Title: Cognitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures: A multi-centre randomised controlled trial (CODES)
Funder: Department of Health and Social Care

Abstract: DESIGN: A single-blind randomised controlled trial (RCT) of Cognitive Behavioural Therapy (CBT) for dissociative non-epileptic seizures (DS) (plus standardised medical care - SMC) vs. SMC alone. Follow-up will be at 6 and 12 months post randomisation. SETTING: Initial recruitment will be from secondary/tertiary epilepsy/neurology clinics at the time of diagnosis. Patients will be seen 3m later in neuro/liaison psychiatry clinics. Those continuing to have seizures for the previous 8 weeks will be randomised. SMC will consist of out-patient neurology and psychiatry input. CBT will be delivered in out-patient clinics. STRATEGY FOR REVIEWING LITERATURE: Reviews of the DS treatment literature [e.g. 1, 2] and Cochrane reviews [3] highlight the need for multi-centre RCTs. TARGET POPULATION: Collaborating neurologists will deliver DS diagnosis to adults aged at least 18 years old, with DS and no current comorbid epilepsy. Patients will be told about the study by the diagnosing doctor, given an information sheet about DS and about the study and asked if LCRN/research staff can contact them. This person will then obtain consent, complete the case report form, explain how patients should complete seizure diaries and that different treatments will be compared if DS persist. Patients will record DS frequency, with regular reminders from a researcher. At 3m, the literature suggests that 85% are likely to still experience DS. Following psychiatric review, eligible patients continuing to have DS in the previous 8 weeks and who are willing to take part will be consented for the trial, and after structured psychiatric assessment (using the MINI) by a trained researcher and completion of baseline measures, will be randomised to CBT+SMC or to SMC alone. From our prior trial experience 70% will agree to randomisation. HEALTH TECHNOLOGY BEING ASSESSED: 12 CBT sessions delivered by a trained CBT therapist over 4-5m (plus 1 booster session) using our manualised treatment [4]. This focuses on cognitive, emotional, physiological and behavioural aspects of DS. Treatment includes seizure-directed techniques, attention refocusing, relaxation, addressing avoidance behaviours, negative cognitions and traumatic experiences and involves family members. Homework tasks are set and psychoeducational handouts given. Therapists will be trained to deliver the manualised treatment and will receive supervision. Treatment fidelity will be measured. SMC will be from neurologists and psychiatrists, will include anti-epileptic drug (AED) management and may involve psychotropic drugs but not CBT-type techniques. MEASUREMENT OF COST AND OUTCOMES: Outcomes, health service use and cost-effectiveness will be measured with valid self-report questionnaires pre-, then 6 and 12m post randomisation. Our primary outcome is seizure frequency, a continuous variable taking into account all participants’ outcomes. Secondary outcomes include seizure severity, number of patients with >50% reduction in DS, informants’ ratings of seizure outcome, duration of seizure freedom in the last 6m of the trial, number of seizure-free patients in last 3m of trial[4], health-related quality of life (SF-12v2), psychosocial adjustment (Work & Social Adjustment Scale), psychiatric symptoms and psychological distress [anxiety and depression (GAD7; PHQ9), somatic symptom severity (extended PHQ15); global psychological distress (CORE-10)]. We will measure quality-adjusted life years (QALYS; via the EQ5D). Health service use, informal care, lost work time, work status and benefits will be measured via a Client Service Receipt Inventory. Health service costs will combine the service use data with appropriate unit cost information. Costs will be linked to QALYs in the economic evaluation. Health service use will also be measured using independent centrally-held measures. Service users have informed our choice of short questionnaires. Qualitative research will describe patients’ experiences of treatment, barriers to participation and future concerns to inform NHS roll-out. We will sample purposively and analyse data using Framework analysis. SAMPLE SIZE: Post diagnosis, data show that DS may stop in about 15% of patients by 3m, so these patients will not be part of our target population. Our power calculation is based on the primary ITT analysis that will compare two equally-sized treatment arms, CBT (+ SMC) or SMC alone in patients who continue to have DS 3m post diagnosis. Regarding DS frequency, our pilot RCT found an effect size of d=0.42 at 6m after treatment end. This approximates to 12m post-randomisation follow-up in this new study. A total sample size of 368 patients (randomised 1:1) will provide 92.6% power to detect this effect size using 2-tailed t-tests at 5% significance level. Our sample size calculation allows for likely therapist effects related to 15 therapists with average caseloads of 10 patients (intraclass correlation 0.02), a 17% loss to follow-up and a precision gain by covarying for pre-randomisation DS frequency. It is possible that 25% of patients initially receiving DS diagnosis may refuse to enrol in our study, 15% may no longer have DS at 3m and 30% may decline randomisation, so we must identify a total of approx 668 newly-diagnosed patients. We have agreement from multiple neurology/specialist epilepsy services and mental health services in the UK to participate. We will monitor recruitment rates monthly and extend recruitment sites if numbers are initially lower than expected, or close at month 24, if recruitment remains too low at month 18. PROJECT TIMETABLE (INCL. RECRUITMENT RATE): months 1-3 Finalisation of permissions at clinical services, meetings with doctors over content of SMC; set-up recruitment systems at sites; months 2-4 train RWs to administer MINI; months 3-6 train CBT therapists; months 3-30 recruitment in neurology services (estimated recruitment rate 18 patients/month); months 6-33 psychiatric assessment, randomisation; month 45 last 12 month follow-up; month 46 database locked; months 42-45 qualitative data analysis; months 46-50 quantitative analysis, dissemination. EXPERTISE IN TEAM: The team includes experts in CBT for somatoform disorders and DS (T Chalder), clinical psychology (L Goldstein), neuropsychiatry (J Mellers, A Carson, and N Medford), neurology, epilepsy and functional neurological symptoms (M Richardson, M Reuber, and J Stone), health service economics (P McCrone), qualitative methods (J Murray) and statistics (S Landau). T Chalder is an expert trialist for complex interventions. L Goldstein, T Chalder and J Mellers conducted a pilot RCT of CBT for DS. L Goldstein, S Landau, P McCrone and J Murray collaborate in other health service studies. M Reuber has led other NIHR-funded DS studies. 1) Carson A et al JNNP 2012;83:842-50 2) Goldstein L, Mellers J. Curr Neurol Neurosci Rep 2012;12:436–44 3) Martlew J et al Cochrane Epilepsy Group.2009. Epub 7 Oct 2009 4) Goldstein L et al Neurology 2010;74:1986-94

Lay abstract: About 12-20% of patients who attend neurology or specialist epilepsy clinics because of seizures do not in fact have epilepsy. Most of these people have what are referred to as dissociative nonepileptic seizures (DS). This means that they have episodes that resemble epileptic seizures but which have no medical reason for their occurrence and instead are due to psychological factors. It is not unusual for people with DS to have a history of trauma or abuse (physical or sexual) and in younger adults DS are about four times more common in women than men. A high percentage of these individuals will have other psychological or psychiatric problems, such as anxiety, depression, or post-traumatic stress disorder and may have other medically unexplained symptoms. Unfortunately, because of the appearance of their seizures, people with DS may initially be misdiagnosed with epilepsy and the correct diagnosis may take a number of years. People with DS often have poor outcome in terms of work and disability status, It is generally thought that people with DS will benefit from psychological treatments. Over the past 10 years or so there has been increasing interest in providing treatments for people with DS. However, the studies looking at how people with DS benefit from psychological therapy have generally been very small or have not compared the psychological therapy with the treatment people normally receive (referred to as standard medical care). This means that results have been inconclusive. There is some indication that cognitive behavioural therapy (CBT), which is a widely accepted talking therapy that focuses on the person's thoughts, emotions and behaviour, as well as considering the physical reactions and sensations that may occur in people’s bodies, may produce a reduction in the occurrence of DS. Unfortunately there have been no studies yet that meet the requirements for the National Institute for Health and Care Excellence to make psychological treatments widely available for DS patients. In fact treatment provision at present for this patient group in the UK is extremely variable. Our group's previous work in this area has consisted of developing a CBT package for people with DS. We have written papers about this work. In a relatively small study where patients were allocated at random to either receive their standard medical care or CBT plus standard medical care, we found that people receiving CBT overall showed greater reduction in their DS occurrence than did the group only receiving standard care. However, the size of the two groups was not large enough for the results of this earlier study to be accepted with certainty. We are now proposing to undertake a larger study, across several different hospitals, which will enable us to obtain more definitive results about the effectiveness of our CBT approach for DS. We will measure treatment effectiveness in terms of reducing the frequency of people’s seizures and improving a number of aspects of their psychological functioning such as mood and quality of life. We will also measure the reduction in people's use of health services, time lost from work by themselves or their family due to their DS, their dependence on informal care by family and friends and the level of financial state benefits that they receive. We will also ask people who have received either the CBT and standard care, or standard care alone how they have found the treatment and what improvements we might make when considering how this treatment might be offered more widely in the NHS. We plan to invite patients with DS, who have been given their diagnosis by a neurologist or specialist in epilepsy, to take part in our study. We will collect some initial information about these patients and ask them to keep a record of how often they have their DS following diagnosis. Three months after the diagnosis, those who have agreed to take part in the study will be seen by a psychiatrist who will undertake a psychiatric assessment and ask them about factors which may have led to the development of their DS. We anticipate at this point that about 85% of people who received the DS diagnosis will still be having seizures. We will ask those who are continuing to have seizures to consider taking part in the comparison of standardised medical care versus CBT (plus standardised medical care) as further treatment for their seizures. For those willing to do this, a research worker will then also undertake a structured psychiatric interview asking the same questions of all patients so that we can describe the people who are taking part in our study more clearly. The research worker will also then ask people to fill in questionnaires about the severity of their seizures, their mood and other symptoms, quality of life and use of health services over the previous 6 months. After that, 368 patients will be allocated at random (i.e. they cannot choose which treatment they receive) and will either continue to receive standardised medical care from their neurologist and psychiatrist (149 people) or to receive 12 CBT sessions from a trained CBT therapist over a 5-month period, as well as their standardised medical care (149 people). We will measure outcomes in both groups of patients at 6 months after randomisation using a postal survey and again at 12 months post randomisation, when a research worker will interview all the individuals in person. We will provide travel expenses to enable patients to take part in the study and research workers will regularly remind individuals about keeping records of how often they are having their seizures. The CBT therapists will receive training and supervision in the use of our particular approach to working with DS patients and we will measure how consistently the treatment is delivered. Service users who have DS will be members of our study management committees. They will receive support from the research team and training from Epilepsy Action (EA; the largest member-led epilepsy charity in the UK). EA is experienced in helping service user involvement in research projects. If CBT (plus standardised medical care) is more effective than standardised medical care alone in reducing DS frequency and improving patients' psychological functioning, as well as reducing health service use, research could inform the NHS and the Department of Health to increase the availability of services for this patient group.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH;NEUROLOGICAL