Cognitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures: A multi-centre randomised controlled trial (CODES)

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