Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Cognitive-behavioural therapy compared with standardised medical care for adults with dissociative non-epileptic seizures: the CODES RCT.

BACKGROUND: Dissociative (non-epileptic) seizures are potentially treatable by psychotherapeutic interventions; however, the evidence for this is limited. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of dissociative seizure-specific cognitive-behavioural therapy for adults with dissociative seizures. DESIGN: This was a pragmatic, multicentre, parallel-arm, mixed-methods randomised controlled trial. SETTING: This took place in 27 UK-based neurology/epilepsy services, 17 liaison psychiatry/neuropsychiatry services and 18 cognitive-behavioural therapy services. PARTICIPANTS: Adults with dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous year and meeting other eligibility criteria were recruited to a screening phase from neurology/epilepsy services between October 2014 and February 2017. After psychiatric assessment around 3 months later, eligible and interested participants were randomised between January 2015 and May 2017. INTERVENTIONS: Standardised medical care consisted of input from neurologists and psychiatrists who were given guidance regarding diagnosis delivery and management; they provided patients with information booklets. The intervention consisted of 12 dissociative seizure-specific cognitive-behavioural therapy 1-hour sessions (plus one booster session) that were delivered by trained therapists, in addition to standardised medical care. MAIN OUTCOME MEASURES: The primary outcome was monthly seizure frequency at 12 months post randomisation. The secondary outcomes were aspects of seizure occurrence, quality of life, mood, anxiety, distress, symptoms, psychosocial functioning, clinical global change, satisfaction with treatment, quality-adjusted life-years, costs and cost-effectiveness. RESULTS: In total, 698 patients were screened and 368 were randomised (standardised medical care alone, n = 182; and cognitive-behavioural therapy plus standardised medical care, n = 186). Primary outcome data were obtained for 85% of participants. An intention-to-treat analysis with multivariate imputation by chained equations revealed no significant between-group difference in dissociative seizure frequency at 12 months [standardised medical care: median of seven dissociative seizures (interquartile range 1-35 dissociative seizures); cognitive-behavioural therapy and standardised medical care: median of four dissociative seizures (interquartile range 0-20 dissociative seizures); incidence rate ratio 0.78, 95% confidence interval 0.56 to 1.09; p = 0.144]. Of the 16 secondary outcomes analysed, nine were significantly better in the arm receiving cognitive-behavioural therapy at a p-value < 0.05, including the following at a p-value ≤ 0.001: the longest dissociative seizure-free period in months 7-12 inclusive post randomisation (incidence rate ratio 1.64, 95% confidence interval 1.22 to 2.20; p = 0.001); better psychosocial functioning (Work and Social Adjustment Scale, standardised treatment effect -0.39, 95% confidence interval -0.61 to -0.18; p < 0.001); greater self-rated and clinician-rated clinical improvement (self-rated: standardised treatment effect 0.39, 95% confidence interval 0.16 to 0.62; p = 0.001; clinician rated: standardised treatment effect 0.37, 95% confidence interval 0.17 to 0.57; p < 0.001); and satisfaction with treatment (standardised treatment effect 0.50, 95% confidence interval 0.27 to 0.73; p < 0.001). Rates of adverse events were similar across arms. Cognitive-behavioural therapy plus standardised medical care produced 0.0152 more quality-adjusted life-years (95% confidence interval -0.0106 to 0.0392 quality-adjusted life-years) than standardised medical care alone. The incremental cost-effectiveness ratio (cost per quality-adjusted life-year) for cognitive-behavioural therapy plus standardised medical care versus standardised medical care alone based on the EuroQol-5 Dimensions, five-level version, and imputed data was £120,658. In sensitivity analyses, incremental cost-effectiveness ratios ranged between £85,724 and £206,067. Qualitative and quantitative process evaluations highlighted useful study components, the importance of clinical experience in treating patients with dissociative seizures and potential benefits of our multidisciplinary care pathway. LIMITATIONS: Unlike outcome assessors, participants and clinicians were not blinded to the interventions. CONCLUSIONS: There was no significant additional benefit of dissociative seizure-specific cognitive-behavioural therapy in reducing dissociative seizure frequency, and cost-effectiveness over standardised medical care was low. However, this large, adequately powered, multicentre randomised controlled trial highlights benefits of adjunctive dissociative seizure-specific cognitive-behavioural therapy for several clinical outcomes, with no evidence of greater harm from dissociative seizure-specific cognitive-behavioural therapy. FUTURE WORK: Examination of moderators and mediators of outcome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05681227 and ClinicalTrials.gov NCT02325544. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 43. See the NIHR Journals Library website for further project information.

Dissociative seizures resemble epileptic seizures or faints, but can be distinguished from them by trained doctors. Dissociation is the medical word for a 'trance-like' or 'switching off' state. People with dissociative seizures commonly have other psychological or physical problems. Quality of life may be low. The condition accounts for about one in every six patients seen in hospitals because of seizures. We wanted to find out if people with dissociative seizures receiving standardised treatment would also benefit from a talking therapy, called cognitive­behavioural therapy, made specific to this disorder. We did a randomised controlled trial to find out if people with dissociative seizures given standardised treatment and cognitive­behavioural therapy (talking therapy) would do better than those given standardised treatment alone. Standardised treatment of dissociative seizures began with careful diagnosis from a neurologist and then further assessment and treatment from a psychiatrist. In total, 368 people with dissociative seizures participated, with half receiving standardised treatment alone and half having talking therapy plus standardised treatment. We measured seizures and psychological and physical health in both trial groups. We also investigated whether or not cognitive­behavioural therapy was good value for money. After 12 months, patients in both trial groups seemed to have fewer monthly seizures, but there was no advantage in the talking therapy group. Patients in the talking therapy group had more consecutive days without seizures, reporting less impact from them in everyday situations. Patients in the talking therapy group, and their doctors, considered improvements to be better, and patients in this group reported greater satisfaction with treatment. However, the talking therapy was expensive and not as cost-effective as hoped. Interviews with patients and study clinicians showed that they valued aspects of both treatments and of the care provided by the multidisciplinary teams. Overall, cognitive­behavioural therapy designed for dissociative seizures plus standardised treatment was not better at reducing the total numbers of seizures reported, but did produce several positive benefits for participants compared with standardised treatment alone.

Emotional dysregulation, alexithymia, and attachment in psychogenic nonepileptic seizures.

OBJECTIVES: Psychogenic nonepileptic seizures (PNESs) are poorly understood and difficult to treat. Research and theory suggest that problems with recognizing, acknowledging, and regulating emotional states (i.e., emotional dysregulation) may contribute to the development and maintenance of PNESs. However, there is a lack of well-controlled studies using dedicated measures of emotional regulation with patients with PNESs. The current study sought to address this gap. METHODS: Forty-three patients with PNESs and 24 with epilepsy completed a postal survey comprising measures of emotional dysregulation (Difficulties in Emotion Regulation Scale), alexithymia (Toronto Alexithymia Scale), attachment (Relationship Scales Questionnaire), and psychopathology (Generalized Anxiety Disorder-7; Patient Health Questionnaire-9; Somatoform Dissociation Questionnaire-20). Cluster analysis was used to identify possible subgroups of patients with PNESs characterized by distinct patterns of emotional dysregulation. RESULTS: Two clusters of patients with PNESs were identified. The first (n=11) was characterized by higher levels of psychopathology, somatization, alexithymia, and difficulties with most aspects of emotional regulation (including identifying, accepting, and describing feelings, accessing adaptive regulatory strategies, performing goal-directed behaviors, and controlling feelings and actions) compared with the group with epilepsy. The second (n=32) was characterized by relatively high somatization and depression scores but comparatively normal levels of alexithymia and emotional regulation. CONCLUSIONS: The findings suggest that patients with PNESs can be divided into at least two meaningful subgroups characterized by distinct psychological profiles, only one of which is characterized by significant problems with emotional dysregulation. Further research is needed to determine whether the relatively normal emotional dysregulation and high somatization scores of some patients with PNESs are due to emotional avoidance or more basic problems with perceptual and behavioral control.

A prospective pilot study measuring muscle volumetric change in amyotrophic lateral sclerosis.

Our objective was to investigate the potential of muscle volume, measured with magnetic resonance (MR), as a biomarker to quantify disease progression in patients with amyotrophic lateral sclerosis (ALS). In this longitudinal pilot study, we first sought to determine the stability of volumetric muscle MR measurements in 11 control subjects at two time-points. We assessed feasibility of detecting atrophy in four patients with ALS, followed at three-month intervals for 12 months. Muscle power and MR volume were measured in thenar eminence (TEm), first dorsal interosseous (1DIO), tibialis anterior (TA) and tongue. Changes over time were assessed using linear regression models and t-tests. Results demonstrated that, in controls, no volumetric MR changes were seen (mean volume variation in all muscles < 5%, p > 0.1). In patients, between-subject heterogeneity was identified. Trends for volume loss were found in TEm (mean, - 26.84%, p = 0.056) and TA (- 8.29%, p = 0.077), but not in 1DIO (- 18.47%, p = 0.121) or tongue (< 5%, p = 0.367). In conclusion, volumetric muscle MR appears a stable measure in controls, and progressive volume loss was demonstrable in individuals with ALS in whom clinical weakness progressed. In this small study, subclinical atrophy was not demonstrable using muscle MR. Clinico-radiological discordance between muscle weakness and MR atrophy could reflect a contribution of upper motor neuron pathology.

Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS).

BACKGROUND: Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B. CONCLUSIONS/SIGNIFICANCE: We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype.

Tailored psychotherapy for patients with functional neurological symptoms: a pilot study.

OBJECTIVE: The objective of this study was to assess whether individually tailored psychotherapy for patients with functional neurological symptoms is associated with improvements in patient-centered measures of emotional well-being, quality of life, as well as somatic symptoms and whether this treatment modality is likely to be cost-effective. METHODS: We conducted an uncontrolled prospective pilot study of consecutive patients with functional symptoms referred from neurology outpatient clinics to a single psychotherapist using validated questionnaires [Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM), Short Function (SF)-36 Health Survey, and Patient Health Questionnaire (PHQ)-15]. Patients had a median of 6 treatment sessions (range=1-24). Ninety-one patients completed questionnaires at referral, 63 did at the end of treatment, and 34 did at follow-up after 6 months. Significant improvements were seen on all measures and were maintained at follow-up (CORE-OM, P=.003; SF-36, P<.001; PHQ-15, P=.001). Significance was not lost in an intention-to-treat analysis. Of all the patients, 49.2% improved by at least 1 S.D. in at least one of the measures. The number of patients needed to be treated to see an improvement of at least 1 S.D. in one of the three outcome measures was 2; that in two measures, 3.9; and that in all measures, 7. The mean cost of the intervention was pound231; the cost per quality-adjusted life year was estimated as pound5,328. RESULTS: Psychotherapy was associated with significant improvements in patient-centered measures, which seemed to be achieved at a comparatively low cost. CONCLUSIONS: The results indicate that psychotherapy may be a cost-effective intervention for patients presenting with functional neurological symptoms. The findings warrant further assessment of this treatment with a randomized and controlled trial.