Neuropsychological and psychological interventions for people with newly diagnosed epilepsy

Abstract

Background

Many people with epilepsy report experiencing psychological difficulties such as anxiety, depression and neuropsychological deficits including memory problems. Research has shown that these difficulties are often present not only for people with chronic epilepsy but also for people with newly diagnosed epilepsy. Despite this, there are very few published interventions that detail means to help people with newly diagnosed epilepsy manage these problems.

Objectives

To identify and assess possible psychological and neuropsychological interventions for adults with newly diagnosed epilepsy.

Search methods

We searched the following databases on 30 June 2015: the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), SCOPUS, PsycINFO, CINAHL, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).

Selection criteria

This review includes all randomised controlled trials, quasi‐randomised controlled trials, prospective cohort controlled studies, and prospective before and after studies which include psychological or neuropsychological interventions for people with newly diagnosed epilepsy. We excluded studies that included people with epilepsy and any other psychological disorder or neurological condition. We excluded studies carried out which recruited only children.

Data collection and analysis

We used the standard methodological procedure expected by The Cochrane Collaboration. Two authors independently completed data extraction and risk of bias analysis. The results of this were cross‐checked and third author resolved any discrepancies. In the event of missing data, we contacted the study authors. Meta‐analysis was not completed due to differences in the intervention and outcomes reported in the two studies.

Main results

We included two randomised controlled trials assessing psychological interventions for people with newly diagnosed epilepsy. One study assessed a cognitive behavioural intervention (CBI) in an adolescent population. This study was rated as low quality. One study assessed a specialist nurse intervention in an adult population. This study was rating as very low quality.

We rated one study as having unclear risk of bias and one study as having high risk of bias.

The CBI study indicated that this intervention could significantly reduce depressive symptoms in people with subthreshold depressive disorder. However, the study assessing the effectiveness of a nurse intervention found no significant benefit for depressive symptoms,but did find that in individuals with the least knowledge of epilepsy, a nurse intervention could increase their knowledge of epilepsy scores.

Authors' conclusions

Meta‐analysis was not possible as we identified only two studies and they utilised different interventions and outcome measures.

Previous research has highlighted the impact of psychological and neuropsychological difficulties experienced by people with epilepsy and the negative effect this has on their quality of life. The main finding of this review is that there is a paucity of research assessing possible neuropsychological and psychological interventions for adults with newly diagnosed epilepsy.

Plain language summary

Neuropsychological and psychological treatments for adults with newly diagnosed epilepsy

Background

Epilepsy is a neurological condition characterised by involuntary activity of the brain which manifests in seizures. People with newly diagnosed epilepsy often report psychological (such as symptoms of depression or anxiety) and neuropsychological (for example, memory or thinking problems) difficulties. Despite this, there is little research into interventions for these difficulties for people with newly diagnosed epilepsy. We reviewed the available evidence for these interventions within this population

Study characteristics

The evidence in this review is current to 30 June 2015. We found two studies that evaluated the effectiveness of psychological interventions targeting depression and anxiety symptoms in people with newly diagnosed epilepsy. One study compared the effectiveness of treatment as usual (TAU) versus usual care plus two 20‐minute appointments, three months apart, with a specialist nurse. This was conducted in a sample of 90 people with newly diagnosed epilepsy.

The second study assessed the effectiveness of a cognitive behavioural intervention (CBI). This approach aims to challenge individuals' negative thoughts alongside behavioural interventions such as graded exposure to situations that prompt anxiety. This entailed 12 group sessions over a six‐month period compared with an equal number of sessions in which counselling without CBI was delivered. This control group was referred to as TAU.

We identified no studies that evaluated the effectiveness of neuropsychological interventions aimed at addressing memory and thinking problems.

Key results

There were two main findings from these studies. First, CBI was more effective than TAU in reducing self reported depressive symptoms. Second, more time spent with a medical professional may have some benefit in improving individuals' knowledge of epilepsy.

Quality of evidence

Of the interventions included in this review, one study enrolled people aged from 13 to 19 years (adolescents) rather than just adults and, therefore, generalising these results to all adults with newly diagnosed epilepsy is limited. The second study used an individualised patient‐led approach, in which the patient guided the content of each session. Therefore, it is difficult to determine which intervention factor(s) were effective and which were not. The content of the interventions assessed in the studies within this review was unclear. Overall, the present review identified a paucity of information for assessing the effectiveness of psychological and neuropsychological interventions for epilepsy and, therefore, we can draw no robust conclusions from the evidence presented.

Summary of findings

Summary of findings for the main comparison. Cognitive behavioural intervention compared with treatment as usual for people with newly diagnosed epilepsy.

Cognitive behavioural intervention compared with treatment as usual for people with newly diagnosed epilepsy
Patient or population: adolescents with newly diagnosed epilepsy Settings: Serbia Intervention: cognitive behavioural intervention Comparison: treatment as usual
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Depression: Sub‐threshold depressive disorder improved in the intervention group	30 (1)	⊕⊕⊝⊝ low	As the participants of this study consisted only of adolescents, the generalisability of these findings to the adult population are limited. In addition, there is insufficient information given about the qualifications of the people administering the interventions. Therefore, we rated the quality of this evidence as low
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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. Very low quality: We are very uncertain about the estimate.

Summary of findings 2. Nurse intervention compared with treatment as usual for people with newly diagnosed epilepsy.

Nurse intervention compared with treatment as usual for people with newly diagnosed epilepsy
Patient or population: people with newly diagnosed epilepsy Settings: UK Intervention: nurse intervention Comparison: treatment as usual
Outcomes	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Knowledge: nurse intervention appeared to help people with the least knowledge of epilepsy improve their knowledge scores	90 (1)	⊕⊝⊝⊝ very low	We rated the evidence for the effectiveness of a nurse‐led intervention as very low due to the individualistic nature of the interventions being administered. As the nurse intervention was participant‐led it is impossible to know what information was being given to participants and, therefore, we are unable to identify what were the effective element(s)
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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. Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Epilepsy is a common neurological disorder and approximately 3% of the general population will be diagnosed with epilepsy in their lifetime (Rugg‐Gunn 2012). The prevalence of epilepsy is around 5/1000 people to 10/1000 people with 50/100,000 new diagnoses each year (Sander 2003). It is estimated that nearly 50 million people in the world have some form of epilepsy (WHO 2009).

Epilepsy is linked with co‐morbidities that include psychological disorders and neurological deficits (Bell 2011). There has been extensive research into the nature of these difficulties, providing evidence that accompanying problems make a significant contribution to reduced quality of life (Fisher 2000). Seizure frequency is not a consistent predictor of a poorer quality of life (Taylor 2011), but people do state that cognitive complaints have the biggest effect on their quality of life (Fisher 2000). Despite this, there is a paucity of research into possible interventions, particularly for people with newly diagnosed with epilepsy.

Psychological disorders

The prevalence of co‐morbid mood disorders, such as anxiety and depression, in epilepsy are estimated at 50% or 60% (Beyenburg 2005), compared with an estimated prevalence rate of 16% in the general population (Singleton 2000). Mood disorder is more common in people with epilepsy compared with other long‐term medical conditions such as asthma and diabetes (Blum 2002). Psychological problems are more reliable determinants of a reduced quality of life than seizure frequency (Boylan 2004). The high rates of psychological difficulties contribute to poorer quality of life and often increases demand on healthcare services and, therefore, cost of healthcare (Mehndiratta 2013).

Neuropsychological deficits

Approximately 20% to 30% of people with epilepsy report poor memory (Hendriks 2002), making it the most commonly reported difficulty in this population. This was supported by a large survey completed by Fisher 2000. Cognitive impairments have a detrimental effect on quality of life for people with epilepsy (Hall 2009).

Most memory deficits, particularly those arising from hippocampal lesions, result in memory retrieval problems that are evident after a 20‐ to 30‐minute delay (Miller 1998). People with epilepsy often perform within the normal range on neuropsychological tests that adopt this 20‐ to 30‐minute delay (Fitzgerald 2013), but there is evidence to suggest that some people experience a rapid decline in memory days or weeks later, despite normal learning and initial retention. This accelerated long‐term forgetting (Manes 2005; Butler 2007) is most evident when assessing episodic memory (Viskontas 2000; Voltzenlogel 2006). The cause of these memory deficits is inconclusive as there are many factors that could have an effect on the memory of a person with epilepsy, such as seizure foci, antiepileptic medications, interictal activity (Hall 2009), and reduced effective connectivity in the brain (Milton 2012).

Two longitudinal studies that compared neuropsychological assessment outcomes for people with newly diagnosed epilepsy and a control group demonstrated that there was a lack of practice effect in the epilepsy group at follow‐up (Hermann 2006; Baker 2011). The duration of follow‐up varied between 12 months and four years. Both studies demonstrated that a lack of practice effect may reflect accelerated long‐term forgetting that is present within the first year of diagnosis. Therefore, intervention programmes are best offered at the time of diagnosis to prevent the negative impact that memory problems can have on quality of life.

Description of the intervention

Psychological interventions

Psychological interventions are designed to facilitate change to promote an improvement in psychological well‐being. This can range from psychoeducation in a group or one‐one setting, to therapy. Cognitive behavioural therapy (CBT) or acceptance and commitment therapy (ACT) are therapeutic approaches that have been designed to facilitate change in behaviour or to re‐assess cognitions. Counselling is another form of therapeutic intervention, but in this instance, there is a more person‐centred approach.

Neuropsychological interventions

Restoration strategies

Some neuropsychological interventions aim to restore memory functioning through re‐training. An example would be using an 'internal' mnemonic, which can be either visual or verbal (Wilson 2009). Interventions focusing on optimising encoding and retrieval involve an intensive training period in which people attend structured training lessons to receive verbal‐ or imagery‐based training. In the first stage of training, an acquisition stage, participants practice using the mnemonic while trying to remember basic objects or words; in the second stage, the transfer stage, the technique is practiced with stimuli specific to them. While research has shown that memory training may be effective in participants with both mild and moderate memory impairments (Cicerone 2005), research involving participants with severe memory impairments have not replicated these findings (Ptak 2010).

Spaced retrieval training is another example of a restoration strategy. This method involves recalling information at shorter intervals then gradually increasing the interval period to aid memory over time. Spaced retrieval training can be an effective strategy for people with Alzheimer's disease (Small 2012).

Another method that is often used in the rehabilitation of memory impairments is errorless learning (Clare 2008). Here, the possibility of the person making errors is eliminated during the learning process. This is achieved by encouraging the person to avoid guessing, immediately correcting errors and gradually reducing prompts (Sohlberg 2005).

Compensation strategies

Compensation strategies aim to minimise the impact of memory impairments. It is usually suggested to use external aids and systems, such as diaries, calendars, mobile telephones or notebooks. Research into the use of external aids has largely yielded inconclusive findings (Ptak 2010), arguably because it can be contended that remembering to use these is also a memory task (Sohlberg 2001). The exception is that the use of mobile telephones as an external memory aid has shown some success (Fish 2007; Culley 2010).

How the intervention might work

Psychological interventions

Psychoeducation

Psychoeducation can take place in a one‐to‐one or group setting. A trained professional provides information about a specific disorder and explains the mechanisms, experiences and factors that may affect that condition. In this way, increasing an individual's understanding of their condition or disorder allows them to cope better with the difficulties they experience.

Cognitive behavioural therapy

CBT aims to challenge irrational attributions and, therefore, alter their effect on behaviour and emotions. ACT utilises acceptance and mindfulness alongside commitment and behavioural change strategies to help the person to increase their psychological flexibility.

Counselling

By providing a forum for people to express their emotions and concerns, counselling offers people the opportunity to acknowledge their difficulties and explore possible solutions. This is a person‐centred approach, wherein a trained counsellor can guide conversation to enable the person to develop their own solutions.

Neuropsychological interventions

Restoration strategies

Methods that adopt the restoration approach to memory rehabilitation are based on the premise that training through repeated practice will improve memory functioning. According to this approach, encoding and retrieval can be optimised through repetition, gradually increasing intervals, carefully removing cues or using internal mnemonic strategies.

Compensation strategies

Methods that adopt a compensation approach focus on providing external aids to support memory. This aims to minimise dependency on memory functioning and, therefore, reduce the difficulties experienced by the person.

Why it is important to do this review

Epilepsy rarely exists without psychological or neuropsychological complaints. People with epilepsy will describe these problems as more distressing than seizures (Fisher 2000). There has been extensive research into the nature and severity of anxiety, depression and cognitive deficits that often accompany epilepsy. Research into psychological and neuropsychological interventions is a growing field; however, there remains a paucity of literature into possible interventions for people with newly diagnosed epilepsy.

Psychological problems in epilepsy are often undiagnosed, but if untreated, these conditions can cause further complications and become increasingly resistant to treatment. Therefore, it is arguable that if a psychological intervention is implicated, it should begin at the time of diagnosis to prevent and minimise the impact of psychological problems. Similarly, cognitive deficits associated with epilepsy have been identified at the time of diagnosis. If support is not offered, the cognitive deficits may become increasingly distressing and contribute to the development of psychological problems. Ideally, neuropsychological interventions should begin at the time of diagnosis to provide effective strategies that can form part of a routine, and to reduce worry caused by the accompanying neuropsychological difficulties.

In summary, both psychological and neuropsychological problems are evident at the time of diagnosis for people with epilepsy. By providing both of these interventions at the time of diagnosis, the adverse effects caused by these accompanying problems can be significantly reduced. The effectiveness of early psychological intervention to reduce symptoms and improve mental health is supported in practice and in research (Roberts 2009).

Objectives

To identify and assess possible psychological and neuropsychological interventions for adults with newly diagnosed epilepsy.

Methods

Criteria for considering studies for this review

Types of studies

We considered the following types of study:

• randomised controlled trials (RCT) and quasi‐randomised and cluster randomised controlled trials where people with newly diagnosed epilepsy were randomised to either an intervention group or a control group;

• prospective cohort controlled studies where people with newly diagnosed epilepsy were assigned to either an intervention group or a control group due to certain determining factors;

• prospective before‐and‐after studies where there was only an intervention group and outcomes before and after the intervention were assessed against the baseline measures.

Types of participants

The following participants were eligible for the interventions:

• adults with newly diagnosed epilepsy who have been diagnosed for less than 18 months, which is consistent with previous research.

We excluded studies reporting interventions for the following participants:

• people without epilepsy;

• people with non‐epileptic attack disorder (NEAD) or co‐morbid epilepsy plus NEAD;

• people with epilepsy and other neurological conditions (such as traumatic brain injuries);

• people with epilepsy and significant psychiatric disorders;

• solely children (under 16 years old).

We excluded studies that had a mixed sample of participants and, therefore, met both the inclusion and exclusion criteria. However, we considered a mixed sample of children and adult populations for inclusion depending on the range of ages included.

Types of interventions

Intervention group

People with newly diagnosed epilepsy receiving one or more of the following psychological and neuropsychological interventions: CBT, ACT, psycho‐education, counselling, cognitive re‐training, cognitive rehabilitation, cogmed training language interventions or a combination of these interventions.

Control group

In prospective before‐and‐after studies, the intervention group served as its own control group in that the control measures will be the baseline measures taken before the intervention begins.

In both RCTs and prospective cohort controlled trials, the control group will be people with newly diagnosed epilepsy who were on a waiting list for the intervention and, therefore, not receiving any interventions or receiving normal care. In addition, some studies may have a control group of people with a new diagnosis who were undergoing pharmacological interventions.

Types of outcome measures

Primary outcomes

• Improved quality of life: any overall significant improvements in validated self reported quality‐of‐life measures;

• Description of risk factors: whether there are any associated risks with the interventions.

Secondary outcomes

• Enhanced day‐to‐day neuropsychological functioning or improved outcomes on validated neuropsychological assessments as a marker of improved cognitive functioning;

• Improved mood: decreased symptoms of anxiety and depression assessed by validated measures;

• Knowledge of epilepsy: increased knowledge about epilepsy;

• Seizure frequency/recency of epileptic seizure.

Search methods for identification of studies

Electronic searches

We searched the following databases on 30 June 2015:

• Cochrane Epilepsy Group Specialized Register using the search strategy outlined in Appendix 1;

• Cochrane Central Register of Controlled Trials (CENTRAL Issue 5, The Cochrane Library May 2015), using the search strategy outlined in Appendix 2;

• MEDLINE (Ovid) 1946 to date of search, using the search strategy outlined in Appendix 3;

• SCOPUS 1823 to date of search, using the search strategy outlined in Appendix 4;

• PsycINFO (EBSCOhost) 1887 to date of search, using the search strategy outlined in Appendix 5;

• CINAHL Plus (EBSCOhost) 1937 to date of search, using the search strategy outlined in Appendix 6;

• ClinicalTrials.gov (ClinicalTrials.gov) using the search strategy outlined in Appendix 7;

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/) using the search strategy outlined in Appendix 8.

We applied no language restrictions in the search.

Searching other resources

We handsearched:

• three relevant journals from 2009 to 2014: Epilepsia, Epilepsy and Behaviour and Epilepsy Research;

• conference abstracts from 2009 to 2014 from the International League Against Epilepsy and European Epilepsy Congress annual meetings;

• the Epilepsia journal supplements from 2009 to 2014 for congress proceedings;

• references lists of included studies.

Data collection and analysis

Selection of studies

Two authors (CJ, SMM) reviewed the titles and abstract of the studies identified by the electronic searches and removed studies that did not meet the inclusion criteria. The same two authors reviewed the full‐text reports to determine eligibility. We discussed any disagreements and if necessary consulted the third author (GAB). In the event of there being multiple reports deriving from one study, we linked the reports together. We generated a final list of studies to be included in the review.

Data extraction and management

Two authors (CJ, SMM) independently completed data extraction on the included studies and cross‐checked the results. We extracted data using pre‐standardised data extraction forms.

We extracted the following information from the included studies.

• Participants:

  • total sample size;

  • total number of participants allocated to each group;

  • setting;

  • inclusion criteria;

  • age;

  • gender;

  • country.

• Methods:

  • study design;

  • duration of study;

  • confounding variables considered and controlled for;

  • sequence generation and allocation concealment;

  • method of blinding;

  • any other concerns about bias.

• Outcomes:

  • name and definition of outcome;

  • units of measurement.

• Results:

  • number of participants allocated to each intervention and control group;

  • sample size for each outcome;

  • missing data;

  • summary data for intervention and control groups (e.g. means and standard deviations for all outcomes). See Types of outcome measures.

Assessment of risk of bias in included studies

Two authors (CJ, SMM) independently assessed the risk of bias and compared the results from these assessments to identify any inconsistencies. In the event of disagreement, we sought the opinion of the third author (GAB).

Due to the observational design of some of the studies, we planned to assess risk of bias for non‐randomised studies using a tool developed by the Cochrane Non‐Randomised Studies Methods Group for assessing risk of bias. This method examines selection bias (sequence generation, allocation concealment), performance bias (blinding), detection bias (blinding, other potential threats to validity), reporting bias (selective outcome reporting) and the influence of confounding variables. The domains of blinding, incomplete outcome data, selective outcome reporting, confounding variables and other bias are rated on a 5‐point scale ranging from low risk of bias to high risk of bias according to the risk on the outcome. See Appendix 9; Appendix 10 for extended 'Risk of bias' tools. The authors determined the parameters of this scale. See Table 3 for scale parameters.

1. Table of scale parameters.

	1	2	3	4	5
Confounding	All important1 confounders considered2 and suitable method of adjustment3 employed. Outcome unlikely to be affected	Most important4 confounders considered and suitable method of adjustment employed. Outcome unlikely to be affected	Some confounders5 considered and full or partial adjustment employed6. Possible implication on outcome	Some confounders considered and no adjustment employed. Likely to affect outcome	No important confounders considered and no adjustment employed. Likely to affect outcome
Blinding	Assessors blinded to participant's intervention and participants blinded to intervention. Outcome unlikely to be affected	Assessors blinded to participants intervention. Outcome unlikely to be affected	Partial blinding7 involved in study. Possible implication on outcome	Partial or no blinding involved in study. Outcome likely to be affected	No blinding involved in study. Outcome likely to be affected
Incomplete outcome data	No missing data or appropriate analysis8 (or both) used to deal with missing data. Unlikely to affect outcome	Smaller amount (< 25%) of missing data with reasons given, balanced across groups. Unlikely to affect outcome	Larger amount of missing data (> 25%) with or without reasons given, balanced across groups. Possible implication on outcome	Larger amount (> 25%) of missing data, imbalance across groups. Outcome likely to be affected	No information provided regarding missing data. Likely to affect outcome
Selective outcome reporting	A priori outcomes measured, analysed and reported in main report. Protocol available. Unlikely to affect outcome	A priori outcomes measured, analysed and reported in main report9. Protocol not available. Unlikely to affect outcomes	Limited information regarding a priori outcomes and measures. Possible implication on outcome	Outcomes measured but not analysed or reported. Outcome likely to be affected	Outcomes measured but not analysed or reported and clinical judgement infers the presence of an unreported measured outcome10
Other bas	No bias identified	Bias identified. Unlikely to affect outcome	Bias identified. Possible implication on outcome	Bias identified. Likely to affect outcome	Bias identified. Extremely likely to affect outcome

¹ Important confounders include: socioeconomic status, epilepsy type, seizure frequency, age of onset, employment, mental health/co‐morbidities, learning disability/developmental disorder, years of education.

² Reported demographic information and other confounders.

³ Matching scores, multiple regression, analysis of co‐variance, stratification.

⁴ At least 5 out of 8 of important confounders including: epilepsy type, seizure frequency, age of onset, employment, mental health/co‐morbidities.

⁵ At least 2 out of 8 of important confounders.

⁶ Full adjustment of confounding variables (e.g. see footnote 2) or partial adjustment (e.g. researchers select limited number of variables to adjust for).

⁷ Assessors of outcome were only blinded to certain groups (e.g. blinded to intervention groups but not controls).

⁸ Intention‐to‐treat analysis.

⁹ An a priori statement is made in methods section of main report regarding measurement and analysis of outcome.

¹⁰ For example: sub‐tests or results from sub‐tests on cognitive measures or mood questionnaires unreported.

For RCTs, we assessed all domains of the current Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). We made an overall summary judgement of risk of bias for each study per outcome, followed by an overall judgement per outcome across studies. We planned to incorporate the risk of bias judgement into the analysis using sensitivity analysis. This analysis of the data would have included only studies rated as low risk of bias. We created 'Summary of findings' tables for outcomes, with each outcome graded using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach (Guyatt 2008).

Measures of treatment effect

The ideal method would be to present effect estimates as the mean difference. However, due to the variation in outcome measures available, we planned to present the data as the standardised mean difference (SMD). Should studies report dichotomous data, we planned to present effect estimates in the form of risk ratios using 95% confidence intervals.

Unit of analysis issues

In the event of unit of analysis issues being present across the included studies (e.g. cluster randomised or repeated measures), we planned to:

• determine whether the methods in such studies were conducted appropriately;

• combine extracted effect sizes from such studies through a generic inverse variance meta‐analysis.

Dealing with missing data

We sought missing statistics from studies through contact with the study authors. We sought reasons for missing data to determine if missing data were random or not.

Assessment of heterogeneity

Two authors (CJ, SMM) visually assessed the clinical and methodological heterogeneity (e.g. selection bias in non‐randomised studies) of the included studies and where applicable, we planned to calculate the I² statistic and use the Chi² test to assess the statistical heterogeneity. We judged a Chi² P value of less than 0.1 and an I² statistic of greater than 50% to indicate statistical heterogeneity in accordance with guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Assessment of reporting biases

We investigated outcome reporting bias using the ORBIT matrix system (Kirkham 2010). We requested all protocols from study authors to compare outcomes of interest.

To examine publication bias, we identified any unpublished data by carrying out a comprehensive search of multiple sources and requesting unpublished data from study authors. We planned to look for small‐study effects to establish the likelihood of publication bias. We planned to examine funnel plots in the event of there being 10 or more studies that could be combined, in accordance with The Cochrane Collaboration recommendations (Higgins 2011).

Data synthesis

We planned to employ a random‐effects meta‐analysis to synthesise the data. This is due to the various interventions that were being evaluated and the differing outcomes they would yield.

We planned to present the primary outcome (improvement in quality of life) as an SMD. We planned to present the secondary outcomes (enhanced day‐to‐day neuropsychological functioning, improved mood and enhanced adaption to living with epilepsy) as an SMD. In the event that any outcomes were reported as dichotomous data, we planned to present risk ratios.

In the event that we deemed meta‐analysis inappropriate, for example if there was evidence of clinical heterogeneity, we planned for the review to take a narrative form and discuss all comparisons according to the findings presented within the studies.

We expected to make the following comparisons:

• intervention group versus control group on the effectiveness of an intervention programme to improve quality of life for people with newly diagnosed epilepsy;

• intervention group versus control group on the effectiveness of a neuropsychological intervention on a day‐to‐day neuropsychological functioning for people with newly diagnosed epilepsy;

• intervention group versus control group on the effectiveness of a psychological intervention for symptoms of anxiety and depression for people with newly diagnosed epilepsy.

In the event of clinical heterogeneity, we would not have pooled interventions for meta‐analysis.

If included studies assessed comparisons not listed above, we planned to carry out a post hoc analysis.

We planned to stratify by control group, study design, characteristics, measures used to ensure appropriate combination of study data.

Subgroup analysis and investigation of heterogeneity

We planned to stratify subgroup analyses by type of intervention and duration of intervention. In the event of statistical heterogeneity across studies, we planned to carry out a random‐effects meta‐analysis.

Sensitivity analysis

In the event of any inconsistencies or peculiarities being identified, we planned to carry out sensitivity analysis using only studies that we considered to have a low risk of bias. We would then have compared the results from this second meta‐analysis with the reports from the initial analysis that included all studies.

Results

Description of studies

Results of the search

The search revealed 176 studies identified from the databases outlined in Electronic searches. After we removed 23 duplicates, 153 studies remained. We screened these studies resulting in the exclusion of a further 144 studies due to irrelevance. Nine studies remained for full‐text review and we excluded a further seven studies (see Figure 1 and Characteristics of excluded studies table for reasons for exclusion). Of the remaining two studies, we completed forward and backward referencing but identified no other studies that met the inclusion criteria. Therefore, we included two studies in this review and analyses.

1.

Study flow diagram.

Included studies

The two studies were RCTs. Both studies involved psychological interventions, with neither of them utilising neuropsychological interventions.

The first RCT used a nurse intervention group and compared with a control group (Ridsdale 2000). We used three papers to obtain information about the nature of the intervention used (Kwan 2000; Ridsdale 2000; Ridsdale 2003). Seven neurologists across five hospitals in South East England recruited participants. All participants included in this study were over 17 years of age and had newly diagnosed epilepsy involving two or more seizures. A composite questionnaire was sent to participants at the beginning of the study which consisted of: a list of questions about whether enough advice had been provided on aspects of epilepsy (adapted from the questionnaire used by Jacoby 1996); a "knowledge of epilepsy" questionnaire (Jarvie 1993); the Hospital Anxiety and Depression Scale (Zigmond 1983) and time since last epileptic seizure questions. People who returned the questionnaire were randomised into the intervention or control group. In the intervention group, the results from 43 participants were included in the final analysis; 54% were men and their mean age was 39.8 years. For the control group, the results from 47 participants were included in the final analysis; 47% were men and their mean age was 40.2 years. Participants in the intervention group were offered two appointments, three months apart, with an epilepsy nurse specialist. These appointments included counselling, education and advice about medication, prognoses, work, driving and leisure activities. The content of the sessions were tailored by the nurse according to the expressed needs of the participant. The same questionnaire pack was sent to participants three months after the second appointment. For the outcome measures, changes in psychological well‐being (anxiety and depression), knowledge of epilepsy and time since last epileptic seizures were assessed. A likert scale was used to assess their views about the extent to which aspects of epilepsy had been clearly explained.

The second RCT explored the effectiveness of a cognitive behavioural intervention (CBI) (Martinovic 2006). The inclusion criteria stated that participants must be aged 13 to 19 years old, be of normal intelligence (intelligence quotients ranged from 85 to 132) and received a diagnosis of epilepsy (either focal or generalised) within the last 12 months. Participants were recruited from general practices in Belgrade, Serbia and its surrounding areas. Participants were screened using a variety of assessments. To identify participants with mood or other psychiatric disorders, a semi‐structured diagnostic interview was conducted. Two self assessment questionnaires, the Beck Depression Inventory (BDI; Beck 1961), and the Center for Epidemiological Study on Depression (CES‐D; Radloff 1977), scale were used to screen for depression. Only participants identified as having sub‐threshold depression were included in this study. This was determined as participants who scored between 6 and 8 on the Hospital Anxiety and Depression Scale (HADS; 9 being the threshold indicating mild depressive symptoms) or 9 and 14 on the CES‐D (15 being the threshold for mild‐to‐moderate depressive symptoms). Participants who scored within this range completed an assessor‐administrated questionnaire, Hamilton Depression Scale (HAMD; Hamilton 1960), and had a clinical interview to assess sub‐threshold depression. These participants were randomised into two groups; an intervention group receiving a short CBI and a control group receiving treatment as usual (TAU). Participants in both groups received eight sessions in the first two months and a further four sessions for four months. The intervention group sessions involved cognitive‐behavioural interventions (CBI) targeting the distorted automatic thoughts related to depressive symptoms and behavioural interventions such as activity plans and relaxation. The control group sessions involved counselling without CBI. The parents of participants completed a questionnaire to identify potential risk factors for depression. This questionnaire assessed the risk factors identified by Mrazek 1994 under the headers of individual, familial and environmental risk factors. All participants completed the BDI, CES‐D, Quality of Life in Epilepsy Inventory (QOLIE‐31), HAMD and the risk factors questionnaire at baseline, six months following the intervention and nine months following the intervention. Participants in the CBI group were asked to rate both their positive and negative thoughts on a 4‐point scale and the results at baseline, six months and nine months were assessed. Outcomes from these measures were compared.

Excluded studies

We excluded seven studies for the following reasons: not intervention studies (Chaplin 1995; Guilfoyl 2012; McDonald 2011; Nenadovic 2011), not newly diagnosed epilepsy (Chung 2012) paediatric population only (Rapoff 2013) and pharmacological interventions only (Burneo 2007).

Risk of bias in included studies

We rated Martinovic 2006 overall as unclear risk of bias due to limited information about the individuals delivering CBT. It was also unclear about the exact content of the CBI intervention.

We rated Ridsdale 2000 overall as high risk of bias due to the lack of blinding, limited information about what TAU involved for the control sample and the individualised nature of the interventions provided and whether the content was related to the outcomes measured. In addition, the sample was self selected based on people who returned the questionnaire at stage one.

Allocation

For sequence generation, one study used a computer‐generated method so we rated it as low risk of bias (Martinovic 2006). We rated the second study as unclear due to there being insufficient information about the sequence generation (Ridsdale 2000).

In both studies, it was unclear whether concealment of allocation had been used.

Blinding

It was unclear if there was any blinding in the CBT intervention study due to ambiguity in description of the methodology (Martinovic 2006). However, we rated the nurse intervention paper as high risk of bias due to neither the outcome assessor nor the study personnel being blinded (Ridsdale 2000).

Incomplete outcome data

In the Martinovic 2006 study, two participants withdrew after randomisation, one from each group. Although the study authors did not disclose the reasons for these withdrawals, given the equal withdrawal rate between the groups it is unlikely this had a significant effect on the outcomes. Therefore, we rated this study as low risk of bias.

Ridsdale 2000 reported seven withdrawals in the intervention group (two people moved away, two people had other illnesses and three people were non‐responders) and five withdrawals in the control group (one person moved away, one person had other illnesses and three people were non‐responders). As the drop‐out rate was comparable across the two groups, we rated risk of bias as low.

Selective reporting

We rated selection bias for both the studies as unclear due to the unavailability of the protocol (Ridsdale 2000; Martinovic 2006).

Other potential sources of bias

In one paper, it was unclear whether there were other sources of bias as there was a lack of detail about who funded the research (Martinovic 2006). Similarly, it was unclear who carried out the CBI, whether they were qualified as CBT practitioners and what the content of the CBI was. The control group consisted of participants who were receiving TAU; however, it was unclear what this included. This study included a selective sample in that only participants who has subthreshold levels of depression were included.

We rated the nurse intervention study as unclear for other bias due to the individualistic nature of the intervention (Ridsdale 2000). This review aimed to consider psychological or neuropsychological interventions, or both, but the study did not provide information about whether the facilitators had relevant qualifications to administer a psychological intervention and whether every participant received psychological advice or support. This study included participants who had returned questionnaires and, therefore, represented a self selected sample. In addition, the control group consisted of participants who were receiving TAU; however, it is unclear what this included.

Effects of interventions

See: Table 1; Table 2

The present review identified two papers exploring the effectiveness or either psychological or neuropsychological interventions for people with newly diagnosed epilepsy. These papers assessed different interventions and used different outcome measures and, therefore, we could not perform a meta‐analysis.

Cognitive behavioural intervention versus treatment as usual

One study assessed a CBI compared with TAU (Martinovic 2006).

Sub‐threshold depression levels

At baseline, there was no significant difference in BDI scores between the CBI and TAU group (8.2 with CBI vs. 8.1 with TAU, P value not reported). The BDI scores were significantly lower in the CBI group compared with the TAU group at six‐month follow‐up (5.4 with CBI vs 7.8 with TAU, P value < 0.05) and the nine‐month follow‐up (5.6 with CBI vs 7.7 with TAU, P value < 0.05). There was a significant improvement but all scores (pre‐ and post‐intervention) fell within the normal range.

At baseline, there was no significant difference in CES‐D scores between the CBI and TAU group (14.1 with CBI vs 13.9 with TAU). The CES‐D scores were significantly lower in the CBI group compared with the TAU group at the six‐month follow‐up (9.8 with CBI vs 13.6 with TAU, P value < 0.05) and the nine‐month follow‐up (10.5 with CBI vs 13.8 with TAU, P value < 0.05).

Within group comparison showed that there was a significant decrease in negative thoughts (such as catastrophising, over‐generalisation, personalisation and selective abstraction) and positive thoughts (countermeasures to challenge negative thoughts) at six months and nine months following CBI compared with baseline (P value < 0.01).

Quality of life

At baseline, participants' outcomes on the QOLIE‐31 were comparable between the CBI and TAU groups (36.95 with CBI vs 38.48 with TAU, P value not reported). Participants in the CBI group returned significantly higher QOLIE scores than participants in the TAU group at six‐month follow‐up (56.78 with CBI vs 41.35 with TAU, P value < 0.01) and at nine‐month follow‐up (56.40 with CBI vs 42.23 with TAU, P value < 0.01), indicating a significantly better quality of life.

Risk factors

The number of individual risk factors assessed at baseline were compared with those identified at the six‐ and nine‐month follow‐up. There were significantly fewer individual risk factors in the CBI group compared with the TAU group (P value < 0.05). There was no significant difference between the numbers of familial risk factors for depression between the two groups.

Nurse intervention versus treatment as usual

One study assessed a nurse intervention compared with TAU (Ridsdale 2000).

Knowledge of epilepsy

There was no significant difference between the medians of the CBI and TAU groups at stage two following the nurse intervention. The lower quartile of respondents in the active treatment group was significantly higher than the lower quartile of respondents in the TAU group following the nurse intervention (42.5 with CBI vs 37.2 with TAU; P value < 0.01).

Recency of epileptic seizure

There was no significant difference between the median time since participant's last epileptic seizure between the CBI and TAU groups (4.9 months with CBI vs 6.5 months with TAU, P value not reported). However, the time since last epileptic seizure was significantly longer at stage two than stage one across all participants (5.8 months with CBI vs 2.2 months with TAU; P value < 0.01).

Psychological well‐being

Although median anxiety and depression scores were lower at stage two in the CBI group compared with the TAU group, this difference was not significant (15 with CBI vs 18 with TAU, P value not reported). There was also no significant difference in depression scores at stage two (9 with CBI vs 8 with TAU, P value not reported).

Discussion

Summary of main results

This review identified two studies assessing psychological and neuropsychological interventions for people with newly diagnosed epilepsy. These studies involved psychological interventions; we found no papers that utilised neuropsychological interventions for people with newly diagnosed epilepsy.

Martinovic 2006 evaluated the effectiveness of CBI aimed at analysing and adjusting negative automatic thoughts associated with depressive symptoms, focusing on four main types of cognitive errors: catastrophising, over‐generalisation, personalisation and selective abstraction. They reported that CBI was more effective in reducing depressive symptoms and increasing quality of life than counselling without CBI, which they called treatment as usual (TAU). They also found that CBI reduced cognitive risk factors more than TAU. This would support the role of providing a structured and focused intervention based on cognitive behavioural approaches to increase a person's psychological well‐being and their quality of life.

Ridsdale 2000 reported that providing individualised support and information by a nurse specialist may be beneficial to increase knowledge of epilepsy. This was only evident for participants who had less knowledge of epilepsy before the intervention. It was reported that there was no significant effect on psychological well‐being. This study supports the role of nurse‐led, patient‐guided psychoeducation appointments for people with newly diagnosed epilepsy, but this may only be effective for people who have less understanding of the condition at the outset. However, the indications from this study are that knowledge alone may not produce better psychological well‐being. Therefore, an intervention based solely on psychoeducation may not be the most effective form of intervention for all people with newly diagnosed epilepsy.

Overall completeness and applicability of evidence

Despite the growing interest in understanding the nature and severity of psychological and neuropsychological complaints in newly diagnosed epilepsy, it is evident from this review that there is a paucity of research exploring interventions in this population. In recent years, there has been an increased focus on neuropsychological problems for people with newly diagnosed epilepsy, specifically memory complaints (Manes 2005; Butler 2007). This review revealed no studies that explored potential neuropsychological interventions for people with newly diagnosed epilepsy. This reflects a significant gap in research into this field.

The papers identified in this review offer tentative evidence for the benefits of providing psychological interventions for people with newly diagnosed epilepsy. However, the two studies use different interventions and different outcome measures, and so meta‐analysis was not possible. Therefore, the key finding of this review is that there is a paucity of research into psychological and neuropsychological interventions to support people with newly diagnosed epilepsy.

Quality of the evidence

There were several limitations within the Martinovic 2006 study. The age range of participants varied from 13 to 19 years old. As stated in the protocol, only adult studies were to be included (participants aged 16 years and above). We included this study due to the overlap in ages; however, this may limit the generalisability of the results. In addition, there was only limited information about the qualifications of the people delivering CBI and, therefore, the level of psychological intervention was unclear. Overall, we rated the quality of this study as low. We rated the overall risk of bias as unclear due to the lack of details about funding of the research and blinding.

There were several limitations to the Ridsdale 2000 study. The nurse intervention provided was participant led and so the information provided was not standardised. The individualistic nature of the intervention made it difficult to attribute the positive outcomes to specific factor(s). Although the intervention includes an aspect of counselling, it is unclear whether the people conducting the study had specific training in delivering psychological therapy. Thus, it could be argued that this is not a psychological intervention. Overall, we rated the quality of this study as very low. We rated the overall risk of bias as unclear due to the lack of details about sequence generation, lack of protocol and the individualised nature of the intervention.

Potential biases in the review process

There is a strong possibility that not all relevant data was identified. Despite the thorough search strategies, we cannot be certain that all relevant studies were identified and included in this review.

There was limited information about the included studies on which to base decisions within the risk of bias assessment, resulting in a number of unclear risk of bias judgements.

Prior to the searches, the protocol did not make reference to whether studies with a mixed sample would be included in the review. This was changed post‐protocol in light of the Martinovic 2006 paper being identified. We chose to include this paper and amend the protocol in order to be as inclusive as possible, given the paucity of literature in this area.

Agreements and disagreements with other studies or reviews

Ramaratnam 2008 completed a Cochrane Review to evaluate interventions for people with chronic epilepsy. The authors identified two studies that showed that CBT had a significant effect in reducing depression and improving quality of life. This was consistent with the findings of one study in the present review, which found that CBI had a significant effect on reducing depressive symptoms.

Ramaratnam 2008 identified one study reporting that group cognitive therapy had a significant effect in reducing seizure frequency. The present review did not identify any studies that evaluated group interventions.

Authors' conclusions

Implications for practice.

There are very few conclusions that can be drawn from this review regarding implications for clinical practice. In the first instance, good‐quality, focused studies need to be completed to ascertain whether psychological and neuropsychological interventions are effective within this population. Once that has been completed, then clinicians will be in a better position to apply that information to clinical practice and to develop services accordingly.

There is some tentative evidence that a cognitive behavioural intervention may be effective in preventing the development of depression‐related symptomology within this population (Martinovic 2006), but this is an area that needs more research. In addition, it remains unclear whether cognitive behavioural therapy, or other types of psychological intervention, would be effective in treating people with clinically significant levels of depression or anxiety.

It is noteworthy to mention that the present review did not identify any studies assessing the effectiveness of neuropsychological interventions for people with newly diagnosed epilepsy. Given that research has continually shown that people with newly diagnosed epilepsy often report neuropsychological deficits, particularly memory difficulties, the interventions available to alleviate such difficulties are limited.

Implications for research.

The present review highlighted the need for more evaluated interventions using a range of psychological and neuropsychological therapies. It is well established within clinical and research settings that people with epilepsy have psychological or neuropsychological difficulties, or both, around the time of diagnosis. However, there is little research exploring possible psychological and neuropsychological interventions to manage these difficulties, particularly in newly diagnosed epilepsy.

There are two large studies into different psychological interventions for people with epilepsy that are currently in the recruitment stage (Caller 2014; Kralj‐Hans 2014). However, these studies are focusing on people with chronic epilepsy rather than newly diagnosed. It may be that these reviews highlight useful strategies that can be assessed as possible interventions for people with newly diagnosed epilepsy.

It remains unclear whether there are distinct difficulties that would necessitate specific interventions for people with newly diagnosed versus people with chronic epilepsy or whether there will be transferable strategies.

Appendices

Appendix 1. Cochrane Epilepsy Group Specialized Register search strategy

#1 MeSH DESCRIPTOR Early Diagnosis

#2 (recent* OR new* OR early) NEAR2 (diagnos* OR onset)

#3 "first seizure" OR "first fit"

#4 #1 OR #2 OR #3

#5 MeSH DESCRIPTOR Neuropsychology Explode All WITH CL EC ED ES HI IS LJ MA MT OG ST SN TD

#6 MeSH DESCRIPTOR Rehabilitation Explode All WITH CL EC ED ES HI IS LJ MA MT OG PX ST SN TD

#7 MeSH DESCRIPTOR Mind‐Body Therapies Explode All WITH AE CL CT EC ED ES HI IS LJ MA MT MO NU OG PX ST SN TD UT VE

#8 MeSH DESCRIPTOR Psychotherapy Explode All WITH CL EC ED ES HI IS LJ MA MT OG ST SN TD

#9 abreaction OR behav* modification OR bibliotherap* OR biofeedback OR catharsis OR conditioning OR classical conditioning OR counsel?ing OR crisis intervention OR desensiti?ation OR early intervention OR emotional freedom tapping OR (eye movement NEAR2 (desensiti?ation OR reprocessing)) OR (feedback NEAR1 (psycholog* OR sensory)) OR flooding OR free association OR hypnosis OR hypnotherapy OR imagery OR logotherapy OR meditation OR mindfulness OR operant conditioning OR post traumatic stress disorder OR PTSD OR psychodrama OR psychotherap* OR residential treatment? OR rewind technique? OR stress manag* OR transactional analysis

#10 ((acceptance NEAR2 commitment) OR anxiety OR art OR assertive OR autogenic OR autosuggestion OR aversive OR behav* OR client cent* OR cognitive OR colo?r OR compassion* OR coping OR couples OR dance OR depression OR directive OR exercise OR family OR gestalt OR human givens OR humanistic OR implosive OR interpersonal OR language OR marital OR memory OR mentali?ation OR narrative OR nondirective OR nonpharmacol* OR non‐pharmacol*) NEAR2 (therap* OR treatment* OR train* OR retrain* OR rehabilitat* OR adapt* OR intervention* OR manag*)

#11 (panic OR patient cent* OR psycho* OR quality of life OR QOL OR rational‐emotive OR rational emotive OR relaxation OR self‐esteem OR socioenvironmental OR socio‐environmental OR stigma OR systemic OR systems OR therapeutic community OR trauma) NEAR2 (therap* OR treatment* OR train* OR retrain* OR rehabilitat* OR adapt* OR intervention* OR manag*)

#12 (adjustment OR attention OR confidence OR "day to day" OR loss OR reality OR suggestion) NEAR1 (therap* OR treatment* OR train* OR retrain* OR rehabilitat* OR adapt* OR intervention* OR manag*)

#13 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12

#14 #4 AND #13

#15 MeSH DESCRIPTOR Anticonvulsants Explode All WITH AD AE AG AN AI BL CF CS CH CL CT DU EC HI IM IP ME PK PD PO RE ST SD TU TO UR

#16 antiepilep* OR anti‐epilep* OR anticonvuls* OR anti‐convuls* OR aed OR aeds OR acetazolamide OR alodorm OR antilepsin OR arem OR ativan OR barbexaclone OR beclamide OR brivaracetam OR carbagen OR carbamazepine OR celontin OR cerebyx OR chlonazepam OR chloracon OR cloazepam OR clobazam OR clonazepamum OR clonex OR clonopin OR clorazepate OR convulex OR depacon OR depak* OR depamide OR desitin OR diacomit OR diamox OR diastat OR diazepam OR dilantin OR diphenin* OR diphenylhydantoin OR divalpr* OR dormicum OR ecovia OR emeside OR epanutin OR epiject OR epilim OR episenta OR epival OR eptoin OR ergenyl OR erimin OR eslicarbazepine OR ethadione OR ethosuximide OR ethotoin OR ethylphenacemide OR exalief OR excegran OR ezogabine OR fanatrex OR felbamate OR felbatol OR fosphenytoin OR frisium OR fycompa OR gabapentin OR gabarone OR gabitril OR gabrene OR ganaxolone OR garene OR gralise OR halogabide OR halogenide OR hibicon OR hypnovel OR iktorivil OR inovelon OR insoma OR intensl OR keppra OR klonopin OR kriadex OR lacosamide OR lamict* OR lamitor OR lamitrin OR lamogine OR lamotrigine OR lamotrine OR landsen OR levetiracetam OR liskantin OR loraz OR lorazepam OR losigamone OR luminal OR lyrica OR mebaral OR mephenytoin OR mephobarbit* OR mephyltaletten OR mesantoin OR mesuximide OR methazolamide OR methsuximide OR methylphenobarbit* OR midazolam OR mogadon OR mylepsinum OR mysoline OR neogab OR neptazane OR neurontin OR nimetazepam OR nitrados OR nitrazadon OR nitrazepam OR normison OR novo‐clopate OR nupentin OR nydrane OR onfi OR orfiril OR orlept OR ormodon OR ospolot OR oxcarbazepine OR pacisyn OR paraldehyde OR paramethadione OR paxadorm OR paxam OR peganone OR perampanel OR petinutin OR petril OR phemiton OR phenacemide OR pheneturide OR phenobarbit* OR phensuximide OR phenytek OR phenytoin OR posedrine OR potiga OR pregabalin OR primidone OR prodilantin OR progabide OR prominal OR prysoline OR ravotril OR remacemide OR remnos OR resimatil OR restoril OR retigabine OR riv?tril OR rufinamide OR sabril OR seclar OR selenica OR seletracetam OR sertan OR somnite OR stavzor OR stedesa OR stiripentol OR sulthiam* OR sultiam* OR talampanel OR tegretol OR temazepam OR temesta OR teril OR tiagabine OR timonil OR topamax OR topiramate OR tranxene OR tridione OR trileptal OR trimethadione OR trobalt OR urbanol OR valance OR valcote OR valium OR valnoctamide OR valparin OR valpro* OR versed OR vigabatrin OR vimpat OR zalkote OR zarontin OR zebinix OR zonegran OR zonisamide

#17 #15 OR #16

#18 #14 NOT #17

Appendix 2. CENTRAL search strategy

#1 MeSH descriptor: [Early Diagnosis] this term only

#2 (recent* or new* or early) near/2 (diagnos* or onset)

#3 "first seizure" or "first fit"

#4 #1 or #2 or #3

#5 MeSH descriptor: [Epilepsy] explode all trees

#6 epilep*

#7 #5 or #6

#8 MeSH descriptor: [Neuropsychology] explode all trees

#9 MeSH descriptor: [Rehabilitation] explode all trees

#10 MeSH descriptor: [Mind‐Body Therapies] explode all trees

#11 MeSH descriptor: [Psychotherapy] explode all trees

#12 abreaction or behav* modification or bibliotherap* or biofeedback or catharsis or conditioning or classical conditioning or counsel?ing or crisis intervention or desensiti?ation or early intervention or emotional freedom tapping or (eye movement near/2 (desensiti?ation or reprocessing)) or (feedback near/1 (psycholog* or sensory)) or flooding or free association or hypnosis or hypnotherapy or imagery or logotherapy or meditation or mindfulness or operant conditioning or post traumatic stress disorder or PTSD or psychodrama or psychotherap* or residential treatment? or rewind technique? or stress manag* or transactional analysis

#13 ((acceptance near/2 commitment) or anxiety or art or assertive or autogenic or autosuggestion or aversive or behav* or client cent* or cognitive or colo?r or compassion* or coping or couples or dance or depression or directive or exercise or family or gestalt or human givens or humanistic or implosive or interpersonal or language or marital or memory or mentali?ation or narrative or nondirective or nonpharmacol* or non‐pharmacol*) near/2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

#14 (panic or patient cent* or psycho* or quality of life or QOL or rational‐emotive or rational emotive or relaxation or self‐esteem or socioenvironmental or socio‐environmental or stigma or systemic or systems or therapeutic community or trauma) near/2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

#15 (adjustment or attention or confidence or day to day or loss or reality or suggestion) near/1 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

#16 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15

#17 #4 and #7 and #16 in Trials

#18 MeSH descriptor: [Anticonvulsants] explode all trees

#19 antiepilep* or anti‐epilep* or anticonvuls* or anti‐convuls* or aed or aeds or acetazolamide or alodorm or antilepsin or arem or ativan or barbexaclone or beclamide or brivaracetam or carbagen or carbamazepine or celontin or cerebyx or chlonazepam or chloracon or cloazepam or clobazam or clonazepamum or clonex or clonopin or clorazepate or convulex or depacon or depak* or depamide or desitin or diacomit or diamox or diastat or diazepam or dilantin or diphenin* or diphenylhydantoin or divalpr* or dormicum or ecovia or emeside or epanutin or epiject or epilim or episenta or epival or eptoin or ergenyl or erimin or eslicarbazepine or ethadione or ethosuximide or ethotoin or ethylphenacemide or exalief or excegran or ezogabine or fanatrex or felbamate or felbatol or fosphenytoin or frisium or fycompa or gabapentin or gabarone or gabitril or gabrene or ganaxolone or garene or gralise or halogabide or halogenide or hibicon or hypnovel or iktorivil or inovelon or insoma or intensl or keppra or klonopin or kriadex or lacosamide or lamict* or lamitor or lamitrin or lamogine or lamotrigine or lamotrine or landsen or levetiracetam or liskantin or loraz or lorazepam or losigamone or luminal or lyrica or mebaral or mephenytoin or mephobarbit* or mephyltaletten or mesantoin or mesuximide or methazolamide or methsuximide or methylphenobarbit* or midazolam or mogadon or mylepsinum or mysoline or neogab or neptazane or neurontin or nimetazepam or nitrados or nitrazadon or nitrazepam or normison or novo‐clopate or nupentin or nydrane or onfi or orfiril or orlept or ormodon or ospolot or oxcarbazepine or pacisyn or paraldehyde or paramethadione or paxadorm or paxam or peganone or perampanel or petinutin or petril or phemiton or phenacemide or pheneturide or phenobarbit* or phensuximide or phenytek or phenytoin or posedrine or potiga or pregabalin or primidone or prodilantin or progabide or prominal or prysoline or ravotril or remacemide or remnos or resimatil or restoril or retigabine or riv?tril or rufinamide or sabril or seclar or selenica or seletracetam or sertan or somnite or stavzor or stedesa or stiripentol or sulthiam* or sultiam* or talampanel or tegretol or temazepam or temesta or teril or tiagabine or timonil or topamax or topiramate or tranxene or tridione or trileptal or trimethadione or trobalt or urbanol or valance or valcote or valium or valnoctamide or valparin or valpro* or versed or vigabatrin or vimpat or zalkote or zarontin or zebinix or zonegran or zonisamide

#20 #18 or #19

#21 #17 not #20

Appendix 3. MEDLINE search strategy

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

1. early diagnosis/

2. ((recent$ or new$ or early) adj2 (diagnos$ or onset)).tw.

3. ("first seizure" or "first fit").tw.

4. 1 or 2 or 3

5. exp Epilepsy/ or epilep$.tw.

6. (validation studies or clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv or comparative study or evaluation studies or multicenter study).pt.

7. ((observation$ or cohort or case$ or cross?section$ or "cross section$" or "time‐series" or "time series" or "before and after" or "before‐and‐after" or retrospective) adj2 (study or trial or method)).mp.

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

9. clinical trials as topic.sh.

10. trial.ti.

11. 6 or 7 or 8 or 9 or 10

12. exp animals/ not humans.sh.

13. 11 not 12

14. 13 not case reports.pt.

15. exp Neuropsychology/ or exp Rehabilitation/ or exp Mind‐Body Therapies/ or exp psychotherapy/

16. (abreaction or behav$ modification or bibliotherap$ or biofeedback or catharsis or conditioning or classical conditioning or counsel?ing or crisis intervention or desensiti?ation or early intervention or emotional freedom tapping or (eye movement adj2 (desensiti?ation or reprocessing)) or (feedback adj1 (psycholog$ or sensory)) or flooding or free association or hypnosis or hypnotherapy or imagery or logotherapy or meditation or mindfulness or operant conditioning or post traumatic stress disorder or PTSD or psychodrama or psychotherap$ or residential treatment? or rewind technique? or stress manag$ or transactional analysis).tw.

17. (((acceptance adj2 commitment) or anxiety or art or assertive or autogenic or autosuggestion or aversive or behav$ or client cent$ or cognitive or colo?r or compassion$ or coping or couples or dance or depression or directive or exercise or family or gestalt or human givens or humanistic or implosive or interpersonal or language or marital or memory or mentali?ation or narrative or nondirective or nonpharmacol$ or non‐pharmacol$) adj2 (therap$ or treatment$ or train$ or retrain$ or rehabilitat$ or adapt$ or intervention$ or manag$)).tw.

18. ((panic or patient cent$ or psycho$ or quality of life or QOL or rational‐emotive or rational emotive or relaxation or self‐esteem or socioenvironmental or socio‐environmental or stigma or systemic or systems or therapeutic community or trauma) adj2 (therap$ or treatment$ or train$ or retrain$ or rehabilitat$ or adapt$ or intervention$ or manag$)).tw.

19. ((adjustment or attention or confidence or day to day or loss or reality or suggestion) adj1 (therap$ or treatment$ or train$ or retrain$ or rehabilitat$ or adapt$ or intervention$ or manag$)).tw.

20. 15 or 16 or 17 or 18 or 19

21. 5 and 14 and 20

22. 4 and 21

Appendix 4. SCOPUS search strategy

((TITLE‐ABS‐KEY(((recent* or new* or early) PRE/2 (diagnos* or onset)) OR "first seizure" OR "first fit")) AND ((TITLE‐ABS‐KEY(abreaction or "behav* modification" or bibliotherap* or biofeedback or catharsis or conditioning or "classical conditioning" or counselling or "crisis intervention" or desensitization or "early intervention" or "emotional freedom tapping" or ("eye movement" PRE/2 (desensitization or reprocessing)) or (feedback W/1 (psycholog* or sensory)) or flooding or "free association" or hypnosis or hypnotherapy or imagery or logotherap* or meditation or mindfulness or "operant conditioning" or "post traumatic stress disorder" or PTSD or psychodrama or psychotherap* or "residential treatment" or "rewind technique" or "stress manag*" or "transactional analysis")) OR (TITLE‐ABS‐KEY(((acceptance PRE/2 commitment) or anxiety or art or assertive or autogenic or autosuggestion or aversive or behav* or "client centred" or cognitive or colour or compassion* or coping or couples or dance or depression or directive or exercise or family or gestalt or "human givens" or humanistic or implosive or interpersonal or language or marital or memory or mentalization or narrative or nondirective or nonpharmacol* or non‐pharmacol*) PRE/2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*))) OR (TITLE‐ABS‐KEY((panic or "patient centred" or psycho* or "quality of life" or QOL or "rational emotive" or relaxation or self‐esteem or selfesteem or socio‐environmental or socioenvironmental or stigma or systemic or systems or "therapeutic community" or trauma) PRE/2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*))) OR (TITLE‐ABS‐KEY((adjustment or attention or confidence or "day to day" or loss or reality or suggestion) PRE/1 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)))) AND (((((TITLE‐ABS‐KEY(epilep* OR "infantile spasm" OR "ring chromosome 20" OR "R20" OR "myoclonic encephalopathy" OR "pyridoxine dependency")) OR (TITLE‐ABS‐KEY(syndrome W/2 (aicardi OR angelman OR doose OR dravet OR janz OR jeavons OR "landau kleffner" OR "lennox gastaut" OR ohtahara OR panayiotopoulos OR rasmussen OR rett OR "sturge weber" OR tassinari OR "unverricht lundborg" OR west)))) OR (TITLE(seizure OR convuls*))) OR ((TITLE‐ABS‐KEY(lafora* W/4 (disease OR epilep*))) AND NOT (TITLE(dog OR canine) OR INDEXTERMS(dog OR canine)))) AND NOT (TITLE(*eclampsia) OR INDEXTERMS(*eclampsia))) AND ((TITLE((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover OR "cross over" OR cluster OR "head to head") PRE/2 (trial OR method OR procedure OR study)) OR ABS((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover OR "cross over" OR cluster OR "head to head") PRE/2 (trial OR method OR procedure OR study))) OR (TITLE((validation OR clinical OR cohort OR comparative OR controlled OR evaluation OR multicenter OR observation* OR "case control" OR "case series" OR "cross section*" OR "time series" OR "before and after" OR prospective OR retrospective or "record linkage") PRE/2 (trial OR method OR procedure OR study)) OR ABS((validation OR clinical OR cohort OR comparative OR controlled OR evaluation OR multicenter OR observation* OR "case control" OR "case series" OR "cross section*" OR "time series" OR "before and after" OR prospective OR retrospective or "record linkage") PRE/2 (trial OR method OR procedure OR study))))) AND NOT ((TITLE((nonepileptic or non‐epileptic or psychogenic) PRE/2 (attack* or seizure*))) OR (TITLE(acupuncture or anorexi* or autis* or cancer or canine or "cerebral palsy" or chemotherap* or clozapine or contracepti* or dog or ECT or EEG or electro* or embryo* or "deep brain" or diet* or febrile or haloperidol or immunol* or genetic* or lobect* or MRI or magnetic or mice or mouse or neonatal or neoplasm or pharmaco* or pseudoseizure* or psychopharm* or neurosurg* or rat or surgical or surgery or tumour* or vagus or vagal)) OR (TITLE(antianxiety OR anti‐anxiety OR antidepressant* OR anti‐depressant* OR antineoplastic* OR anti‐neoplastic* OR antipsychotic* OR anti‐psychotic* OR antisickling OR anti‐sickling OR antiviral* OR anti‐viral* OR neurofibromatos*OR neuropath* OR vaccin*)) OR (ABS(antianxiety OR anti‐anxiety OR antidepressant* OR anti‐depressant* OR antineoplastic* OR anti‐neoplastic* OR antipsychotic* OR anti‐psychotic* OR antisickling OR anti‐sickling OR antiviral* OR anti‐viral* OR neurofibromatos*OR neuropath* OR vaccin*)) OR (TITLE(antiepilep* or anti‐epilep* or anticonvuls* or anti‐convuls* or AED or AEDs or Acetazolamide or Alodorm or Antilepsin or Arem or Ativan or Barbexaclone or Beclamide or Brivaracetam or Carbagen or Carbamazepine or Celontin or Cerebyx or Chlonazepam or Chloracon or Cloazepam or Clobazam or Clonazepamum or Clonex or Clonopin or Clorazepate or Convulex or Depacon or Depak* or Depamide or Desitin or Diacomit or Diamox or Diastat or Diazepam or Dilantin or Diphenin* or Diphenylhydantoin or Divalpr* or Dormicum or Ecovia or Emeside or Epanutin or Epiject or Epilim or Episenta or Epival or Eptoin or Ergenyl or Erimin or Eslicarbazepine or Ethadione or Ethosuximide or Ethotoin or Ethylphenacemide or Exalief or Excegran or Ezogabine or Fanatrex or Felbamate or Felbatol or Fosphenytoin or Frisium or Fycompa or Gabapentin or Gabarone or Gabitril or Gabrene or Ganaxolone or Garene or Gralise or Halogabide or Halogenide or Hibicon or Hypnovel or Iktorivil or Inovelon or Insoma or Intensl or Keppra or Klonopin or Kriadex or Lacosamide or Lamict* or Lamitor or Lamitrin or Lamogine or Lamotrigine or Lamotrine or Landsen or Levetiracetam or Liskantin or Loraz or Lorazepam or Losigamone or Luminal or Lyrica or Mebaral or Mephenytoin or Mephobarbit* or Mephyltaletten or Mesantoin or Mesuximide or Methazolamide or Methsuximide or Methylphenobarbit* or Midazolam or Mogadon or Mylepsinum or Mysoline or Neogab or Neptazane or Neurontin or Nimetazepam or Nitrados or Nitrazadon or Nitrazepam or Normison or Novo‐Clopate or Nupentin or Nydrane or Onfi or Orfiril or Orlept or Ormodon or Ospolot or Oxcarbazepine or Pacisyn or Paraldehyde or Paramethadione or Paxadorm or Paxam or Peganone or Perampanel or Petinutin or Petril or Phemiton or Phenacemide or Pheneturide or Phenobarbit* or Phensuximide or Phenytek or Phenytoin or Posedrine or Potiga or Pregabalin or Primidone or Prodilantin or Progabide or Prominal or Prysoline or Ravotril or Remacemide or Remnos or Resimatil or Restoril or Retigabine or Riv?tril or Rufinamide or Sabril or Seclar or Selenica or Seletracetam or Sertan or Somnite or Stavzor or Stedesa or Stiripentol or Sulthiam* or Sultiam* or Talampanel or Tegretol or Temazepam or Temesta or Teril or Tiagabine or Timonil or Topamax or Topiramate or Tranxene or Tridione or Trileptal or Trimethadione or Trobalt or Urbanol or Valance or Valcote or Valium or Valnoctamide or Valparin or Valpro* or Versed or Vigabatrin or Vimpat or Zalkote or Zarontin or Zebinix or Zonegran or Zonisamide)))

Appendix 5. PsycINFO search strategy

S23 S22 NOT S21

S22 S3 AND S6 AND S15

S21 S16 OR S17 OR S18 OR S19 OR S20

S20 TI antiepilep* or anti‐epilep* or anticonvuls* or anti‐convuls* or AED or AEDs or Acetazolamide or Alodorm or Antilepsin or Arem or Ativan or Barbexaclone or Beclamide or Brivaracetam or Carbagen or Carbamazepine or Celontin or Cerebyx or Chlonazepam or Chloracon or Cloazepam or Clobazam or Clonazepamum or Clonex or Clonopin or Clorazepate or Convulex or Depacon or Depak* or Depamide or Desitin or Diacomit or Diamox or Diastat or Diazepam or Dilantin or Diphenin* or Diphenylhydantoin or Divalpr* or Dormicum or Ecovia or Emeside or Epanutin or Epiject or Epilim or Episenta or Epival or Eptoin or Ergenyl or Erimin or Eslicarbazepine or Ethadione or Ethosuximide or Ethotoin or Ethylphenacemide or Exalief or Excegran or Ezogabine or Fanatrex or Felbamate or Felbatol or Fosphenytoin or Frisium or Fycompa or Gabapentin or Gabarone or Gabitril or Gabrene or Ganaxolone or Garene or Gralise or Halogabide or Halogenide or Hibicon or Hypnovel or Iktorivil or Inovelon or Insoma or Intensl or Keppra or Klonopin or Kriadex or Lacosamide or Lamict* or Lamitor or Lamitrin or Lamogine or Lamotrigine or Lamotrine or Landsen or Levetiracetam or Liskantin or Loraz or Lorazepam or Losigamone or Luminal or Lyrica or Mebaral or Mephenytoin or Mephobarbit* or Mephyltaletten or Mesantoin or Mesuximide or Methazolamide or Methsuximide or Methylphenobarbit* or Midazolam or Mogadon or Mylepsinum or Mysoline or Neogab or Neptazane or Neurontin or Nimetazepam or Nitrados or Nitrazadon or Nitrazepam or Normison or Novo‐Clopate or Nupentin or Nydrane or Onfi or Orfiril or Orlept or Ormodon or Ospolot or Oxcarbazepine or Pacisyn or Paraldehyde or Paramethadione or Paxadorm or Paxam or Peganone or Perampanel or Petinutin or Petril or Phemiton or Phenacemide or Pheneturide or Phenobarbit* or Phensuximide or Phenytek or Phenytoin or Posedrine or Potiga or Pregabalin or Primidone or Prodilantin or Progabide or Prominal or Prysoline or Ravotril or Remacemide or Remnos or Resimatil or Restoril or Retigabine or Riv?tril or Rufinamide or Sabril or Seclar or Selenica or Seletracetam or Sertan or Somnite or Stavzor or Stedesa or Stiripentol or Sulthiam* or Sultiam* or Talampanel or Tegretol or Temazepam or Temesta or Teril or Tiagabine or Timonil or Topamax or Topiramate or Tranxene or Tridione or Trileptal or Trimethadione or Trobalt or Urbanol or Valance or Valcote or Valium or Valnoctamide or Valparin or Valpro* or Versed or Vigabatrin or Vimpat or Zalkote or Zarontin or Zebinix or Zonegran or Zonisamide

S19 MM "Anticonvulsive Drugs" OR MM "Carbamazepine" OR MM "Chloral Hydrate" OR MM "Clonazepam" OR MM "Diphenylhydantoin" OR MM "Nitrazepam" OR MM "Oxazepam" OR MM "Pentobarbital" OR MM "Phenobarbital" OR MM "Pregabalin" OR MM "Primidone" OR MM "Valproic Acid"

S18 AB antianxiety OR anti‐anxiety OR antidepressant* OR anti‐depressant* OR antineoplastic* OR anti‐neoplastic* OR antipsychotic* OR anti‐psychotic* OR antisickling OR anti‐sickling OR antiviral* OR anti‐viral* OR neurofibromatos*OR neuropath* OR vaccin*

S17 TI antianxiety OR anti‐anxiety OR antidepressant* OR anti‐depressant* OR antineoplastic* OR anti‐neoplastic* OR antipsychotic* OR anti‐psychotic* OR antisickling OR anti‐sickling OR antiviral* OR anti‐viral* OR neurofibromatos*OR neuropath* OR vaccin*

S16 TI acupuncture or anorexi* or autis* or cancer or canine or "cerebral palsy" or chemotherap* or clozapine or contracepti* or dog or ECT or EEG or eclampsia or electro* or embryo* or "deep brain" or diet* or febrile or haloperidol or immunol* or genetic* or lobect* or MRI or magnetic or mice or mouse or neonatal or neoplasm or pharmaco* or pseudoseizure* or psychopharm* or neurosurg* or nonepileptic or non‐epileptic or pre‐eclampsia or psychogenic or rat or surgical or surgery or tumour* or vagus or vagal

S15 S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14

S14 (adjustment or attention or confidence or "day to day" or loss or reality or suggestion) W1 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

S13 (panic or "patient cent*" or psycho* or "quality of life" or QOL or rational‐emotive or relaxation or self‐esteem or socioenvironmental or socio‐environmental or stigma or systemic or systems or "therapeutic community" or trauma) W2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

S12 ((acceptance W2 commitment) or anxiety or art or assertive or autogenic or autosuggestion or aversive or behav* or "client cent*" or cognitive or colo#r or compassion* or coping or couples or dance or depression or directive or exercise or family or gestalt or "human givens" or humanistic or implosive or interpersonal or language or marital or memory or mentali#ation or narrative or nondirective or nonpharmacol* or non‐pharmacol*) W2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

S11 abreaction or "behav* modification" or bibliotherap* or biofeedback or catharsis or conditioning or "classical conditioning" or counsel#ing or "crisis intervention" or desensiti#ation or "early intervention" or "emotional freedom tapping" or ("eye movement" N2 (desensiti#ation or reprocessing)) or (feedback N1 (psycholog* or sensory)) or flooding or "free association" or hypnosis or hypnotherapy or imagery or logotherapy or meditation or mindfulness or "operant conditioning" or "post traumatic stress disorder" or PTSD or psychodrama or psychotherap* or "residential treatment#" or "rewind technique#" or "stress manag*" or "transactional analysis"

S10 MM "Mind Body Therapy"

S9 MM "Rehabilitation" OR MM "Psychotherapeutic Techniques" OR MM "Active Listening" OR MM "Animal Assisted Therapy" OR MM "Cotherapy" OR MM "Dream Analysis" OR MM "Empty Chair Technique" OR MM "Ericksonian Psychotherapy" OR MM "Mirroring" OR MM "Morita Therapy" OR MM "Motivational Interviewing" OR MM "Mutual Storytelling Technique" OR MM "Network Therapy" OR MM "Paradoxical Techniques" OR MM "Cognitive Rehabilitation" OR MM "Neuropsychological Rehabilitation" OR MM "Neurorehabilitation" OR MM "Occupational Therapy" OR MM "Physical Therapy" OR MM "Psychosocial Rehabilitation" OR MM "Therapeutic Social Clubs" OR MM "Vocational Rehabilitation" OR MM "Activities of Daily Living" OR MM "Adaptive Behavior" OR MM "Disability Management" OR MM "Habilitation" OR MM "Independent Living Programs" OR MM "Intervention" OR MM "Crisis Intervention" OR MM "Early Intervention" OR MM "Family Intervention" OR MM "Group Intervention" OR MM "School Based Intervention" OR MM "Rehabilitation Counseling" OR MM "Self Care Skills" OR MM "Support Groups" OR MM "Twelve Step Programs"

S8 MM "Psychotherapy" OR MM "Adlerian Psychotherapy" OR MM "Adolescent Psychotherapy" OR MM "Analytical Psychotherapy" OR MM "Autogenic Training" OR MM "Behavior Therapy" OR MM "Brief Psychotherapy" OR MM "Brief Relational Therapy" OR MM "Child Psychotherapy" OR MM "Client Centered Therapy" OR MM "Cognitive Behavior Therapy" OR MM "Cognitive Therapy" OR MM "Conversion Therapy" OR MM "Eclectic Psychotherapy" OR MM "Emotion Focused Therapy" OR MM "Existential Therapy" OR MM "Experiential Psychotherapy" OR MM "Expressive Psychotherapy" OR MM "Eye Movement Desensitization Therapy" OR MM "Feminist Therapy" OR MM "Geriatric Psychotherapy" OR MM "Gestalt Therapy" OR MM "Group Psychotherapy" OR MM "Guided Imagery" OR MM "Humanistic Psychotherapy" OR MM "Hypnotherapy" OR MM "Individual Psychotherapy" OR MM "Insight Therapy" OR MM "Integrative Psychotherapy" OR MM "Interpersonal Psychotherapy" OR MM "Logotherapy" OR MM "Narrative Therapy" OR MM "Network Therapy" OR MM "Persuasion Therapy" OR MM "Primal Therapy" OR MM "Psychoanalysis" OR MM "Psychodrama" OR MM "Psychodynamic Psychotherapy" OR MM "Psychotherapeutic Counseling" OR MM "Rational Emotive Behavior Therapy" OR MM "Reality Therapy" OR MM "Relationship Therapy" OR MM "Solution Focused Therapy" OR MM "Supportive Psychotherapy" OR MM "Transactional Analysis"

S7 (MM "Neuropsychology")

S6 S4 OR S5

S5 "first seizure" OR "first fit"

S4 (recent* or new* or early) W2 (diagnos* or onset)

S3 S1 OR S2

S2 epilep* OR seizure* OR convuls*

S1 MM "Epilepsy" OR MM "Epileptic Seizures" OR MM "Experimental Epilepsy" OR MM "Grand Mal Seizures" OR MM "Petit Mal Seizures" OR MM "Status Epilepticus"

Appendix 6. CINAHL search strategy

S24 S17 NOT S23

S23 S18 OR S19 OR S20 OR S21 OR S22

S22 (MM "Anticonvulsants+")

S21 TI antiepilep* or anti‐epilep* or anticonvuls* or anti‐convuls* or AED or AEDs or Acetazolamide or Alodorm or Antilepsin or Arem or Ativan or Barbexaclone or Beclamide or Brivaracetam or Carbagen or Carbamazepine or Celontin or Cerebyx or Chlonazepam or Chloracon or Cloazepam or Clobazam or Clonazepamum or Clonex or Clonopin or Clorazepate or Convulex or Depacon or Depak* or Depamide or Desitin or Diacomit or Diamox or Diastat or Diazepam or Dilantin or Diphenin* or Diphenylhydantoin or Divalpr* or Dormicum or Ecovia or Emeside or Epanutin or Epiject or Epilim or Episenta or Epival or Eptoin or Ergenyl or Erimin or Eslicarbazepine or Ethadione or Ethosuximide or Ethotoin or Ethylphenacemide or Exalief or Excegran or Ezogabine or Fanatrex or Felbamate or Felbatol or Fosphenytoin or Frisium or Fycompa or Gabapentin or Gabarone or Gabitril or Gabrene or Ganaxolone or Garene or Gralise or Halogabide or Halogenide or Hibicon or Hypnovel or Iktorivil or Inovelon or Insoma or Intensl or Keppra or Klonopin or Kriadex or Lacosamide or Lamict* or Lamitor or Lamitrin or Lamogine or Lamotrigine or Lamotrine or Landsen or Levetiracetam or Liskantin or Loraz or Lorazepam or Losigamone or Luminal or Lyrica or Mebaral or Mephenytoin or Mephobarbit* or Mephyltaletten or Mesantoin or Mesuximide or Methazolamide or Methsuximide or Methylphenobarbit* or Midazolam or Mogadon or Mylepsinum or Mysoline or Neogab or Neptazane or Neurontin or Nimetazepam or Nitrados or Nitrazadon or Nitrazepam or Normison or Novo‐Clopate or Nupentin or Nydrane or Onfi or Orfiril or Orlept or Ormodon or Ospolot or Oxcarbazepine or Pacisyn or Paraldehyde or Paramethadione or Paxadorm or Paxam or Peganone or Perampanel or Petinutin or Petril or Phemiton or Phenacemide or Pheneturide or Phenobarbit* or Phensuximide or Phenytek or Phenytoin or Posedrine or Potiga or Pregabalin or Primidone or Prodilantin or Progabide or Prominal or Prysoline or Ravotril or Remacemide or Remnos or Resimatil or Restoril or Retigabine or Riv?tril or Rufinamide or Sabril or Seclar or Selenica or Seletracetam or Sertan or Somnite or Stavzor or Stedesa or Stiripentol or Sulthiam* or Sultiam* or Talampanel or Tegretol or Temazepam or Temesta or Teril or Tiagabine or Timonil or Topamax or Topiramate or Tranxene or Tridione or Trileptal or Trimethadione or Trobalt or Urbanol or Valance or Valcote or Valium or Valnoctamide or Valparin or Valpro* or Versed or Vigabatrin or Vimpat or Zalkote or Zarontin or Zebinix or Zonegran or Zonisamide

S20 AB antianxiety OR anti‐anxiety OR antidepressant* OR anti‐depressant* OR antineoplastic* OR anti‐neoplastic* OR antipsychotic* OR anti‐psychotic* OR antisickling OR anti‐sickling OR antiviral* OR anti‐viral* OR neurofibromatos*OR neuropath* OR vaccin*

S19 TI antianxiety OR anti‐anxiety OR antidepressant* OR anti‐depressant* OR antineoplastic* OR anti‐neoplastic* OR antipsychotic* OR anti‐psychotic* OR antisickling OR anti‐sickling OR antiviral* OR anti‐viral* OR neurofibromatos*OR neuropath* OR vaccin*

S18 TI acupuncture or anorexi* or autis* or cancer or canine or "cerebral palsy" or chemotherap* or clozapine or contracepti* or dog or ECT or EEG or eclampsia or electro* or embryo* or "deep brain" or diet* or febrile or haloperidol or immunol* or genetic* or lobect* or MRI or magnetic or mice or mouse or neonatal or neoplasm or pharmaco* or pseudoseizure* or psychopharm* or neurosurg* or nonepileptic or non‐epileptic or pre‐eclampsia or psychogenic or rat or surgical or surgery or tumour* or vagus or vagal

S17 S3 AND S7 AND S16

S16 S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15

S15 (adjustment or attention or confidence or "day to day" or loss or reality or suggestion) W1 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

S14 (panic or "patient cent*" or psycho* or "quality of life" or QOL or rational‐emotive or relaxation or self‐esteem or socioenvironmental or socio‐environmental or stigma or systemic or systems or "therapeutic community" or trauma) W2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

S13 ((acceptance W2 commitment) or anxiety or art or assertive or autogenic or autosuggestion or aversive or behav* or "client cent*" or cognitive or colo#r or compassion* or coping or couples or dance or depression or directive or exercise or family or gestalt or "human givens" or humanistic or implosive or interpersonal or language or marital or memory or mentali#ation or narrative or nondirective or nonpharmacol* or non‐pharmacol*) W2 (therap* or treatment* or train* or retrain* or rehabilitat* or adapt* or intervention* or manag*)

S12 abreaction or "behav* modification" or bibliotherap* or biofeedback or catharsis or conditioning or "classical conditioning" or counsel#ing or "crisis intervention" or desensiti#ation or "early intervention" or "emotional freedom tapping" or ("eye movement" N2 (desensiti#ation or reprocessing)) or (feedback N1 (psycholog* or sensory)) or flooding or "free association" or hypnosis or hypnotherapy or imagery or logotherapy or meditation or mindfulness or "operant conditioning" or "post traumatic stress disorder" or PTSD or psychodrama or psychotherap* or "residential treatment#" or "rewind technique#" or "stress manag*" or "transactional analysis"

S11 (MM "Mind Body Techniques+")

S10 (MM "Rehabilitation+")

S9 (MM "Psychotherapy+")

S8 (MM "Neuropsychology")

S7 S4 OR S5 OR S6

S6 "first seizure" OR "first fit"

S5 (recent* or new* or early) W2 (diagnos* or onset)

S4 (MH "Early Diagnosis")

S3 S1 OR S2

S2 epilep* OR seizure* OR convuls*

S1 MM ("Epilepsy+" OR "Seizures")

Appendix 7. ClinicalTrials.gov search strategy

Search Terms: recently diagnosed OR newly diagnosed OR early onset

Conditions: epilepsy

Interventions: NOT drug

Appendix 8. WHO ICTRP search strategy

recently diagnosed epilepsy OR newly diagnosed epilepsy OR early onset epilepsy

(drug trials excluded manually)

Appendix 9. Extended 'Risk of bias' tool for non‐randomised studies

'Risk of bias' table (non‐randomised studies)

Item		Judgement a	Description (quote from paper, or describe key information)
1. Sequence generation
2. Allocation concealment
3a. Confounding b	Outcome 1
3b. Confounding b	Outcome 2
4a. Blinding?	Outcome 1
4b. Blinding?	Outcome 2
5a. Incompl. outcome data addressed?	Outcome 1
5b. Incompl. outcome data addressed?	Outcome 2
6a. Free of selective reporting?	Outcome 1
6b. Free of selective reporting?	Outcome 2
7. Free of other bias?
8. A priori protocol? c
9. A priori analysis plan? d

^a Some items on low/high risk/unclear scale (double‐line border), some on 5 point scale/unclear (single line border), some on yes/no/unclear scale (dashed border). For all items, record "unclear" if inadequate reporting prevents a judgement being made.

^b Based on list of confounders considered important at the outset and defined in the protocol for the review (and assessment against worksheet)

^c Did the researchers write a protocol defining the study population, intervention and comparator, primary and other outcomes, data collection methods, etc. in advance of starting the study? N.B. May be outcome specific.

^d Did the researchers have an analysis plan defining the primary and other outcomes, statistical methods, subgroup analyses, etc. in advance of starting the study?

Risk of bias (RoB) tool for non‐randomised studies (NRS)

Studies for which RoB tool is intended

Only suitable for 'cohort‐like' studies, individually or cluster‐allocated. This can include secondary analyses of clinical databases providing the analysis is clearly structured as a comparison of control and intervention participants. Refer to Ch.13, tables 13.2.a and b:

Table 13.2.a: individually allocated study designs

• RCT ‐ randomised controlled trial

• Q‐RCT ‐ quasi randomised controlled trial

• NRCT ‐ non‐randomised controlled trial

• CBA ‐ controlled before and after study (not common use of this label, see CChBA below)

• PCS ‐ prospective cohort study

• RCS ‐ retrospective cohort study

Table 13.2.b: cluster allocated study designs

• ClRCT ‐ cluster randomised controlled trial

• ClQ‐RCT ‐ cluster quasi randomised controlled trial

• ClNRCT ‐ cluster non‐randomised controlled trial

• CITS ‐ controlled interrupted time series

• CChBA ‐ controlled cohort before and after study (Shadish, Cook & Campbell)

Assessment of risk of bias

Issues when using modified RoB tool to assess cohort‐like non‐randomised studies:

• Follow principle for existing Cochrane RoB tool: score judgement and provide information (preferably direct quote) to support judgement

• Modified RoB tool include an additional item on confounding.

• 5‐point scale for some items (distinguish "unclear" from intermediate risk of bias).

• Keep in mind the general philosophy – assessment is not about whether researchers could have done better but about risk of bias; the assessment tool must be used in a standard way whatever the difficulty / circumstances of investigating the research question of interest and whatever study design features were used.

• Use of a 5‐point scale is uncharted territory; very interested to know whether this makes things easier or more difficult for reviewers.

• Anchors for 5‐point scale: "1/No/low risk" of bias should correspond to a high quality RCT. "5/high risk" of bias should correspond to a risk of bias that means the findings should not be considered (too risky, too much bias, more likely to mislead than inform).

1. Sequence generation

• Low/high/unclear RoB item

• Always high RoB (not random) for a non‐randomised study

• Might argue that this item redundant for NRS since always high RoB ‐ but important to include in RoB table ('level playing field' argument)

2. Allocation concealment

• Low/high/unclear RoB item

• Potentially low RoB for a non‐randomised study, e.g. quasi‐randomised (so high RoB to sequence generation) but concealed (reviewer judges that the people making decisions about including participants didn't know how allocation was being done, e.g. odd/even date of birth/hospital number)

3. RoB from confounding (additional item for NRS; assess for each outcome)

• Assumes a prespecified list of potential confounders defined in the protocol for the systematic review

• Low(1) / 2 / 3 / 4 / high(5) / unclear RoB item

• Judgement needs to factor in (see 'worksheet'):

  • proportion of confounders (from prespecified list) that were considered

  • whether most important confounders (from prespecified list) were considered

  • resolution / precision with which confounders were measured

  • extent of imbalance between groups at baseline

  • care with which adjustment was done (typically a judgement about the statistical modelling carried out by authors)

• Low RoB requires that all important confounders are balanced at baseline, i.e.

  • not primarily / not only a statistical judgement, OR

  • measured 'well' and 'carefully' controlled for in the analysis.

We have provided an optional 'worksheet' to help reviewers to focus on the task (rows=confounders and columns=factors to consider). Reviewers should make a RoB judgement about each factor first and then combine these (by eyeballing rather than quantitatively) to make the judgement in the main RoB table.

4. RoB from lack of blinding (assess for each outcome, as per existing RoB tool)

• Low(1) / 2 / 3 / 4 / high(5) / unclear RoB item

• Judgement needs to factor in:

  • nature of outcome (subjective / objective; source of information)

  • who was / was not blinded and the risk that those who were not blinded could introduce performance or detection bias

  • see Ch.8

5. RoB from incomplete outcome data (assess for each outcome, as per existing RoB tool)

• Low(1) / 2 / 3 / 4 / high(5) / unclear RoB item

• Judgement needs to factor in:

  • reasons for missing data

  • whether amount of missing data balanced across groups, with similar reasons

  • whether group comparison appropriate (e.g. 'analysed in allocated group' issue)

  • see Ch.8

6. RoB from selective reporting (assess for each outcome, N.B. more wide ranging than existing Ch.8 recommendation). Key issue is whether outcomes were clearly defined, and methods of analysis, were pre‐specified and adhered to.

• Low(1) / 2 / 3 / 4 / high(5) /unclear RoB item

• Judgement needs to factor in:

  • existing RoB guidance on selective outcome reporting, see Ch.8

  • also, extent to which analyses (and potentially other choices) could have been manipulated to bias the findings reported, e.g. choice of method of model fitting, potential confounders considered / included

  • look for evidence that there was a protocol in advance of doing any analysis / obtaining the data (difficult unless explicitly reported); NRS very different from RCTs. RCTs must have a protocol in advance of starting to recruit (for REC/IRB/other regulatory approval); NRS need not (especially older studies)

  • Hence, separate yes/no items asking reviewers whether they think the researchers had a prespecified protocol and analysis plan?

Appendix 10. Assessment of confounding variables

Assessment of how researchers dealt with confounding
Method for identifying relevant confounders described by researchers: yes no If yes, describe the method used:	o o
Relevant confounders described: yes no List confounders described below	o o
Method used for controlling for confounding At design stage: matching by characteristics of subjects (see below for matching by propensity score) Variables on which subjects matched: …………………………………. …………………………………. …………………………………. …………………………………. At analysis stage: stratification multivariable regression propensity scores (matching) propensity scores (multivariable regression) Describe confounders controlled for below	o o o o o

Confounders described by researchers

Enter / preprint prespecified list of confounders (rank order in importance? Important in bold?)
 Tick (yes/no judgement) if confounder considered by the researchers [Cons’d?]
 Score (1 to 5) precision with which confounder measured
 Score (1 to 5) imbalance between groups
 Score (1 to 5) care with which adjustment for confounder was carried out.

Confounder	Considered	Precision	Imbalance	Adjustment
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o
	o	o	o	o

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Martinovic 2006.

Methods	Randomised controlled trial 2 groups, CBI and TAU The randomisation procedure was achieved using a computer‐generated list of numbers assigned to participants
Participants	30 adolescents aged 13‐19 were randomised; 15 into the CBI group and 15 into the TAU group All participants were newly diagnosed with epilepsy (within 12 months) and showed sub‐threshold depression (score of 6‐8 on the BDI or 9‐14 on the CES‐D) All participants were within the normal intelligence range (intelligence quotients 85‐132)
Interventions	CBI involved helping participants recognise and correct 4 main types of cognitive errors: catastrophising, over‐generalisation, personalisation and selective abstraction. The CBI group received 8 sessions in 2 months then 4 sessions in 4 months TAU involved the same number of sessions based on therapeutic counselling without CBI
Outcomes	BDI ‐ subjective scale of depressive symptoms CES‐D ‐ subjective scale of depressive symptoms HAMD ‐ subjective scale of depressive symptoms QOLIE‐31 ‐ subjective scale of quality of life
Notes	2 participants dropped out in the first 2 months. These participants were excluded from the study and not included in the analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated allocation of numbers to randomise participants into intervention and control group
Allocation concealment (selection bias)	Unclear risk	Unclear which assessor administered which intervention; whether the same assessor administered both intervention and control group sessions or not
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Although the participants were blinded, it is unclear whether the study personnel were
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Unclear which assessor administered which intervention, therefore, whether they were effectively blinded to the differences between the interventions is unclear
Incomplete outcome data (attrition bias) All outcomes	Low risk	It was reported that 2 participants withdrew in the first 2 months of the study; 1 in the treatment group and 1 in the intervention group. Their results were withdrawn from the study. Therefore, an intention‐to‐treat analysis was not possible. The reasons for withdrawal are unlikely to be associated with the study.
Selective reporting (reporting bias)	Unclear risk	The primary and secondary outcomes were analysed and reported in the results section
Other bias	Unclear risk	There were no details about the funding of this research or who carried out the CBI and their qualifications. It is also unclear what the content of the CBI and TAU intervention was.

Ridsdale 2000.

Methods	Randomised controlled trial 2 groups; a nurse intervention and TAU group Unclear how randomisation was achieved; states participants were randomised in blocks
Participants	102 participants were randomised; 54 into the nurse intervention group and 48 into the TAU group All participants were newly diagnosed (time unspecified) and were over the age of 17 years Participants with learning or language difficulties were excluded
Interventions	The nurse intervention consisted 2 additional appointments with a nurse specialist; one 45‐ to 50‐minute appointment and one 15‐ to 20‐minute appointment 3 months later The nurse intervention involved advice on driving, self help groups, epilepsy types and causes, adverse effects and interactions of antiepileptic drugs, and risk avoidance. These sessions were patient‐led
Outcomes	Adapted satisfaction questionnaire 'Knowledge of epilepsy' questionnaire HADS ‐ subjective scale of anxiety and depression symptoms
Notes	88% of participants returned the questionnaires at stage 2. Therefore, results from 90 participants (43 in the TAU group and 47 in the nurse intervention group) were included in the analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	States only that the participants were randomised in blocks. There were no details about how this randomisation was achieved
Allocation concealment (selection bias)	Unclear risk	Insufficient information pertaining to randomisation process
Blinding of participants and personnel (performance bias) All outcomes	High risk	Although participants were blinded, study personnel were not
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcome assessors were not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	In the intervention group, 7 participants withdrew after randomisation; 2 moved away, 2 had other illnesses and 3 were non‐responders. In the control group, 5 participants withdrew after randomisation; 1 moved away, 1 had other illnesses and 3 were non‐responders. As withdrawal rate was comparable between the intervention and control group, we rated incomplete outcome data bias as low
Selective reporting (reporting bias)	Unclear risk	Insufficient information about secondary outcomes due to unavailability of protocol
Other bias	Unclear risk	The intervention delivered by nurse specialists was individualised to each participant, therefore the nature and content of the intervention given was unclear

BDI: Beck Depression Inventory; CBI: cognitive behavioural intervention; CES‐D: Center for Epidemiological Study on Depression; HADS: Hospital Anxiety and Depression Scale; HAMD: Hamilton Depression Scale; QOLIE‐31: Quality of Life in Epilepsy; TAU: treatment as usual.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Burneo 2007	Pharmacological intervention only
Chaplin 1995	Not intervention
Chung 2012	Not newly diagnosed epilepsy
Guilfoyl 2012	Not intervention
McDonald 2011	Not intervention
Nenadovic 2011	Not intervention
Rapoff 2013	Children only; intervention for adherence to medication only

Differences between protocol and review

The objective has been reworded and no longer states for improving quality of life.

The criteria for including studies ‐ types of participants has been amended and now states newly diagnosed within 18 months, rather than two years and now also states that studies with a mixed sample in terms of age were included.

One additional primary outcome has been added (description of risk factors) and two secondary outcomes have been added (knowledge of epilepsy and seizure frequency/recency).

More detail has been added to the Unit of analysis issues section.

Following comments from peer reviewers, the 'Background' section has been condensed.

Contributions of authors

CJ: responsible for developing the protocol, assessing studies for eligibility, data extraction, assessing risk of bias and writing up the review.

SMM: contributed to developing the protocol, assessing studies for eligibility, data extraction, assessing risk of bias and supervising the write up of the review.

GAB: supervised the review process and provided expert opinion and feedback.

Sources of support

Internal sources

• No sources of support supplied

External sources

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

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

Declarations of interest

None known.

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