The CODES trial for dissociative seizures: a landmark study and inflection point

Dissociative seizures, also known as psychogenic non-epileptic or functional seizures, are a common and disabling subtype of functional neurological disorder.1Perez DL LaFrance Jr, WC Nonepileptic seizures: an updated review.CNS Spectr. 2016; 21: 239-246Crossref PubMed Scopus (86) Google Scholar While patients with dissociative seizures were largely neglected for much of the 20th century by clinicians and academics alike, interest with regard to understanding and effectively treating the condition has increased in the past two decades. Across academic medical centres worldwide, very few treatment pathways are available for these patients. Psychotherapy, particularly cognitive behavioural therapy (CBT), has been highly regarded by leaders in the field as a promising treatment for dissociative seizures.2Goldstein LH Chalder T Chigwedere C et al.Cognitive-behavioral therapy for psychogenic nonepileptic seizures: a pilot RCT.Neurology. 2010; 74: 1986-1994Crossref PubMed Scopus (330) Google Scholar, 3LaFrance Jr, WC Baird GL Barry JJ et al.Multicenter pilot treatment trial for psychogenic nonepileptic seizures: a randomized clinical trial.JAMA Psychiatry. 2014; 71: 997-1005Crossref PubMed Scopus (292) Google Scholar As such, the publication of the COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES) clinical trial4Goldstein LH Robinson EJ Mellers JDC et al.Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.Lancet Psychiatry. 2020; 7: 491-505Summary Full Text Full Text PDF PubMed Scopus (109) Google Scholar by Laura Goldstein and colleagues is an important and landmark event in this area of research. In the CODES trial, patients with dissociative seizures were recruited from 27 neurology and epilepsy services in the UK and subsequently randomly assigned from 17 liaison or neuropsychiatry services following psychiatric assessment. 368 patients were randomly assigned (1:1) to 12 sessions of manualised CBT (1 h duration), based on fear avoidance models, plus standardised medical care (n=186) or to standardised medical care alone (n=182). The two groups were matched for demographic and clinical characteristics across neurological and psychiatric factors, and post-treatment follow-up data were collected for more than 80% of individuals across both treatment groups. At 12 months post-randomisation, intention-to-treat analysis showed no statistically significant difference in the primary outcome of monthly dissociative seizure frequency (ie, frequency in previous 4 weeks) between the two groups (median 4 seizures [IQR 0–20] in the CBT plus standardised medical care group vs 7 seizures [1–35] in the standardised medical care group; estimated incidence rate ratio 0·78 [95% CI 0·56–1·09]; p=0·144). In nine of 16 secondary outcomes, CBT plus standardised medical care showed clinical benefit compared with standardised medical care alone. Benefits in the CBT plus standardised medical care treatment group included a longer period without dissociative seizures in the last 6 months of the study, fewer somatic symptoms, better health-related quality of life, and improved psychosocial functioning, compared with those who received standardised medical care alone. Although the clinical benefits of CBT for dissociative seizures are highlighted by the improvements observed across secondary outcome measures, the study did not identify a statistically significant treatment effect on the primary outcome of seizure frequency. Thus, it is necessary to question whether this large, well-conducted clinical trial with a negative primary outcome proves that CBT is not incrementally effective for the treatment of dissociative seizures. In my opinion, CBT remains an effective treatment for dissociative seizures. I have witnessed how some patients with dissociative seizures can benefit greatly from a CBT approach that equips the patient with new psychotherapeutic tools, which in certain individuals can lead to robust and sustained clinical improvement. However, there are two major questions raised by the CODES trial findings. The first question is whether seizure frequency should be the preferred primary outcome measure in clinical trials for dissociative seizures. Associations between dissociative seizure frequency and health-related quality of life are complex and multifactorial, and psychosocial and psychiatric factors might relate more closely to health-related quality of life than seizure frequency itself.5Rawlings GH Brown I Reuber M Predictors of health-related quality of life in patients with epilepsy and psychogenic nonepileptic seizures.Epilepsy Behav. 2017; 68: 153-158Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar An international group for functional neurological disorder core outcome measures recently published two articles noting the importance of not only considering functional neurological symptom severity (eg, dissociative seizure frequency), but also concurrently assessing other physical (eg, pain or fatigue) and mental health (eg, post-traumatic stress disorder or panic attack) symptoms.6Pick S Anderson DG Asadi-Pooya AA et al.Outcome measurement in functional neurological disorder: a systematic review and recommendations.J Neurol Neurosurg Psychiatry. 2020; (published online Feb 28.)DOI:10.1136/jnnp-2019-322180Crossref PubMed Scopus (51) Google Scholar, 7Nicholson TR Carson A Edwards MJ et al.Outcome measures for functional neurological disorder: a review of the theoretical complexities.J Neuropsychiatry Clin Neurosci. 2020; 32: 33-42Crossref PubMed Scopus (41) Google Scholar Possible alternatives to consider for primary outcomes include using composite scores, or the development of a new outcome measure that incorporates multiple aspects of the symptom complex. The second and equally necessary question pertains to whether the research community should continue pursuing a one-size-fits-all type of design for clinical trials involving dissociative seizures, in light of the trial findings to date, and the well established heterogeneity observed in this population. For example, some patients with dissociative seizures might experience prominent so-called panic-without-panic autonomic symptoms and increased avoidance (sometimes with comorbid panic disorder), whereas others with the same diagnosis might experience comorbid post-traumatic stress disorder or borderline personality disorder traits. Other individuals with dissociative seizures might not report prominent mood, anxiety, or trauma-related symptoms, and might experience dissociative seizures only after head trauma. In moving towards a more patient-centred, precision medicine type of clinical trial design for dissociative seizures, there is a need to consider testing modular approaches that evaluate the efficacy of psychotherapy treatments on the basis of clinical formulations that consider not only the diagnosis of dissociative seizures, but a range of other medical, neurological, psychiatric, and psychosocial factors that might be present. Patients with prominent affective dysregulation and poor distress tolerance could be triaged to dialectical behaviour therapy,8Bullock KD Mirza N Forte C Trockel M Group dialectical-behavior therapy skills training for conversion disorder with seizures.J Neuropsychiatry Clin Neurosci. 2015; 27: 240-243Crossref PubMed Scopus (22) Google Scholar while those with dissociative seizures and post-traumatic stress disorder could potentially derive the most benefit from prolonged exposure-based psychotherapy.9Myers L Vaidya-Mathur U Lancman M Prolonged exposure therapy for the treatment of patients diagnosed with psychogenic non-epileptic seizures (PNES) and post-traumatic stress disorder (PTSD).Epilepsy Behav. 2017; 66: 86-92Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar Alternatively, others might benefit from mindfulness-based interventions.10Baslet G Ehlert A Oser M Dworetzky BA Mindfulness-based therapy for psychogenic nonepileptic seizures.Epilepsy Behav. 2020; 103106534Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar Many challenges exist when evaluating the optimal path forward within this field of research, including the need to better engage funding agencies. Nonetheless, the time is now for the international research community to engage in these important discussions, following the results of this landmark study. I have received honoraria from Harvard Medical School, the American Academy of Neurology, the Movement Disorder Society, Toronto Western Hospital, and Newton-Wellesley Hospital for continuing medical education lectures in functional neurological disorder. Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trialCBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Full-Text PDF Open Access

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