Epilepsy: behavioural, psychological, and ketogenic diet treatments Search date April 2014 Professor Helen Cross 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.
QUESTIONS What are the effects of behavioural and psychological treatments in people with epilepsy?. . . . . . . . . . . . . . . . 4 What are the effects of ketogenic diet in people with epilepsy?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERVENTIONS BEHAVIOURAL AND PSYCHOLOGICAL TREATMENTS FOR EPILEPSY Likely to be beneficial Educational programmes . . . . . . . . . . . . . . . . . . . . . 6 Unknown effectiveness Biofeedback . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Cognitive behavioural therapy (CBT) . . . . . . . . . . . . 4 Family counselling . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Relaxation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 9
KETOGENIC DIET IN PEOPLE WITH EPILEPSY Likely to be beneficial Ketogenic diet versus no change to treatment (improves seizure frequency in the short-term in children not responding to anticonvulsants; no evidence in adults, or longer term) New . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Unknown effectiveness Different implementation methods of ketogenic diet therapies versus each other (limited evidence on comparisons available from RCTs) New . . . . . . . . . . . 12
Relaxation plus behavioural modification therapy . . 9 Yoga for people with epilepsy . . . . . . . . . . . . . . . . . 10
Covered elsewhere in Clinical Evidence 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.
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.
© BMJ Publishing Group Ltd 2015. All rights reserved.
.................... 1 ....................
Clinical Evidence 2015;07:1214
Neurological disorders
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• 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. 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, [1] 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, [3] 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 [4] 74.4/1000 people, studies in Asia reporting overall prevalence rates of 1.5 to 14.0/1000 people, [5] [6] and studies in Latin America reporting rates of 17 to 22/1000 people. The annual incidence [2] [7] rates of epilepsy are 24 to 56/100,000 people in Europe, 44/100,000 in the US, 63 to [4] [6] 158/100,000 people in sub-Saharan Africa, 113 to 190/100,000 people in Latin America, and [5] 28 to 60/100,000 people in Asia. The worldwide incidence of single unprovoked seizures is 23 [8] to 61/100,000 person-years. About 3% of people will be diagnosed with epilepsy at some time [9] in their lives.
© BMJ Publishing Group Ltd 2015. All rights reserved.
[2]
........................................................... 2
Neurological disorders
Epilepsy: behavioural, psychological, and ketogenic diet treatments
AETIOLOGY/ Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving RISK FACTORS 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 [1] 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 unpro[10] voked 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, [11] which is often treated with multiple anticonvulsant drugs.
AIMS OF To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; INTERVENTION 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 interven-
© BMJ Publishing Group Ltd 2015. All rights reserved.
...........................................................
3
Neurological disorders
Epilepsy: behavioural, psychological, and ketogenic diet treatments
tions included in this review (see table, p 17 ). 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). QUESTION
What are the effects of behavioural and psychological treatments in people with epilepsy?
OPTION
BIOFEEDBACK. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We don't know whether biofeedback is more effective than placebo or control as we found no RCTs of sufficient quality. For GRADE evaluation of interventions for epilepsy, see table, p 17 . Benefits:
Electroencephalographic biofeedback versus placebo or control: [12] We found one systematic review (search date 2011), which identified one three-armed controlled [13] 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 [14] date 2005), which found no further RCTs. We found no subsequent RCTs. Galvanic skin response biofeedback versus placebo or control: [12] 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) [12] [13] 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 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) [27] 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[28] 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 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). [38] 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 7 seizures per week, on median of three anticonvulsants) compared a modified Atkins diet with no change in treatment [39] (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
QUESTIONS What are the effects of behavioural and psychological treatments in people with epilepsy?. . . . . . . . . . . . . . . . 4 What are the effects of ketogenic diet in people with epilepsy?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERVENTIONS BEHAVIOURAL AND PSYCHOLOGICAL TREATMENTS FOR EPILEPSY Likely to be beneficial Educational programmes . . . . . . . . . . . . . . . . . . . . . 6 Unknown effectiveness Biofeedback . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Cognitive behavioural therapy (CBT) . . . . . . . . . . . . 4 Family counselling . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Relaxation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 9
KETOGENIC DIET IN PEOPLE WITH EPILEPSY Likely to be beneficial Ketogenic diet versus no change to treatment (improves seizure frequency in the short-term in children not responding to anticonvulsants; no evidence in adults, or longer term) New . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Unknown effectiveness Different implementation methods of ketogenic diet therapies versus each other (limited evidence on comparisons available from RCTs) New . . . . . . . . . . . 12
Relaxation plus behavioural modification therapy . . 9 Yoga for people with epilepsy . . . . . . . . . . . . . . . . . 10
Covered elsewhere in Clinical Evidence 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.
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.
© BMJ Publishing Group Ltd 2015. All rights reserved.
.................... 1 ....................
Clinical Evidence 2015;07:1214
Neurological disorders
..................................................
• 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. 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, [1] 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, [3] 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 [4] 74.4/1000 people, studies in Asia reporting overall prevalence rates of 1.5 to 14.0/1000 people, [5] [6] and studies in Latin America reporting rates of 17 to 22/1000 people. The annual incidence [2] [7] rates of epilepsy are 24 to 56/100,000 people in Europe, 44/100,000 in the US, 63 to [4] [6] 158/100,000 people in sub-Saharan Africa, 113 to 190/100,000 people in Latin America, and [5] 28 to 60/100,000 people in Asia. The worldwide incidence of single unprovoked seizures is 23 [8] to 61/100,000 person-years. About 3% of people will be diagnosed with epilepsy at some time [9] in their lives.
© BMJ Publishing Group Ltd 2015. All rights reserved.
[2]
........................................................... 2
Neurological disorders
Epilepsy: behavioural, psychological, and ketogenic diet treatments
AETIOLOGY/ Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving RISK FACTORS 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 [1] 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 unpro[10] voked 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, [11] which is often treated with multiple anticonvulsant drugs.
AIMS OF To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; INTERVENTION 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 interven-
© BMJ Publishing Group Ltd 2015. All rights reserved.
...........................................................
3
Neurological disorders
Epilepsy: behavioural, psychological, and ketogenic diet treatments
tions included in this review (see table, p 17 ). 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). QUESTION
What are the effects of behavioural and psychological treatments in people with epilepsy?
OPTION
BIOFEEDBACK. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
We don't know whether biofeedback is more effective than placebo or control as we found no RCTs of sufficient quality. For GRADE evaluation of interventions for epilepsy, see table, p 17 . Benefits:
Electroencephalographic biofeedback versus placebo or control: [12] We found one systematic review (search date 2011), which identified one three-armed controlled [13] 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 [14] date 2005), which found no further RCTs. We found no subsequent RCTs. Galvanic skin response biofeedback versus placebo or control: [12] 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) [12] [13] 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 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) [27] 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[28] 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 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). [38] 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 7 seizures per week, on median of three anticonvulsants) compared a modified Atkins diet with no change in treatment [39] (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
