Laura H. Goldstein

Background: Functional seizures (FS) and functional motor symptoms (FMS), subtypes of functional neurological disorder, may involve shared and distinct predisposing, precipitating, perpetuating and triggering (PPPT) factors. This study investigated potential self-reported PPPT factors in FS and FMS separately. Methods: 200 participants (FS=50, FMS=50, individuals with anxiety and/or depression (clinical controls [CC]=50, healthy controls [HC]=50) completed an in-depth medical history interview and online questionnaires to assess potential aetiological factors including traumatic/adverse life events, alexithymia, autistic traits, psychological and physical symptoms, illness perceptions, cognitive-behavioural responses and outcome measures of general functioning and health-related quality of life (HRQoL). Results: Participants with FS more frequently reported traumatic/adverse events and psychopathology (eg, dissociation, posttraumatic stress disorder) as possible illness causes/precipitating factors and sensory symptom triggers, relative to FMS and/or CCs. In contrast, participants with FMS endorsed physical illness causes/precipitating factors and physical activity and emotion-related symptom triggers more frequently than FS and/or CCs. Physical and dissociative symptoms were elevated, alongside reductions in HRQoL and general functioning in FS/FMS compared with CCs/HCs. Greater current, threatening illness-related beliefs/cognitions were disclosed in FS/FMS compared with CCs. Negative associations between HRQoL, cognitive-behavioural responses and traumatic/adverse events were also seen in FS/FMS. Conclusions: Traumatic events and psychopathology may be more prominently involved in the development/maintenance of FS and physical illness/injury, physical functioning and alexithymia may be more central to FMS. Unhelpful illness-related beliefs and impacts on HRQoL and general functioning are shared between these subtypes. The results of this study provide insight into potential unique and overlapping characteristics of FS/FMS, with implications for treatment.

Background: Cognitive symptoms are common in functional neurological disorder (FND), yet evidence of impaired neurocognitive test performance is variable. We aimed to assess self-reported cognitive symptoms, neurocognitive test performance, and metacognitive confidence in patients with functional seizures (FS) and functional motor symptoms (FMS). Methods: Participants with FS (n = 50) and FMS (n = 50) were compared to age- and gender-matched healthy controls (HC, n = 50), and clinical controls with depression and/or anxiety disorders (CC, n = 50). The Cambridge Neuropsychological Test Automated Battery was used to examine response speed, working memory, executive functions, and social–emotional processing, with subjective confidence rated for each test. Intellectual functioning, performance validity, and self-reported cognitive symptoms were also assessed. Results: The FND groups reported elevated cognitive symptoms compared to HC and CC (p-values<0.001). Impaired performance was demonstrated in both FND groups on tests of sustained attention (p-values = 0.03- < 0.001) and set-shifting (p-values = 0.01–0.001). Performance validity was comparable between groups (p = 0.64). The FND groups reported reduced post-diction confidence for sustained attention (p < 0.001). Executive performance deficits correlated with reduced test-specific confidence in FS/FMS (p-values = 0.02- < 0.001). In FMS, post-diction confidence for sustained attention performance correlated negatively with cognitive symptoms (p = 0.002). Cognitive symptoms were associated with psychological/physical symptom load, quality-of-life, and/or general functioning in FND and CC groups (p-values = 0.04- < 0.001). Conclusions: Patients with FS and FMS displayed localized deficits on tests of executive functioning, with reduced domain-specific metacognitive confidence, alongside significant cognitive symptoms. These neurocognitive features were associated with poorer clinical status, warranting interventions targeting cognitive control and/or cognitive symptoms in everyday life.

This guideline provides evidence-based recommendations for clinicians, patients, and other stakeholders on the management of functional seizures. Following a National Academy of Medicine-compliant process, a multidisciplinary panel conducted a systematic review and integrated the findings with the authors' clinical experience to develop recommendations. A systematic review of the available evidence from first published articles to February 25, 2025, identified 12 Class II-III studies. The review found that psychological interventions are possibly effective in increasing the likelihood of achieving freedom from functional seizures, decreasing the frequency of functional seizures, decreasing anxiety, and improving health-related quality of life and psychosocial functioning for individuals with functional seizures. Key recommendations state that, when evaluating patients with seizure-like episodes, clinicians should seek historical and semiological information (including smartphone videos) from both patients and witnesses and may obtain video-EEG of all typical seizure-like episodes where feasible. Clinicians should evaluate patients diagnosed with functional seizures for co-occurring psychiatric disorders and co-occurring epilepsy. Clinicians should adhere to universal standards of care for patients, including speaking respectfully, refraining from unnecessary harm, and avoiding stigmatizing behavior. Clinicians should provide a specific diagnostic label and rationale for the diagnosis, should engage in shared decision making regarding the treatment plan, and should provide continuity of care to individuals diagnosed with functional seizures. When psychological interventions for functional seizures are indicated, clinicians should counsel patients regarding the potential benefits and risks of these interventions and should refer interested and appropriate patients to these interventions for the treatment of functional seizures. Clinicians should involve family, caregivers, or others in the social support network in the psychological treatment of individuals with functional seizures. Clinicians should not prescribe benzodiazepines or antiseizure medications for patients with functional seizures without co-occurring epilepsy or another indication for these medications and should counsel patients regarding the potential risks and lack of evidence of benefit for using these medications for functional seizures. Clinicians should taper off antiseizure medications for patients with functional seizures and without another indication for these medications. The guideline also identifies gaps in the available evidence and outlines potentially clinically impactful avenues for future research.

Background: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Formal psychological therapies are not routinely part of United Kingdom standard motor neuron disease care due to a lack of evidence-based guidance resulting from a paucity of clinical trials. We aimed to evaluate the clinical and cost-effectiveness of Acceptance and Commitment Therapy plus usual care compared to usual care alone for improving psychological health in people living with motor neuron disease. Methods: We conducted qualitative interviews with 15 people living with motor neuron disease, 10 caregivers and 12 healthcare professionals. Findings were used to develop an Acceptance and Commitment Therapy intervention specifically for people living with motor neuron disease. Next, we examined its acceptability and feasibility in an uncontrolled feasibility study with 29 people living with motor neuron disease. Findings from qualitative interviews with 14 people living with motor neuron disease and 11 therapists were used to revise the intervention. Finally, we conducted a multicentre, parallel, two-arm randomised controlled trial in 16 United Kingdom motor neuron disease care centres/clinics. Eligible participants were aged ≥ 18 years with motor neuron disease. Participants were randomly assigned (1 : 1) to receive up to eight sessions of Acceptance and Commitment Therapy plus usual care or usual care alone and followed up at 6 and 9 months post randomisation by blinded outcome assessors. The primary outcome was total score on the McGill Quality of Life Questionnaire-Revised at 6 months. Secondary outcomes included health status using the EuroQol-5 Dimensions, five-level version. Primary analyses were by intention to treat. Results: Acceptance and Commitment Therapy was acceptable to people living with motor neuron disease, and it was feasible to recruit participants, hence trial progression criteria were met. From September 2019 to August 2022, 191 participants were recruited: 97 were allocated to Acceptance and Commitment Therapy plus usual care and 94 to usual care alone. Mean age was 61.9 years (standard deviation 11.4), 58% were male and 95% were White/White British. Acceptance and Commitment Therapy plus usual care was superior to usual care alone on the McGill Quality of Life Questionnaire-Revised at 6 months [adjusted mean difference 0.66 (95% confidence interval 0.22 to 1.10); Cohen’s d = 0.46 (95% confidence interval 0.16 to 0.77); p = 0.003] and 9 months [adjusted mean difference 0.76 (95% confidence interval 0.30 to 1.22); Cohen’s d = 0.53 (95% confidence interval 0.21 to 0.85); p = 0.001]. Mean differences in total costs and quality-adjusted life-years at 9 months between Acceptance and Commitment Therapy plus usual care versus usual care alone were not statistically significant [costs: £1019 (95% confidence interval −£34 to £2074); quality-adjusted life-years: 0.019 (95% confidence interval −0.07 to 0.05)]. The incremental cost-effectiveness ratio was £88,507/quality-adjusted life-year: this decreased to £13,817/quality-adjusted life-year in those with medium disease-related deterioration in subgroup analyses. Conclusion: Acceptance and Commitment Therapy plus usual care is clinically effective at maintaining or improving psychological health, as measured by the McGill Quality of Life Questionnaire-Revised, in people living with motor neuron disease compared to usual care alone. It was not cost-effective overall when calculated using a standard health status measure (EuroQol-5 Dimensions, five-level version). However, it was cost-effective in a subgroup of people experiencing a medium rate of disease-related deterioration. Limitations: Participants from ethnic minorities were under-represented, despite recruiting from sites with diverse communities. Between-group differences in outcomes may have been partly attributable to expectancy or non-specific therapeutic effects due to the lack of an active control. Cost-effectiveness analyses may have been underpowered to detect significant between-group differences. Future work: Studies should examine the effectiveness of Acceptance and Commitment Therapy in diverse populations, compared to an active control, using a more appropriate measure to assess cost-effectiveness, and in those with different rates of disease-related deterioration. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/81/01.

Background: Functional motor disorder often causes persistent disabling symptoms that are associated with high healthcare costs. In recent years, specialist physiotherapy, informed by an understanding of functional motor disorder, has emerged as a promising treatment, but there is an absence of evidence of its effectiveness from large randomised controlled trials. Methods: We conducted a pragmatic, multicentre, randomised controlled trial, comparing specialist physiotherapy for functional motor disorder to treatment as usual, which was defined as community neurological physiotherapy. The primary outcome was the Short Form questionnaire-36 items Physical Functioning domain at 12 months (scale range 0–100, with 100 indicating optimum health). The trial was powered to detect a 9-point difference in the primary outcome with 90% power at the 5% level of significance. Secondary domains of measurement included a patient perception of improvement, health-related quality of life, mobility, anxiety, depression and illness perception. We also completed a health economic analysis with the primary aim of calculating the mean incremental cost per quality-adjusted life-year over 12 months. In prespecified analysis plans, we excluded participants from the primary analysis if they were unable to receive their trial-allocated treatment due to COVID-19 lockdown restrictions. Sensitivity analysis explored the impact of this decision. Results: Between 19 October 2018 and 31 January 2022, 355 adults with functional motor disorder were randomised (1 : 1) to specialist physiotherapy (n = 179) and treatment as usual (n = 176). Eighty-nine participants were excluded due to COVID-19 disruptions. Retention for the primary analysis was 90% for both groups, leaving 241 participants in the primary analysis. At 12 months, there was no between-group difference in the primary outcome (adjusted mean difference 3.5, 95% confidence interval −2.3 to 9.3). However, several secondary outcomes favoured specialist physiotherapy, including the participant perception of improvement, Short Form questionnaire-36 items Mental Health domain, confidence in the diagnosis and two subscales (Personal Control and Illness Coherence) of the Revised Illness Perception Questionnaire. There were no differences in the remaining outcomes. At 6 months, the following outcome measures were significantly different, in favour of specialist physiotherapy: participant perception of improvement, the Short Form questionnaire-36 items Physical Role Limitations, Short Form questionnaire-36 items Social Functioning, Short Form questionnaire-36 items Mental Health, EuroQol-5 Dimensions five-level version utility score, confidence in the diagnosis and three subscales (Timeline Cyclical, Personal Control and Treatment Control) of the Revised Illness Perception Questionnaire. No outcomes significantly favoured treatment as usual. In the health economic analysis, the incremental cost per quality-adjusted life-year gained from a health and social care cost perspective was £4133 with an 86% probability that specialist physiotherapy is cost-effective compared to treatment as usual at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained. There were no adverse events related to physiotherapy. Conclusion: Specialist physiotherapy was not superior to treatment as usual for the primary outcome, the Short Form questionnaire-36 items Physical Functioning domain at 12 months. However, a number of secondary outcome measures favoured specialist physiotherapy at 6 and 12 months. There is a high probability that specialist physiotherapy is cost-effective. Limitations: Participants in treatment as usual waited longer to start physiotherapy, which resulted in a shorter time between concluding treatment and completing the primary outcome. Most outcome measures, including the primary outcome, were participant reported, which may have been biased by perceptions of the randomised treatment allocation. Future work: Future work should identify or develop more suitable outcome measures for functional motor disorder research, explore who is most likely to benefit from specialist physiotherapy and identify alternative interventions for those unlikely to benefit from this treatment. Additional work is needed to adapt treatment to meet the needs of minority groups and young people. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/31/63.

Functional motor disorder (FMD), a motor-dominant variant of functional neurologic disorder, is a disabling condition associated with high health and social care resource use and poor employment outcomes. Specialist physiotherapy presents a possible treatment option, but there is limited evidence for clinical effectiveness and cost-effectiveness. Physio4FMD is a multicenter randomized controlled trial of specialist physiotherapy for FMD compared with treatment as usual (TAU). The aim of the analysis was to conduct a randomized trial based on economic evaluation of specialist physiotherapy compared with TAU. Eleven centers in England and Scotland randomized participants 1:1 to specialist physiotherapy or TAU (referral to community neurologic physiotherapy). Participants completed the EuroQoL EQ-5D-5L, Client Service Receipt Inventory, and Work Productivity and Activity Impairment Questionnaire at baseline, 6 months, and 12 months. The mean incremental cost per quality-adjusted life year (QALY) for specialist physiotherapy compared with TAU over 12 months was calculated from a health and social care and wider societal perspective. The probability of cost-effectiveness and 95% CIs were calculated using bootstrapping. The analysis included 247 participants (n = 141 for specialist physiotherapy, n = 106 for TAU). The mean cost per participant for specialist physiotherapy was £646 (SD 72) compared with £272 (SD 374) for TAU. Including the costs of treatment, the adjusted mean health and social care cost per participant at 12 months for specialist physiotherapy was £3,814 (95% CI £3,194–£4,433) compared with £3,670 (95% CI £2,931–£4,410) for TAU, with a mean incremental cost of £143 (95% CI £–825 to £1,112). There was no significant difference in QALYs over the 12-month duration of the trial (0.030, 95% CI –0.007 to 0.067). The mean incremental cost per QALY was £4,133 with an 86% probability of being cost-effective at a £20,000 threshold. When broader societal costs such as loss of productivity were taken into consideration, specialist physiotherapy was dominant (incremental cost: £−5,169, 95% CI £–15,394 to £5,056). FMD was associated with high health and social care costs. There is a high probability that specialist physiotherapy is cost-effective compared with TAU particularly when wider societal costs are taken into account. International Standard Randomised Controlled Trial registry, ISRCTN56136713.

The increasing prevalence of large-scale neuroimaging initiatives has created a need for efficient and anatomically accurate methods for analysing tractography data. Here, we present MegaTrack, a framework designed to combine the anatomical precision of manual dissections with the efficiency required for big data analysis. At its core, MegaTrack operates by normalising individual tractography datasets to a standard space, concatenating them into a single "mega" tractography dataset the user manually dissects before automatically extracting subject-specific tracts and metrics in native space. This approach permits identifying and extracting tracts not yet available in existing templates or automatic dissection tools. We validated this approach using multiple datasets and applications. Comparison with individual manual dissections showed high spatial agreement (weighted dice coefficient > 0.95) and strong correlations in tract-specific metrics (R2 > 0.9). In a longitudinal dataset, MegaTrack demonstrated improved reproducibility across time points and higher inter-rater reliability compared to manual dissections. In a motor neuron disease cohort, MegaTrack replicated known group differences in corticospinal tract microstructure with comparable sensitivity to manual dissections (p = 0.001) but with significantly reduced processing time. Finally, we showcase MegaTrack's scalability by creating a comprehensive white matter atlas from 140 healthy adults and demonstrate its application for lesion analysis in stroke patients. This framework is accompanied by an interactive online tool that allows users to explore these atlases and perform customised lesion analyses. The MegaTrack framework is a time-efficient solution for the anatomically precise analysis of large tractography datasets, enabling the rapid simultaneous dissection of multiple subjects while preserving individual anatomical features. The framework's ability to efficiently process large datasets makes it an excellent tool for generating training data for machine learning and deep learning algorithms in tractography analysis. This approach has broad applications in both research and clinical settings, from group comparisons to personalised lesion mapping, and can significantly contribute to the development of advanced automated tractography methods.

Background: The cognitive and behavioural changes that occur in around 50% of people with amyotrophic lateral sclerosis (ALS) may significantly affect people around them, contributing to heightened burden, anxiety, and depression. Despite existing evidence linking behavioural impairment to caregiver distress, the role of cognitive impairment remains less clear, with mixed findings on its impact. Methods: This study assessed the influence of cognitive and behavioural impairments in people with ALS on the distress of their nominated informants. The data were collected face-to-face and remotely due to the COVID-19 pandemic. The cognitive and behavioural impairments were measured using established screening tools. Informants’ distress was evaluated through composite measures of burden, anxiety, and depression. Regression analyses were employed to determine the predictive value of cognitive and behavioural impairment on informant distress. Results: A total of 98 ALS patients and 84 informants participated. Behavioural impairment predicted informant distress across various tools. In contrast, cognitive impairment was a less consistent predictor of informant distress across screening measures and did not significantly interact with behavioural impairment in predicting distress. Administration mode did not affect predictive relationships. Conclusions: Behavioural impairment in ALS significantly predicts informant distress, with varying predictive power across different screening tools. Cognitive impairment also affects informant distress, but its impact is less substantial compared to behavioural factors. The interaction between cognitive and behavioural impairments did not significantly predict informant distress.

Objective: This study investigated whether cognitive screening tools used for people with amyotrophic lateral sclerosis (pwALS) are affected by the screen being administered face-to-face or remotely online. It also investigated whether demographic variables predicted total cognitive screen scores. Methods: The cognitive component of the Edinburgh Cognitive and Behavioural ALS Screen (ECASc), the cognitive component of the ALS Cognitive Behavioural Screen (ALS-CBSc), and the Mini Addenbrooke’s Cognitive Examination (Mini-ACE) were administered to 41 pwALS and 41 controls face-to-face. Versions of the cognitive screens designed to be administered remotely were administered to 57 pwALS and 44 controls via videoconferencing methods. Backwards stepwise linear regressions were conducted to assess whether total scores on the ECASc, ALS-CBSc, and Mini-ACE scores were predicted by administration mode (face-to-face or remote) or demographic variables. Results: Mode of administration significantly affected scores on the ECASc and ALS-CBSc; remote administration was associated with better total scores. Administration mode did not significantly affect Mini-ACE scores. All cognitive screens were significantly affected by IQ scores; higher IQ scores predicted better screening tool scores. Only ECASc scores were significantly affected by age, with older age predicting poorer scores. Being female was associated with better Mini-ACE scores; sex did not predict ECASc and ALS-CBSc scores. Conclusions: Our results suggest that videoconferencing versions of the ECASc and ALS-CBSc may function differently to the original, face-to-face versions. There are advantages to using remote versions of cognitive screening tools but clinicians and researchers who use them should consider that they may not yield equivalent scores.