction in seizure frequency at the end of the study compared with baseline.

  3. Potential adverse effects related to PUFA supplementation due to reduced platelet aggregation, such as bleeding symptoms.

Secondary outcomes
  1. Absolute or percentage reduction in seizure frequency and duration.

  2. Improvement in quality of life, assessed through validated scales.

  3. Drop-out rates due to non-compliance or other reasons.

  4. Gastrointestinal effects (nausea, flatulence and diarrhoea).

  5. Changes in plasma lipid profile (triglycerides, low- and high-density lipoprotein cholesterol).

  6. Other side effects.

Search methods for identification of studies

Electronic searches

We will search the following databases for randomised trials:

  • Cochrane Epilepsy Group Specialised Register (from inception up to present date);

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (current issue);

  • MEDLINE (Ovid, 1946 to present);

  • SCOPUS (1823 to present);

  • LILACS (Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde) (1982 to present);

  • ClinicalTrials.gov;

  • WHO International Clinical Trials Registry Platform (ICTRP).

The proposed search strategy for MEDLINE is set out in Appendix 1. We will modify this strategy for use with the other databases.

Searching other resources

We will contact study authors for additional and unpublished information. We will screen reference lists of retrieved citations for potential eligible studies not identified through the electronic search. We will contact experts in the field for information on additional relevant studies that could have been missed.

Data collection and analysis

Selection of studies

Two review authors (Vasconcelos VS and Morais EPG) will screen the titles and abstracts of the citations identified through the searches. We will read the full texts of potentially relevant studies and include them if they fulfil the aforementioned selection criteria. We will carry out the process of study selection in duplicate and resolve disagreements by discussion. In case of persistent disagreement, a third review author (Torloni MR) will be contacted.

Data extraction and management

Two review authors (Vasconcelos VS and Pedrosa AS) will independently extract data and methodological details from all included studies. We will collect the following specific details: trial design, participant characteristics (age, gender, type of epilepsy, doses and types of antiepileptic drugs in use), treatment details (dose and type of PUFA), duration of treatment, follow-up assessment and outcomes. If details are not available in the published manuscript, we will contact the authors for more information.

Assessment of risk of bias in included studies

We will assess the risk of bias of the included studies according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess six specific domains: selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. Two independent review authors (Vasconcelos VS and Pedrosa AS) will judge each domain and categorise it as being at low, high or unclear risk of bias. We will compare scores and resolve discrepancies through discussion or the intervention of a third review author (Macedo CR).

Measures of treatment effect

We will assess the outcomes using risk ratio (RR) and absolute risk (AR) for dichotomous data, with their respective 95% confidence intervals (CIs). For continuous variables, we will calculate the mean difference (MD) or standard mean difference (SMD) and their 95% CIs.

Unit of analysis issues

The unit of analysis will be the individual participant (unit to be randomised for interventions to be compared). For trials comparing more than two intervention groups, we will assess the groups treated with PUFA supplementation compared to other treatment groups.

Dealing with missing data

We will use an intention-to-treat analysis.

Assessment of heterogeneity

We will assess both statistical and clinical heterogeneity among trials using the Chi2 test (P < 0.1) and the I2 statistic, interpreted according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).

Assessment of reporting biases

If at least 10 studies are included, we will assess reporting bias using a funnel plot.

Data synthesis

We will use the fixed-effect model for meta-analyses if studies are homogeneous. In cases of high heterogeneity between the studies, we will use the random-effects model.

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses if data are available: types of epilepsy, age categories, gender, different doses and types of PUFAs.

Sensitivity analysis

We will evaluate the robustness of the results of meta-analyses by comparing the fixed-effect and random-effects estimates, removing trials with low methodological quality and excluding trials with a large effect size.


We are grateful to the Cochrane Epilepsy Group for their support.


Appendix 1. MEDLINE search strategy

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2011).

1. exp Epilepsy/

2. exp Seizures/

3. (epilep$ or seizure$ or convuls$).tw.

4. 1 or 2 or 3

5. exp Pre-Eclampsia/ or exp Eclampsia/

6. 4 not 5

7. (randomized controlled trial or controlled clinical trial).pt. or (randomized or placebo or randomly).ab.

8. clinical trials as topic.sh.

9. trial.ti.

10. 7 or 8 or 9

11. exp animals/ not humans.sh.

12. 10 not 11

13. Omega-3 fatty acids.mp. or exp Fatty Acids, Omega-3/

14. (Eicosapentaenoic acid or docosahexaenoic acid).mp.

15. (Polyunsaturated fatty acids or n-3 PUFAs).ab,ti.

16. 13 or 14 or 15

17. 6 and 12 and 16

Contributions of authors

Maria Regina Torloni - drafting of protocol, screening and selection of studies, data extraction and quality assessment.

Cristiane R Macedo - drafting of protocol, search strategy, screening and selection of studies.

Vivian Sarmento de Vasconcelos - search strategy, drafting of protocol, screening and selection of studies, data extraction and quality assessment.

Edna Morais - screening and selection of studies, data extraction and quality assessment.

Alexsandra de Souza Pedrosa - screening and selection of studies, data extraction and quality assessment.

Declarations of interest


Sources of support

Internal sources

  • Brazilian Cochrane Centre, Brazil.

External sources

  • No sources of support supplied