Epilepsy: behavioural, psychological, and ketogenic diet treatments

Professor Helen Cross

. 2015 Jul 10;2015:1214.

Epilepsy: behavioural, psychological, and ketogenic diet treatments

Helen Cross ¹

PMCID: PMC4498503 PMID: 26161624

Abstract

Introduction

About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of behavioural and psychological treatments in people with epilepsy? What are the effects of ketogenic diets in people with epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version).

Results

Searching of electronic databases retrieved 259 studies. After deduplication and removal of conference abstracts, 253 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 208 studies and the further review of 45 full publications. Of the 45 full articles evaluated, six systematic reviews and seven RCTs were included at this update. We performed a GRADE evaluation for six PICO combinations.

Conclusions

In this systematic overview we categorised the efficacy for seven interventions, based on information relating to the effectiveness and safety of: biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, ketogenic diet, relaxation therapy (alone or plus behavioural modification therapy), and yoga.

Key Points

During their lifetime, about 3% of people will be diagnosed with epilepsy. First-line treatment in the majority is anticonvulsant medication; about 70% of people with epilepsy respond to medication, or in the longer-term go into spontaneous remission.

Alternative treatments for epilepsy are sought where medication fails and surgery is not an option.

We searched for good-quality RCTs on the effects of selected interventions.

We found few studies, many of which were small or short-term, and most of which were methodically weak.
There is a need for further high-quality trials in this field reporting longer-term outcomes.
However, the difficulties of undertaking trials, particularly in people with refractory epilepsy, should not be underestimated.

Educational programmes may improve some psychosocial functioning outcomes compared with control.

We found insufficient evidence to draw robust conclusions on the effects of CBT or of relaxation plus behavioural modification therapy.

We found no RCTs of sufficient quality on the effects of relaxation therapy, yoga, biofeedback (electroencephalographic or galvanic skin response), or family counselling.

We found evidence from two RCTs that a ketogenic diet or a modified-Atkins diet may improve seizure frequency compared with control in children aged 2 to 16 years who had tried at least two anticonvulsants and had at least daily seizures.

A ketogenic diet may be associated with gastrointestinal (constipation, hunger, vomiting, etc.) and other adverse effects, so continued monitoring is required.
There may also be issues of tolerability and family acceptance.
We found no RCTs in adults or any longer-term data.

We found five RCTs comparing different ketogenic diets, which were of varying methodological quality.

No two trials compared the same interventions in the same population.

Clinical context

General background

Increasingly, alternative therapies are being advocated in the treatment of epilepsy as complementary to medication. Furthermore, there is increasing interest in the use of the ketogenic diet in the treatment of epilepsy, particularly if the person is drug-resistant. The therapy is a high-fat, low-carbohydrate diet, designed to mimic the metabolic effects of starvation, that has been used in the treatment of epilepsy for almost 100 years. This, however, cannot be considered as a natural treatment as it may have side effects, as with any medication, and requires careful monitoring.

Focus of the review

This overview will focus on evidence for the use of alternative therapies in epilepsy, as well as the evidence of the efficacy and tolerability of ketogenic diets.

Comments on evidence

There is limited evidence for the use of alternative therapies in epilepsy, although they may be useful in combination with standard therapy. Evidence for the ketogenic diet as an additional anticonvulsant medication is good in children with resistant seizures that have not responded to at least two anticonvulsants, but there is little evidence for its use in adults.

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, July 2009, to April 2014. A search back-dated to 1966 was performed for the new options added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 259 studies. After deduplication and removal of conference abstracts, 253 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 208 studies and the further review of 45 full publications. Of the 45 full articles evaluated, six systematic reviews and seven RCTs were included at this update.

About this condition

Definition

Epilepsy should now be considered a group of disorders rather than a single disease. Seizures can be classified by type as focal (with or without evolution into a bilateral convulsive seizure, as with tonic clonic seizure) or generalised (categorised as generalised tonic clonic, absence, myoclonic, tonic, and atonic seizures). A person is considered to have epilepsy if they have had two or more unprovoked seizures. Accurate diagnosis is important both for epilepsy and for the type of epilepsy (epilepsy syndrome). Exact medication is based on the type of epilepsy and age of presentation, not only looking for the medication most likely to work but also avoiding aggravation of seizures.This review considers behavioural and psychological treatments of any epilepsy (generalised or focal). See also the separate related review on Epilepsy (generalised) for information on pharmacological and surgical treatments of generalised epilepsy. Status epilepticus is not covered in this review.

Incidence/ Prevalence

Epilepsy is common, with an estimated average prevalence of 5.5/1000 people in Europe, 6.8/1000 people in the US, and 7.5/1000 people in Australia. Prevalence rates in developing countries vary widely, with studies carried out in sub-Saharan Africa reporting rates of 5.2 to 74.4/1000 people, studies in Asia reporting overall prevalence rates of 1.5 to 14.0/1000 people, and studies in Latin America reporting rates of 17 to 22/1000 people. The annual incidence rates of epilepsy are 24 to 56/100,000 people in Europe, 44/100,000 in the US, 63 to 158/100,000 people in sub-Saharan Africa, 113 to 190/100,000 people in Latin America, and 28 to 60/100,000 people in Asia. The worldwide incidence of single unprovoked seizures is 23 to 61/100,000 person-years. About 3% of people will be diagnosed with epilepsy at some time in their lives.

Aetiology/ Risk factors

Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving the brain. The causes/risk factors include birth/neonatal injuries, genetic abnormalities, structural or metabolic disorders (including brain malformations), tumours, infections of the brain or meninges, head injuries, degenerative disease of the brain, or cerebrovascular disease. Epilepsy can be classified by cause. A re-organisation of the epilepsies has considered that, on a diagnosis of epilepsy, the syndrome should be diagnosed where possible. The cause may then be considered according to whether it is genetic, structural, metabolic, immune, infectious, or unknown.

Prognosis

About 60% of untreated people have no further seizures during the 2 years after their first unprovoked seizure; however, community-based studies have suggested a lower percentage. Prognosis is good for most people with epilepsy. About 70% go into remission, defined as being seizure-free for 5 years on or off treatment. This leaves 20% to 30% who develop chronic epilepsy, which is often treated with multiple anticonvulsant drugs.

Aims of intervention

To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; to improve quality of life; in people in remission, to withdraw anticonvulsant drugs without causing seizure recurrence; to minimise adverse effects of treatment, to reduce comorbidity, injury, and mortality.

Outcomes

For behavioural and psychological treatments: improvement in quality of life, including reduction in anxiety, depression, and fear of seizures; coping or adjustment to epilepsy (assessed by validated measures), psychosocial functioning; seizure frequency, including the proportion of responders (response defined as 50% reduction in seizure frequency) and percentage reduction in seizure frequency; adverse effects. For ketogenic diets: seizure frequency; quality of life; adverse effects.

Methods

Search strategy BMJ Clinical Evidence search and appraisal April 2014. Databases used to identify studies for this systematic review included: Medline 1966 to April 2014, Embase 1980 to April 2014, The Cochrane Database of Systematic Reviews 2014, issue 4 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, open-label or single-blinded, and containing 20 or more individuals (with a minimum of 10 participants in each arm), of whom more than 80% were followed up. There was a minimum length of 3 months follow-up from the start of treatment for reporting outcomes, but we reported longer-term outcomes when available. Many of the trials we found were of insufficient quality for this BMJ Clinical Evidence overview. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the BMJ Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for Epilepsy (behavioural, psychological, and ketogenic diet treatment)

Important outcomes	Seizure frequency, quality of life, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of behavioural and psychological treatments for people with epilepsy?
2 (57)	Seizure frequency	CBT v control	4	−2	0	−1	0	Very low	Quality points deducted for sparse data, and weak methods (uncertainty about randomisation/concealment); directness point deducted for baseline differences between groups
4 (167)	Quality of life	CBT v control	4	−3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and weak methods (uncertainty about randomisation/concealment)
1 (37)	Quality of life	CBT v relaxation	4	−3	0	−1	0	Very low	Quality points deducted for sparse data, weak methods (blinding), and incomplete reporting of results; directness point deducted for restricted population (60 years or above)
2 (396)	Quality of life	Educational programmes v control	4	−2	0	−1	0	Very low	Quality points deducted for unclear randomisation, and lack of blinding; directness point deducted for non-standard intervention in 1 RCT (locally developed intervention, also printed module of unclear status given to both groups)
What are the effects of ketogenic diet for people with epilepsy?
2 (247)	Seizure frequency	Ketogenic diet v placebo or control	4	−2	0	0	0	Low	Quality points deducted for lack of blinding and high attrition
5 (327)	Seizure frequency	Different ketogenic diets v each other	4	−3	0	0	0	Very low	Quality points deducted for weak methods (randomisation, blinding, allocation concealment), incomplete reporting of results, and high attrition rates

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Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Atonic seizure: Momentary loss of limb muscle tone causing sudden falling to the ground or droping of the head.
Beck Depression Inventory: Standardised scale to assess depression. This instrument consists of 21 items to assess the intensity of depression. Each item is a list of 4 statements (rated 0, 1, 2, or 3), arranged in increasing severity, about a particular symptom of depression. The range of scores possible are 0 = least severe depression to 63 = most severe depression. It is recommended for people aged 13 to 80 years. Scores of more than 12 or 13 indicate the presence of depression.
Centers for Epidemiological Studies Depression (CES-D) Scale: 20-item 4-point Likert scale, with scores that range from 0 to 60. Higher scores indicate more symptoms of depression.
Cognitive behavioural therapy: A broad category of interventions designed to identify and control stress and minimise its effects, often by using intellectual experience to correct damaging thoughts and behaviour.
Crown Crisp Experiential Index: Formerly known as Middlesex Hospital Questionnaire (MHQ), this is a self-reported questionnaire providing information on psychoneurotic traits. It comprises 48 items with an overall score for neuroticism, with further subscores for free-floating anxiety, phobic anxiety, obsessionality, somatic anxiety, depression, and hysterical anxiety. A higher score indicates more overall neurotic disorder.
Electroencephalographic (EEG) biofeedback: A technique of making EEG activity apparent to a person, who is then taught to produce certain EEG waves that are believed to increase the threshold for seizures.
Hamilton Depression Rating Scale: a measure of depressive symptoms using 17 items, with total scores from 0 to 54 (higher scores indicate increased severity of depression).
Ketogenic diet: A high-fat, low-carbohydrate diet used in the management of epilepsy.
Low-quality evidence: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Minnesota Multiphasic Personality Inventory (MMPI): A battery of standardised tests to assess personality (psychopathology).
Relaxation therapy: Techniques to train people to control muscle tension.
SF-36 score: A scale that assesses health related quality of life across eight domains: limitations in physical activities (physical component); limitations in social activities; limitations in usual role activities because of physical problems; pain; psychological distress and wellbeing (mental health component); limitations in usual role activities because of emotional problems; energy and fatigue; and general health perceptions.
Tonic clonic seizure: Also known as a convulsion or previously as a 'grand mal' attack. The person will become stiff (tonic) and collapse, and have generalised jerking (clonic) movements. Breathing might stop and the bladder might empty. Generalised jerking movements lasting typically for a few minutes are followed by relaxation and deep unconsciousness, before the person slowly comes round. People are often tired and confused, and may remember nothing. Tonic clonic seizures may follow focal seizures. Tonic clonic seizures occurring without warning and in the context of generalised epilepsy are classified as generalised tonic clonic seizures.
Very low-quality evidence: Any estimate of effect is very uncertain.
Washington Psychosocial Inventory (WPSI): A standardised battery of tests to assess adjustment in various spheres (measure of psychosocial difficulties) in people with epilepsy.

Pharmacological and surgical treatments of generalised epilepsy, see overview on Epilepsy (generalised). Treatment of typical absence seizures in children, see overview on Absence seizures in children.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2015 Jul 10;2015:1214.

Biofeedback

Summary

We don't know whether biofeedback is more effective than placebo or control as we found no RCTs of sufficient quality.

Benefits

Electroencephalographic biofeedback versus placebo or control:

We found one systematic review (search date 2011), which identified one three-armed controlled trial (24 adults, including 15 men, with uncontrolled epilepsy) of electroencephalographic biofeedback compared with control treatment. The trial did not fulfil the inclusion criteria for this BMJ Clinical Evidence overview (see Comment). We found one further systematic review (search date 2005), which found no further RCTs. We found no subsequent RCTs.

Galvanic skin response biofeedback versus placebo or control:

We found one systematic review (search date 2011), which found no RCTs of sufficient quality (see Comment). We found no subsequent RCTs.

Harms

Electroencephalographic biofeedback versus control:

We found no RCTs.

Galvanic skin response biofeedback versus control:

We found no RCTs.

Comment

Electroencephalographic biofeedback

The trial compared three treatments: electroencephalographic biofeedback, sham (non-contingent) feedback, and no intervention (8 people in each group). It was below the minimum inclusion criteria of this BMJ Clinical Evidence overview of 10 people per treatment arm. The RCT found a significant reduction in seizure frequency compared with the baseline frequency in people given biofeedback (median seizure reduction with biofeedback 61% v baseline; P <0.005).

The RCT did not provide data about seizure frequency in the control group. The review was, therefore, unable to compare the electroencephalographic-biofeedback and control groups. The study was not blinded and the randomisation method was not clear. The duration of follow-up was only 6 weeks. The evidence is insufficient to draw reliable conclusions about the effects of electroencephalographic biofeedback.

Galvanic skin response biofeedback

The review found one further single-blinded RCT (18 people), which compared galvanic response biofeedback with sham biofeedback. Ten people were randomised to biofeedback and eight people to control. Three people withdrew from the control group. We have, therefore, not reported the RCT further.

Clinical guide

There is insufficient evidence to confirm or refute the use of biofeedback in the management of epilepsy.

Substantive changes

Biofeedback One systematic review updated and one further systematic review added. Existing evidence re-evaluated. Categorisation unchanged (unknown effectiveness).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Cognitive behavioural therapy

Summary

SEIZURE FREQUENCY CBT compared with placebo or control: We don't know whether CBT is more effective than general supportive therapy or no CBT at reducing seizure frequency in adults with refractory epilepsy/inadequate seizure control ( very low-quality evidence ). QUALITY OF LIFE CBT compared with control: We don't know whether CBT is more effective than control at improving pyschosocial functioning or quality-of-life measures at up to 1 year in adults, as we found insufficient and inconsistent evidence from small RCTs (very low-quality evidence). CBT compared with relaxation: We don't know if CBT and relaxation therapy differ in effectiveness at improving outcomes (measured by CIDI-Auto and GDS) at 3 months in adults aged 60 years and older (very low-quality evidence).

Benefits

Cognitive behavioural therapy (CBT) versus control:

We found two systematic reviews (search date 2011; and 2012).

Seizure frequency:

The first systematic review identified two RCTs comparing CBT with control treatments, which examined seizure frequency. The second review did not report on seizure frequency.

The first RCT (30 adults with significant psychological problems and inadequate seizure control, as judged by the treating neurologist) included in the review was a three-armed unblinded trial comparing group CBT with supportive counselling control and with no intervention for 8 weeks. It found no significant difference between CBT and either supportive counselling control or no treatment in reduction in seizure frequency (proportion of people with >67% reduction in seizure frequency: 1/10 [10%] with CBT v 2/10 [20%] with supportive counselling v 1/10 [10%] with control; CBT v supportive counselling OR 0.47, 95% CI 0.04 to 5.19; CBT v no treatment OR 1.00, 95% CI 0.06 to 17.25). However, the RCT was too small to detect a clinically important difference. The method of randomisation and allocation concealment was not clear, and the review noted that there was a considerable variation in mean baseline weekly seizure frequencies between groups.

The second RCT included in the review (27 adults, aged 21–55 years, refractory epilepsy, 4 seizures/3 months) compared acceptance and commitment therapy (ACT, which is developed from the same theory of learning as CBT) with supportive therapy (people instructed to reflect on their lives and problems in a non-judgemental, empathic, and accepting environment, without any active advice). The RCT found that ACT significantly reduced frequency of seizures at 6 and at 12 months' follow-up compared with supportive therapy (27 people in analysis, mean at 6 months: 0.7 with ACT v 5.86 with supportive therapy, mean difference –5.16, 95% CI –7.18 to –3.14, P <0.00001; at 12 months: 0.62 with ACT v 5.8 with supportive therapy; mean difference –5.18, 95% CI –7.14 to –3.22; P <0.0001). The review noted that the results were difficult to interpret as the data were skewed.

Psychosocial functioning:

The first review identified four RCTs assessing the effects of CBT on psychosocial functioning. One of these RCTs (15 people with epilepsy and depression) did not meet our inclusion criteria and is not discussed further.

The first RCT (30 adults with significant psychological problems and inadequate seizure control, as judged by the treating neurologist) included in the review found no significant difference between CBT and control treatments in various psychological scales, such as the Washington Psychosocial Inventory, the Minnesota Multiphasic Personality Inventory, and the Beck Depression Inventory (reported as no significant difference, P values not reported).

The second RCT (27 adults, 21–55 years, refractory epilepsy, 4 seizures/3 months) found that CBT significantly improved quality-of-life scores (measured on the WHO Quality of Life [WHOQOL-BREF] scale and the satisfaction with life scale [SWLS]) at 6 months and at 12 months compared with supportive therapy (mean WHOQOL-BREF scores at 6 months: 61.21 with CBT v 56.08 with supportive therapy; P <0.001; mean SWLS scores: 27.07 with CBT v 14.46 with supportive therapy; P <0.001; mean WHOQOL-BREF scores at 12 months: 66.07 with CBT v 51.85 with supportive therapy; P <0.001; mean SWLS scores: 27.07 with ACT v 15.77 with supportive therapy; P <0.001).

The third RCT (30 people, 13–19 years, newly diagnosed epilepsy and with sub-threshold depression) compared CBT with treatment with counselling as usual (TAU). Assessments were made at baseline, and at 6 and at 9 months, using the Beck Depression inventory (BDI), the Center for Epidemiological Study on depression (CES-D), the Hamilton Depression Scale (HAMD), and the Quality-of-Life Epilepsy Inventory Total Scores (QOLIE-31 Total). The RCT found that CBT significantly improved subthreshold depression compared with TAU during follow-up ([higher QOLIE-31 Total scores, and lower BDI and CES-D scores, indicate an improvement]; mean BDI scores at 9 months: 5.60 with CBT v 7.70 with TAU; CES-D scores at 9 months: 10.5 with CBT v 13.8 with TAU; QOLIE-31 Total scores at 9 months: 56.40 with CBT v 42.23 with TAU; P <0.05 between the two groups for all comparisons). The RCT found that depression was diagnosed in three people in the TAU group and none in the CBT group after 7 to 9 months (reported as not significant; P value not reported).

CBT versus relaxation:

We found one systematic review (search date 2012), which included one RCT (37 people, 60 years or older) comparing group CBT with relaxation (6 weekly sessions of 2 hours each; focused on seizure control). The review reported that it found no significant difference between groups in Composite International Diagnostic Interview-Computerised (CIDI-Auto) for a diagnosis of depression and dysthymia or Geriatric Depression Scale at 3 months (reported as no significant difference, absolute numbers not reported, P value not reported). The review did not report on seizure control.

Harms

The reviews gave no information on harms.

Comment

Publication bias cannot be excluded. The evidence is insufficient to define the effects of CBT in people with epilepsy.

Seizure frequency

One review found one further RCT comparing ACT with yoga. The trial was below the minimum inclusion criteria for this BMJ Clinical Evidence overview (18 people).

Psychosocial functioning

The second review found five RCTs comparing CBT with usual care for depression in people with epilepsy. Three RCTs were also in the first review. The fourth had a drop-out rate of 36%, so this is not reported further. The fifth included RCT (80 people, mean age 43 years, with a formal diagnosis of depression) compared group CBT (8 individual hourly visits over 19 weeks, focused on depression) with usual care. It found a significant difference on two measures at 12 months (Hopkins Symptom Checklist: P = 0.003; suicide items: P = 0.025), and no significant difference on both measures at 18 months (absolute numbers not reported, P values not reported).

Clinical guide

Evidence is weak with regard to determining the effect of CBT on seizures. However, there may be an effect on psychosocial functioning, specifically the risk of depression.

Substantive changes

Cognitive behavioural therapy One systematic review updated and one systematic review added. Categorisation unchanged (unknown effectiveness).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Educational programmes

Summary

QUALITY OF LIFE Educational programmes compared with control: Educational programmes may be more effective than control at improving some outcomes (such as knowledge about what to do, improved competencies, improved participation in activities, reduced anxieties, and AKA scores) in children and adults aged 7 years and above at 3 to 5 months, but we don't know about quality-of-life scores ( very low-quality evidence ). NOTE: We found no direct evidence from RCTs of sufficient quality on the effects of educational programmes compared with control on seizure outcomes.

Benefits

Educational programmes versus control:

We found two systematic reviews (search date 2011; and 2010). The first systematic review included three RCTs and one quasi-randomised trial). Only the second included RCT was of sufficient quality for this BMJ Clinical Evidence overview (see Comment). The second systematic review found no further RCTs. We found one subsequent RCT (see Comment). In addition, we found three further subsequent RCTs, which were not of sufficient quality for this BMJ Clinical Evidence overview (see Comment).

The second unblinded RCT included in the review (252 children aged 7–14 years) found that a child-centred, family-focused educational programme significantly improved questionnaire responses compared with control intervention (knowledge about what to do during a seizure [no objects in mouth, P = 0.002; do not restrain, P = 0.001], purpose of the electroencephalographic examination [P = 0.02], and minimal restriction in activities [P = 0.001]), increased the proportion of children likely to participate in normal activities (P <0.03), improved perceived academic and social competencies of the children (P <0.05), and reduced the anxiety of parents (see Comment) at 5 months.

The first subsequent RCT (144 people with epilepsy, aged 18 or older [mean 31 years], on regular treatment, most generalised seizures [51%]) compared an SMS-based mobile epilepsy education system with a control group in Malaysia. Both groups received a printed epilepsy education module and user manual. The intervention group also received a locally developed Mobile Epilepsy Education System (MEES) based on the Modular Service Package for Epilepsy (MOSES), delivered via text messaging (SMS). The RCT found that MEES significantly improved outcomes (measured by Malay Awareness, Knowledge, and Attitude Epilepsy Form [AKA]) compared with control at 3 months (136 people, total AKA score [range 0–170]: mean score: 7.3 with MEES v 6.2 with control, P <0.01). The RCT found that MEES significantly improved all three individual domains compared with control (awareness, P <0.01; knowledge, P <0.05; attitudes, P <0.05). It found no significant difference between groups in treatment adherence (136 people, adherence score [range 0–1]: mean score: 0.80 with MEES v 0.83 with control, P >0.05)

Harms

Educational programmes versus control:

The following references gave no information on adverse effects.

Comment

The first RCT included in the review (43 adults of 100 initially randomised, including 28 women; 38 people completed study) found that a specific 2-day educational programme significantly improved responses to a 50-item true/false questionnaire compared with control intervention (overall understanding of epilepsy, significant decrease in fear of seizures, significant decrease in hazardous medical self-management) and significantly improved compliance with current medication (shown by serum anticonvulsant drug levels).

The third RCT (242 people out of 383 initially randomised aged 16–80 years, 57% women) included in the review reported on seizure frequency. It found that a 2-day educational programme significantly reduced seizure frequency at 6 months compared with waiting list control (proportion of people with at least 2-point reduction in seizure frequency on a 6-point scale [0 = no seizures in last 6 months, 5 = at least 1 seizure daily]: 19% with education v 7% with control; P value not reported). However, the clinical importance of this effect is unclear. It found that a 2-day educational programme had no significant effect on SF-36 questionnaire scores 6 months after the programme compared with waiting list control (SF-36 mental health component score: 43.7 with educational package v 42.5 with control; P value not reported; SF-36 physical component score: 50.4 with educational package v 52.0 with control; P value not reported). Scales validated using the study population revealed significant improvement in epilepsy knowledge and coping with epilepsy.

The fourth quasi-randomised trial in the review (30 adults, number of women not stated) compared a 2-day modular didactic psycho-educational programme on adjustment to epilepsy, stigma, psychoneurotic traits, depression, and knowledge about epilepsy with waiting list control. It found that the educational programme significantly improved depression and neurotic disorders at 2 months compared with control (change in depression measured using Beck Depression Inventory scores: from 15.0 at baseline to 1.5 with psycho-educational programme v from 15.1 at baseline to 10.0 with control; P <0.0001; neurotic disorders assessed using change in Crown Crisp Experiential Index scores: from 36.4 at baseline to 7.3 with psycho-educational programme v from 35.6 at baseline to 34.1 with control; P <0.0001).

All of the RCTs included in the first review had weak methods. In the second RCT included in the review, randomisation was by random number assignment, but only a proportion of medical records were available to the authors (65% in the psycho-educational programme group v 47% in the control group). In the first RCT, the method of randomisation was not reported. A minority of the people in the first RCT actively participated in the interventions (23/50 [46%] in the psycho-educational programme group v 20/50 [40%] in the control group) or completed the study (20/50 [40%] in the psycho-educational programme group v 18/50 [36%] in the control group). In the third RCT, the method of randomisation was not reported, and, among 383 people randomised, 63% (242 people in total; 113 in the psycho-educational programme group and 119 in the control group) completed the study. The RCT reported that there was a significant difference between groups in duration of epilepsy (P = 0.034) and the control group had a longer duration of epilepsy (median: 18.2 years with control v 13.5 years with educational intervention). In the fourth RCT, randomisation was by alternate allocation (allocated "on alternate first come basis"). It reported that people "were matched according to seizure type and frequency of seizures", but this was not further explained. Outcome assessment was at 2 months.

The interventions used in these studies were similar, but there was some variation, which is outlined below. The first RCT used the Sepulveda Epilepsy Education programme — a 2-day psycho-educational treatment programme designed to provide medical education and psychosocial therapy. In the second RCT, children with epilepsy and their parents attended four 1.5-hour sessions at weekly intervals. The children's sessions included: understanding body messages and how seizures occur; controlling seizures with medication; straightforward methods of talking about seizures; and coping and adapting to epilepsy. The third RCT used MOSES (Modular service package Epilepsy), a programme developed for use in German-speaking countries. It included nine units: living with epilepsy, epidemiology, basic knowledge, diagnostics, therapy, self-control, prognosis, psychosocial aspects, and network. The programme was delivered in 14 hours over 2 days. The fourth RCT used a 2-day modular, didactic, psychoeducational programme, which comprised preliminary assessment and establishment of rapport on day 1 and a didactic modular educational session (covering background information, diagnosis and management of epilepsy, day-to-day adjustments, seizure control, and stigma), with time for group discussions and clarifications, on day 2.

The first subsequent RCT did not state the method of randomisation, the level of blinding was not described, and follow-up was by telephone. It was not clear whether the printed epilepsy module given to both groups was part of usual care, although it described the printed modules as "conventional epilepsy education".

We found one further subsequent RCT, which compared a 1-day health education programme in rural Kenya with no education programme. Its primary outcome was adherence to treatment, but it also reported on seizure frequency. It analysed data for 581/738 (79%) of people randomised. People included were described as having active convulsive epilepsy, defined as at least two unprovoked convulsions, with one in the previous 12 months (further details on diagnosis of epilepsy not reported, about 35%–37% of people on polytherapy, seizure frequency last 3 months: none, 284 people; 1–3, 167 people; 4–6, 52 people; >6, 78 people). The RCT noted that one district hospital supplied phenobarbital, phenytoin, carbamazepine, and sodium valproate, while 13 health clinics stocked only phenobarbital. The intervention was randomised to the participant and designated caregiver, but not to 51 traditional healers and 14 health providers (nurses and clinical officers) from local health facilities who also received an educational intervention. It found no significant difference between groups in less-frequent seizures (defined as 0–3 in last 3 months) at 1 year (243/303 [80%] with education programme v 208/278 [75%] with no intervention; P = 0.12).

Another subsequent RCT compared an online epilepsy self-management programme (WebEase) with a waiting list control group. However, the control group also received the intervention after 6 weeks, so at 12 weeks' follow-up both groups had received the intervention.

A further subsequent RCT (66 people with epilepsy, aged 18–53 years) compared a 1-month self-management educational programme with usual care. Outcomes were measured on the Epilepsy Self-Management Scale (ESMS; 38 items). It did not report outcomes at 3 months or longer. However, the RCT found significantly higher self-management scores with the programme compared with usual care at 1 month after completion of the programme (reported as P <0.001, unclear as to what data this P value relates to).

Clinical guide

There is some evidence that educational programmes targeted at increasing knowledge about epilepsy improve measures of quality of life as well as seizure frequency.

Substantive changes

Educational programmes One systematic review updated, another systematic review added, and one RCT added. Existing evidence re-evaluated. Categorisation unchanged (likely to be beneficial).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Family counselling

Summary

We found no RCTs of sufficient quality on the effects of family counselling in people with epilepsy.

Benefits

Family counselling versus control:

We found one systematic review (search date 2011), which found no RCTs (see Comment). We found no subsequent RCTs.

Harms

Family counselling versus control:

We found no RCTs.

Comment

The systematic review mentioned one small RCT (36 adults, including 26 men, with epilepsy and job loss), which it excluded for weak methods. It compared three interventions: family therapy (no detailed description, but it seems that the family was present for discussion of problems for a mean of 7.8 sessions), one family session (in which information about the seizure profile was given), and usual care (vocational assistance in obtaining a job, with no follow-up other than site visit). It did not report on seizure frequencies, but found a significantly improved psychosocial inventory score with family therapy (Washington Psychosocial Inventory, 27 completers: improved perceived acceptance by family, emotional adjustment, interpersonal adjustment, adjustment to seizures, and overall psychosocial function). It found a trend towards improvement in job stability.

The method of concealment of randomisation was not described in the RCT. Nine of the 36 people (25%) did not complete the study, and withdrawal was uneven across the groups (2 with family therapy, 6 with 1 family session, 1 with no intervention). The available evidence is insufficient to define the effects of family counselling.

Clinical guide

There is no evidence that family therapy leads to any benefit in seizure control. It may, however, improve psychosocial functioning, although data are weak.

Substantive changes

Family counselling One systematic review added. Existing evidence re-evaluated. Categorisation unchanged (unknown effectiveness).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Relaxation therapy

Summary

QUALITY OF LIFE Relaxation therapy compared with CBT: We don't know if relaxation therapy and CBT differ in effectiveness at improving outcomes (measured by CIDI-Auto and GDS) at 3 months in adults aged 60 years and older ( very low-quality evidence ). NOTE: We don't know whether relaxation therapy is more effective than placebo or control as we found no RCTs of sufficient quality.

Benefits

Relaxation therapy versus placebo or control:

We found one systematic review (search date 2011, three small open-label controlled trials, 50 adults in total, including 32 women), which reported on seizure frequency. The trials used weak methods and none fulfilled the inclusion criteria for this BMJ Clinical Evidence overview (see Comment). We found no subsequent RCTs.

Relaxation therapy versus CBT:

See option on CBT.

Harms

Relaxation therapy versus placebo or control:

We found no RCTs.

Comment

In one included trial there were only six participants per group, another included trial had only four participants per group, and the remaining trial used alternating blocks to allocate participants. Two of the studies found a non-significant reduction in seizure frequency (50% or greater reduction) with relaxation therapy compared with no relaxation therapy, and one study found a significantly reduced seizure frequency. The RCTs gave no information on adverse effects. The weak methods preclude reliable conclusions.

All three trials used weak methods. The treatment allocation methods were strict alternation, alternation in blocks of five, or were not reported. The baseline seizure frequency varied considerably among the allocated groups in all of the trials. In one RCT, the review reported that the baseline seizure frequency was 17 with relaxation and 10 with control (units not reported, P value not reported). In this trial, two people in the treatment group had new anticonvulsant medication added during the study period, and one of these had a greater than 50% reduction in seizure frequency; another person discontinued anticonvulsant medication. Anticonvulsant drug treatment was also adjusted during the trial, making it difficult to conclude whether the observed results were due to changes in drug treatment or due to the intervention. The possibility of publication bias cannot be excluded.

One further study included in the review (32 people, alternate allocation, age and gender not reported) compared progressive relaxation training with no training and reported on psychosocial functioning. However, only 16/32 (50%) of people completed the 6-month study, so we have not reported it further. The effects of relaxation therapy remain unclear. The limited duration for which people sustained the therapy suggests that it is unlikely to be of clinical benefit.

Clinical guide

There is insufficient evidence to suggest that relaxation training has a positive effect on epilepsy; the high drop-out rate suggests that it is unlikely to be sustainable.

Substantive changes

Relaxation therapy One systematic review updated and one systematic review added. Existing evidence re-evaluated. Categorisation unchanged (unknown effectiveness).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Relaxation plus behavioural modification therapy

Summary

We found no evidence of sufficient quality from one RCT on the effects of combined relaxation plus behavioural modification therapy compared with control on seizure or quality of life outcomes.

Benefits

Relaxation plus behavioural modification therapy compared with control:

We found one systematic review (search date 2011), which identified two RCTs comparing relaxation plus behavioural modification therapy with control. The first small RCT (18 children with uncontrolled epilepsy) compared three interventions for 6 weeks. This RCT is not discussed further as it did not meet our inclusion criteria. The second RCT (150 adults with uncontrolled epilepsy) compared Jacobson's muscle relaxation plus behavioural therapy with control treatment (allocated in a 2:1 ratio).

Seizure frequency:

The second RCT reported separately the mean seizure frequencies for each seizure type but did not specify the number in each category. It reported separately the mean seizure frequencies for those people with fewer than 20 seizures/month and those with more than 20 seizures/month at baseline. The review reported that the data were skewed and it was, therefore, unable to undertake an analysis of these data.

Psychological outcomes:

The second RCT found that relaxation plus behavioural modification therapy (conditioning, desensitisation, aversion, assertiveness training, and supportive psychotherapy) significantly improved state anxiety, trait anxiety, and adjustment (home, health, social and emotional; absolute numbers not reported for any analysis, P values not reported). However, the review reported that psychological outcomes were only available for 88 people (59/100 [59%] with intervention v 29/50 [58%] with control), which is below the minimum inclusion criteria for this review.

Harms

Relaxation plus behavioural modification therapy compared with control:

The review gave no information on adverse effects.

Comment

The reporting in the review in the second included RCT (150 people) was based on unpublished data from a PhD thesis in 1987. The review reported that baseline, treatment, and follow-up phases were not clear, the trial was unblinded, and there was no allocation concealment.

It is possible that the results of the psychological interventions on psychosocial functioning may depend on the baseline personalities of the people included in the study, and on their education and intelligence.

Clinical guide

It is likely that benefit from relaxation therapy is likely to depend on the individual, underlying comorbidity, and type of epilepsy. The evidence available does not give a clearer view as to who may benefit.

Substantive changes

Relaxation plus behavioural modification therapy One systematic review updated. Existing evidence re-appraised. Categorisation unchanged (unknown effectiveness).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Yoga

Summary

We don't know whether yoga is more effective than placebo or control as we found no RCTs of sufficient quality.

Benefits

Yoga versus placebo or control:

We found one systematic review (search date 2011, 1 quasi-randomised trial, 32 adults, including 30 women). The trial did not fulfil the inclusion criteria for this BMJ Clinical Evidence overview (see Comment). We found no subsequent RCTs.

Harms

Yoga versus placebo or control:

We found no RCTs.

Comment

The unblinded trial divided people into three groups by rolling a dice, and allocation concealment was unclear. The trial compared sahaja yoga (10 people) with control (sham yoga [10 people], and no intervention [12 people]). It found that yoga reduced seizure frequency compared with control, but it used weak methods, which precludes reliable conclusions. The baseline seizure frequency and duration varied among the groups, making results difficult to interpret. The review noted that the mean age, mean duration of epilepsy, and the baseline seizure frequencies were lower in the no-treatment group (mean age: 24.6 years in yoga group v 23.7 years in control group v 19.7 years with no intervention; mean illness duration: 7.3 years v 5.6 years v 4.2 years; baseline seizure frequency [attacks per month]: 3.2 v 3.0 v 2.6). The review reported that there was a significant baseline difference between the yoga and no-treatment groups for seizure duration (P = 0.023) and seizure frequency (P = 0.043), and the durations of epilepsy in the three groups were not comparable. The trial gave no information on adverse effects.

The review included one further RCT comparing acceptance and commitment therapy (ACT) with yoga, but the yoga group only included eight participants, which is below the minimum inclusion criteria for this BMJ Clinical Evidence overview (10 people per treatment arm).

The review concluded that no reliable conclusions could be drawn currently regarding the efficacy of yoga as a treatment for epilepsy. Although no definitive benefit has been demonstrated, no particular harm is rendered by participation in such an intervention.

Clinical guide

Although no evidence has been provided about the benefit of yoga, there is no evidence to suggest that it cannot be used as a complementary therapy to conventional therapy. No assessment has been made as to its effectiveness versus anticonvulsant medication.

Substantive changes

Yoga One systematic review updated. Existing evidence re-evaluated. Categorisation unchanged (unknown effectiveness).

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Ketogenic diet versus no change to treatment

Summary

Ketogenic diet compared to no change in treatment: A ketogenic diet /modified Atkins diet may be more effective than no change in treatment at increasing the proportion of participants with more than 50% seizure reduction at 3 months in children aged 2 to 16 years with at least daily seizures that have not responded to at least two anticonvulsants. We found no evidence in adults and no good evidence on longer-term effects ( low-quality evidence ). NOTE: Ketogenic diets may be associated with gastrointestinal and other adverse effects. We found no RCTs in adults or trials reporting longer-term outcomes.

Benefits

Ketogenic diet versus no change in treatment:

We found one systematic review (search date 2011), which included one RCT. We found one subsequent RCT. We have reported the RCT included in the review directly from the original report. Both RCTs were undertaken in children. We found no RCT in adults.

The RCT included in the review (145 children aged 2–16 years, seizures at least daily or >7 seizures per week, not responded to at least 2 anticonvulsants) compared either classic (LCT; 37 children) or medium-chain triglyceride (MCT) (36 children) diet with control (normal diet with no dietetic input). All ketogenic diets were calculated on an individual basis. The RCT reported that 78 children had epilepsy characterised by generalised seizures and 57 children had focal sizures, and most were on two medications (53 children) or three medications (54 children). The RCT found that ketogenic diet significantly increased the proportion of children with more than 50% seizure reduction at 3 months (28/73 [38%] with diet v 4/72 [6%] with no change in treatment, P <0.0001). It found no significant difference between groups in the proportion of children with more than 90% seizure reduction at 3 months (5/73 [7%] with diet v 0/72 [0%] with no change in treatment, P = 0.0582).

The subsequent RCT (102 children aged 2–14 years [mean age about 5 years], 50% with Lennox-Gastaut syndrome and 19% with West syndrome, seizures at least daily or >7 seizures per week, on median of three anticonvulsants) compared a modified Atkins diet with no change in treatment (normal diet with no additional dietary input). Most children had tonic (48 children), myoclonic (47 children), and atonic (27 children) seizure types, among others. The RCT found that the modified Atkins diet significantly increased the proportion of children with more than 50% seizure reduction at 3 months (102 children, 52% with diet v 11.5% with control, absolute numbers not reported, P <0.001). It also found that the modified Atkins diet significantly increased the proportion of children with greater than 90% seizure control at 3 months (102 children, 30% with diet v 7.7% with control, absolute numbers not reported, P = 0.005).

Harms

Ketogenic diet versus no change in treatment:

The RCT included in the first review reported that adverse effects in the diet group included hunger (12/55 [22%]), vomiting (13/55 [24%]), diarrhoea (7/55 [13%]), abdominal pain (5/55 [9%]), constipation (18/55 [33%]), and lethargy (13/55 [24%]; comparative figures for control group not reported).

The subsequent RCT reported that constipation was the most common adverse effect among children on the diet (23/50 [46%]). Other adverse effects on the diet included anorexia (18%), lethargy (6%), and vomiting (10%). Two children developed frequent chest infections, and one child developed hyperammonaemic encephalopathy 1 week after starting the diet. This child had refractory seizures of unknown aetiology. In these three children, the diet was discontinued. The patient with hyperammonaemic encephalopathy improved after discontinuation of the diet. Comparative adverse effects data for the control group were not reported.

Comment

Methods

The RCT included in the review was unblinded. Although an intention-to-treat analysis was presented, results at 3 months were based on 103/145 (71%) of children randomised. After randomisation, eight children in each group did not receive the dietary treatment, most (10 cases) due to changing their mind. Of the 65 children who received the diet, 10 discontinued, six for poor tolerance of the diet, three for parental unhappiness, and one for seizure increase, and one was excluded owing to inadequate data. Of 65 children in the control group, 15 were excluded owing to inadequate data.

The subsequent RCT was unblinded, and outcome assessment was not masked. Four children discontinued with diet, and three children with control. The RCT included children with epilepsy syndromes.

Both trials noted that the use of parental or career seizure records ran the risk of missing nocturnal seizures and introducing subjective errors. We found no good evidence on outcomes beyond 3 months.

Clinical guide

The evidence suggests that ketogenic diet therapy shows effectiveness over no change in treatment in children resistant to anticonvulsant drug therapy. Children should be referred for consideration of a ketogenic diet when seizures continue despite two anticonvulsant drugs.

Substantive changes

Ketogenic diet versus no change in treatment New option. We found one systematic review and one subsequent RCT. Categorised as 'likely to be beneficial'.

BMJ Clin Evid. 2015 Jul 10;2015:1214.

Different ketogenic diet therapies versus each other

Summary

SEIZURE FREQUENCY Different implementation methods of ketogenic diet therapies compared to each other: We don't know whether one type of ketogenic diet is consistently more effective than all other types at achieving more than 50% reduction in seizures after 3 months in children aged 6 months to 18 years with refractory epilepsy who had tried at least two anticonvulsants. We found no evidence in adults, and no good evidence on longer-term effects ( very low-quality evidence ).

Benefits

Different implementation methods of ketogenic diet therapies versus each other:

We found one systematic review (search date 2011), which included four RCTs. We found one subsequent RCT. The review reported that meta-analysis could not be conducted due to heterogeneity of the studies. We have reported the RCTs included in the review directly from their original reports. The RCTs varied in quality, and were all undertaken in children. We found no RCT in adults.

The first included RCT (48 children, aged 1–14 years [mean age 5.3 years], one or more seizure per 28 days, in whom at least 3 anticonvulsants had failed) compared two different initiation regimens: a fasting ketogenic diet initiation (FAST-KD) or a non-fasting gradual ketogenic diet initiation (GRAD-KD). About 48% of children had generalised seizures, and 52% had partial seizures. The trial tested that outcome rates were no further apart than a pre-specified difference, and did not directly test significance between groups. It reported that the proportion of children with a more than 50% reduction in seizures at 3 months was 58% with FAST-KD versus 67% with GRAD-KD. It reported that the proportion of children with more than 90% reduction in seizures at 3 months was 29% with FAST-KD versus 46% with GRAD-KD; non-significant.

The second included cross-over RCT (20 children, age 3–18 years [mean age 7.5–9.8 years], seizure frequency per week 41–55, mean of 2 current anticonvulsants, 35% with partial seizures) compared two modified Atkins diets (initial of 10 g carbohydrate or initial of 20 g carbohydrate). The RCT reported that causes included idiopathic (15 participants), Rett syndrome (2 participants), and cortical dysplasia (2 participants), among others, and that 13 participants had either generalised or multifocal epilepsy. We have only reported pre-crossover results (see Comment). The RCT found that the initial 10 g diet significantly increased the proportion of children with a more than 50% seizure reduction compared with the initial 20 g diet at 3 months (6/10 [60%] with initial 10 g diet v 1/10 [10%] with initial 20 g diet, P = 0.03). It found no significant difference between groups in the proportion of children who had a greater than 90% reduction in seizures at 3 months (3/10 [30%] with initial 10 g diet v 0/10 [0%] with initial 20 g diet, P = 0.10; see Comment).

The third included RCT (76 children, 4 months–16 years [mean age 44–51 months], mean daily seizure frequency 10.3, seizures not controlled by at least 3 anticonvulsants) compared two ketogenic diets with lipid:nonlipid ratios of 3:1 and 4:1 (non-fasting protocol). In total, 30 participants had infantile spasms, 21 participants had Lennox-Gastaut syndrome, 17 participants had partial seizures, and eight participants had generalised seizures. We have reported outcomes at 3 months (see Comment). The RCT reported that the proportion of participants who were seizure-free at 3 months was 22/40 (55%) with the 4:1 diet versus 11/36 (31%) with 3:1 diet, and a seizure reduction of more than 90% was observed in 2/40 (5%) with the 4:1 diet versus 2/36 (5.6%) with 3:1 diet (P value not reported for either analysis). The RCT reported that the anticonvulsant efficacy was significantly higher in the 4:1 diet than in the 3:1 diet (P = 0.041), but it was unclear what data or timeframe this analysis referred to.

The fourth included RCT was the second part of a previously reported RCT (see option on Ketogenic diet versus control). Initially, some children received their allocated diet immediately or started after a 3-month delay; all children were randomised to receive a classical ketogenic diet or a medium-chain triglyceride diet (MCT). The RCT (145 children aged 2–16 years, seizures at least daily or >7 seizures per week, not responded to at least 2 anticonvulsants) compared the response to the two diets. A non-fasting initiation protocol was used, and all diets were calculated individually by a dietitian. The RCT found no significant difference between the groups in the proportion of children who had a nore than 50% or 90% reduction in seizures at 3 months (>50% reduction: 18/73 [25%] with classical diet v 21/72 [29%] with MCT diet, P = 0.578; >90% reduction: 5/73 (7%) with classical diet v 2/72 [3%] with MCT diet, P = 0.442). The RCT also reported on outcomes at 6 and 12 months (see Comments).

The subsequent RCT (38 children, aged 6 months–5 years [median age 30–36 months], median seizure frequency 10–12 per day, despite use of at least two anticonvulsants including one newer agent) compared a 4:1 or a 2.5:1 lipid:non-lipid ratio ketogenic diet (non-fasting gradual initiation protocol). The RCT reported that 16 participants had West syndrome, 16 participants had Lennox-Gastaut syndrome among others, and seizure types included myoclonic (22 participants), atypical absence (18 participants), generalised tonic (17 participants), and infantile spasms (16 participants) among others. The RCT found no significant difference between groups in the proportion of children who had a greater than 50% reduction in seizures at 3 months (11/19 [58%] with 4:1 group v 12/19 [63%] in the 2.5:1 group, P = 0.78) or became seizure-free at 3 months (5/19 [26%] with 4:1 group v 4/19 [21%] with 2.5:1 group, reported as not significantly different, P value not reported).

Harms

Different implementation methods of ketogenic diet therapies versus each other:

In the first included RCT, five children experienced serious adverse effects during the first 3 months: status epilepticus, pancreatitis, extended hospital stay, acidosis, dehydration, tachycardia of unknown aetiology, and transient elevation in transaminases. Four of the five children were in the FAST-KD group. The RCT found a significant difference between groups in weight loss from days 2 to 6 and hypoglycaemia (weight loss from days 2–6: median –0.95 kg with FAST-KD v –0.30 kg with GRAD-KD, P = 0.006; hypoglycaemia at least once: 33% with FAST-KD v 4% with GRAD-KD, P = 0.023). A greater proportion required intravenous fluids for dehydration in the FAST-KD group: 63% with FAST-KD v 29% with GRAD-KD, P <0.04.

The second included RCT reported no difference in median weight change over the first 3 months between the groups (P = 0.44). It reported that four families found significant constipation (further details not reported).

The third RCT reported that gastrointestinal symptoms (nausea, vomiting, diarrhoea, and poor feeding) were significantly more frequent with the 4:1 diet compared with the 3:1 diet (14/40 [35%] with 4:1 diet v 5/36 [14%] with 3:1 diet, P = 0.038). One participant with the 3:1 diet dropped out due to complicated acute pancreatitis. Two participants with the 4:1 diet and one participant with the 3:1 diet could not maintain the diet due to intolerance.

The fourth included RCT reported that there were no significant differences between the two types of diet, except increased reports of lack of energy after 3 months and vomiting after 12 months with use of the classical protocol. The most common adverse effects (combined for both groups, data for 89 participants) at 3 months were vomiting (24 participants), constipation (35 participants), hunger (26 participants), and lack of energy (23 participants).

The subsequent RCT reported that constipation was the most common adverse effect (5/19 [26%] in 4:1 group v 3/19 [16%] in 2.5:1 group, P value not reported).

Comment

Methods

The first included RCT was unblinded, and there was one drop-out in each arm.

In the second included RCT, although it reported an intention-to-treat analysis, one child did not start the diet, 16 participants (80%) were still on the diet at 3 months, while 12 participants (60%) completed the 6-month trial. We have, therefore, only reported outcomes at 3 months. The reasons for drop-out were not reported, the method of randomisation or allocation concealment was not stated, and the trial was unblinded. The trial noted that the diets containing the 10 g and 20 g carbohydrates were very similar with respect to the actual carbohydrates provided (actual 5 g per day difference when analysed).

In the third included RCT, participants who were seizure-free at 3 months with the 4:1 diet were recommended to change to the 3:1 diet, while those who were not seizure-free with a 3:1 diet were recommended to change to the 4:1 diet. We have, therefore, only reported outcomes up to 3 months. The method of randomisation, allocation concealment, or level of blinding was not described. The RCT reported that there were 12/76 (16%) drop-outs by 3 months.

The fourth included RCT was unblinded. Although an intention-to-treat analysis was presented, results at 3 months were based on 94/145 (64%) of children randomised. After randomisation, 20 children did not receive the dietary treatment, most (10 cases) due to changing their mind. Of the 125 children who received the allocated diet, 25 discontinued before the 3 months assessment. The RCT also presented results at 6 and 12 months. Although these were presented as an ITT analysis, they were based on progressively fewer children initially randomised, so we have not reported them further.

The subsequent RCT was unblinded. Three participants discontinued in each group (unsatisfactory seizure control [3], refusal to eat [2], and non-acceptance by family members [1]).

Clinical guide

There are no data to suggest any difference in efficacy according to the method of implementation of ketogenic diet therapy in children with epilepsy.

Substantive changes

Different ketogenic diet therapies versus each other New option. We found one systematic review, which included four RCTs, and one subsequent RCT. Categorised as 'unknown effectiveness'.

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PERMALINK

Epilepsy: behavioural, psychological, and ketogenic diet treatments

Professor Helen Cross

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

Clinical context

General background

Focus of the review

Comments on evidence

Search and appraisal summary

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table 1.

Glossary

Disclaimer

References

Biofeedback

Summary

Benefits

Electroencephalographic biofeedback versus placebo or control:

Galvanic skin response biofeedback versus placebo or control:

Harms

Electroencephalographic biofeedback versus control:

Galvanic skin response biofeedback versus control:

Comment

Electroencephalographic biofeedback

Galvanic skin response biofeedback

Clinical guide

Substantive changes

Cognitive behavioural therapy

Summary

Benefits

Cognitive behavioural therapy (CBT) versus control:

Seizure frequency:

Psychosocial functioning:

CBT versus relaxation:

Harms

Comment

Seizure frequency

Psychosocial functioning

Clinical guide

Substantive changes

Educational programmes

Summary

Benefits

Educational programmes versus control:

Harms

Educational programmes versus control:

Comment

Clinical guide

Substantive changes

Family counselling

Summary

Benefits

Family counselling versus control:

Harms

Family counselling versus control:

Comment

Clinical guide

Substantive changes

Relaxation therapy

Summary

Benefits

Relaxation therapy versus placebo or control:

Relaxation therapy versus CBT:

Harms

Relaxation therapy versus placebo or control:

Comment

Clinical guide