Publications by authors named "Markus Reuber"

226 Publications

How to do things with words Two seminars on the naming of functional (psychogenic, non-epileptic, dissociative, conversion, …) seizures.

Seizure 2021 Oct 24;93:102-110. Epub 2021 Oct 24.

Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom; Department of Clinical Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Amongst the most important conditions in the differential diagnosis of epilepsy is the one that manifests as paroxysms of altered behaviour, awareness, sensation or sense of bodily control in ways that often resemble epileptic seizures, but without the abnormal excessive or synchronous electrical activity in the brain that defines these. Despite this importance, there remains little agreement - and frequent debate - on what to call this condition, known inter alia as psychogenic non-epileptic seizures (PNES), dissociative seizures (DS), functional seizures (FS), non-epileptic attack disorder (NEAD), pseudoseizures, conversion disorder with seizures, and by many other labels besides. This choice of terminology is not merely academic - it affects patients' response to and understanding of their diagnosis, and their ability to navigate health care systems.This paper summarises two recent discussions hosted by the American Epilepsy Society and Functional Neurological Disorders Society on the naming of this condition. These discussions are conceptualised as the initial step of an exploration of whether it might be possible to build consensus for a new diagnostic label.
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http://dx.doi.org/10.1016/j.seizure.2021.10.016DOI Listing
October 2021

Cochrane systematic review and meta-analysis of the impact of psychological treatment on health-related quality of life in people with epilepsy: an update by the ILAE Psychology Task Force, highlighting methodological changes.

Epileptic Disord 2021 Nov 2. Epub 2021 Nov 2.

Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.

Clinical interest in using psychological interventions for people with epilepsy (PWE) aiming at decreasing mental health difficulties, improving health-related quality of life (HRQOL) and seizure-related outcomes, continues to grow. This article summarizes the 2020 update of the 2017 Cochrane Review and meta-analysis of psychological interventions for PWE, highlighting the reasons for major methodological modifications such as the recategorization of interventions and expanded risk of bias assessment. A 2020 literature search yielded 36 RCTs (n=3526) investigating psychological treatments for PWE with a validated HRQOL measure as an outcome. Twenty-seven trials were skills-based psychological interventions, whilst nine studies were education-only interventions. Among skills-based psychological interventions, 11 studies (n=643) used the Quality of Life in Epilepsy-31 (QOLIE-31) or other QOLIE inventories convertible to QOLIE-31 as an outcome measure and were pooled for meta-analysis. Significant mean changes were observed for the QOLIE-31 total score (mean improvement of 5.23 points; p< 0.001) and in six out of seven subscales (emotional well-being, energy and fatigue, overall QoL, seizure worry, medication and cognitive functioning). The mean changes in the QOLIE-31 total score and the overall QoL subscale exceeded the threshold of minimally important change (MIC), indicating clinically meaningful post-intervention improvement. These results provide moderate evidence that psychological treatments for adults and adolescents with epilepsy enhance HRQOL. In addition to the summary of the Cochrane review, we provide a detailed characterization of the interventions and patient populations of the meta-analyzed studies.
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http://dx.doi.org/10.1684/epd.2021.1357DOI Listing
November 2021

Oro-mucosal midazolam maleate: Use and effectiveness in adults with epilepsy in the UK.

Epilepsy Behav 2021 10 7;123:108242. Epub 2021 Aug 7.

University of Sheffield, United Kingdom.

Background: Oro-mucosal midazolam maleate (OMM) with suitable training to family and carers is being increasingly recognized as the treatment of choice to mitigate the development of status epilepticus in non-hospital community settings. There are no studies to describe the use, effectiveness, and suitable dosing of OMM in adults with epilepsy in community settings.

Purpose: To describe the use, effectiveness, and dosing of OMM in the emergency treatment of epileptic seizures in community settings.

Methods: A retrospective observational study (2016-17) design was used with participant recruitment from four UK NHS secondary care outpatient clinics providing epilepsy management. Study sample was of adult people with epilepsy (PWE) having had a recent seizure requiring OMM. Data on patient demographics, patient care plans, details of a recent seizure requiring emergency medication, and dose of OMM were collected from medical records.

Results: Study data from 146 PWE were included. The mean age of PWE was 41.0 years (SD 15.2) and mean weight was 64.8Kg (SD 18.2). Fifty-three percent of PWE were recorded as having intellectual disability. The most frequently used concomitant medications were lamotrigine (43%). The majority of seizures occurred at people's homes (n = 92, 63%). OMM was most often administered by family/professional care-givers (n = 75, 48.4%). Generalized (tonic/clonic) seizures were recorded in most people (n = 106, 72.6%). The most common initial dose of OMM was 10 mg (n = 124, 84.9%). The mean time to seizure cessation after administration of this initial dose was 5.5 minutes (SD = 4.5, Median 5.0, IQR 2.1-5.0). Only a minority of seizures led to ambulance callouts (n = 18, 12.3%) or hospital admissions (n = 13, 9%).

Conclusion: This is the first observational study describing the use and effectiveness of OMM in adults in community settings. Minimal hospital admissions were reported in this cohort and the treatment was effective in ending seizures in adults in community settings.
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http://dx.doi.org/10.1016/j.yebeh.2021.108242DOI Listing
October 2021

What do we know about non-epileptic seizures in adults with intellectual disability: A narrative review.

Seizure 2021 Oct 23;91:437-446. Epub 2021 Jul 23.

Academic Neurology Unit, University of Sheffield, UK. Electronic address:

Psychogenic non-epileptic seizures (PNES) superficially resemble epileptic seizures, but are not associated with abnormal electrical activity in the brain. PNES are a heterogeneous entity and while there is increasing interest in the characterisation of PNES sub-groups, little is known about individuals with PNES who have an intellectual disability (ID). ID is a lifelong condition characterised by significant limitations in cognitive, social and practical skills. ID (commonly with comorbid epilepsy) has been identified as a risk factor for developing PNES. However, people with ID are often excluded from research in PNES. This has unfortunately resulted in a lack of evidence to help inform practice and policy for this population. This narrative review synthesises the currently available evidence in terms of the epidemiology, demographic and clinical profile of adults with PNES and ID. There is a particular focus on demographics, aetiological factors, PNES characteristics, diagnosis and treatment of the condition in this population. Throughout this article, we critique the existing evidence, discuss implications for clinical practice and highlight the need for further research and enquiry. What emerges from the evidence is that, even within the sub-group of those with ID, PNES are a heterogeneous condition. Individuals with ID and PNES are likely to present with diverse and complex needs requiring multidisciplinary care. This review is aimed at the broad range of healthcare professionals who may encounter this group. We hope that it will stimulate further discussion and research initiatives.
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http://dx.doi.org/10.1016/j.seizure.2021.07.021DOI Listing
October 2021

Use of suggestive seizure manipulation methods in the investigation of patients with possible psychogenic nonepileptic seizures-An international ILAE survey.

Epilepsia Open 2021 Sep 31;6(3):472-482. Epub 2021 Jul 31.

Academic Neurology Unit, Royal Hallamshire Hospital, The University of Sheffield, Sheffield, UK.

Video-encephalographic (vEEG) seizure recordings make essential contributions to the differentiation of epilepsy and psychogenic nonepileptic seizures (PNES). The yield of vEEG examinations can be increased through suggestive seizure manipulation (SSM) (ie, activation/provocation/cessation procedures), but its use has raised ethical concerns. In preparation for guidelines on the investigation of patients with PNES, the ILAE PNES Task Force carried out an international survey to investigate practices of and opinions about SSM. An online questionnaire was developed by the ILAE PNES Task Force. Questions were asked at clinical unit or individual respondent level. All ILAE chapters were encouraged to send questionnaires to their members. The survey was open from July 1, 2019, to August 31, 2019. A total of 487 clinicians from 411 units across 94 countries responded. Some form of SSM was used in 296/411 units (72.0%). Over 90% reported the use of verbal suggestion, over 80% the use of activation procedures also capable of eliciting epileptic activity (hyperventilation or photic stimulation). Only 26.3% of units used techniques specifically intended to provoke PNES (eg, saline injection). Fewer than 10% of units had established protocols for SSM, only 20% of units required written patient consent, in 12.2% of units patients received explicitly false information to provoke seizures. Clinicians using SSM tended to perceive no ethical problems, whereas those not using SSM were likely to have ethical concerns about these methods. We conclude that the use of invasive nocebo techniques intended to provoke PNES in diagnostic settings has declined, but SSM is commonly combined with activation procedures also capable of eliciting epileptic activity. While research suggests that openness about the use of PNES-specific nocebo techniques does not reduce diagnostic yield, very few units have suggestion protocols or seek patient consent. This could be addressed through establishing consensus guidance for the practice of SSM.
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http://dx.doi.org/10.1002/epi4.12521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408588PMC
September 2021

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

Health Technol Assess 2021 06;25(43):1-144

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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,  = 182; and cognitive-behavioural therapy plus standardised medical care,  = 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;  = 0.144]. Of the 16 secondary outcomes analysed, nine were significantly better in the arm receiving cognitive-behavioural therapy at a -value < 0.05, including the following at a -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;  = 0.001); better psychosocial functioning (Work and Social Adjustment Scale, standardised treatment effect -0.39, 95% confidence interval -0.61 to -0.18;  < 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;  = 0.001; clinician rated: standardised treatment effect 0.37, 95% confidence interval 0.17 to 0.57;  < 0.001); and satisfaction with treatment (standardised treatment effect 0.50, 95% confidence interval 0.27 to 0.73;  < 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 ; Vol. 25, No. 43. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273679PMC
June 2021

'It's both challenging and probably the most rewarding work' - A qualitative study of psychological therapy provider's experiences of working with people with dissociative seizures.

Epilepsy Behav 2021 09 25;122:108156. Epub 2021 Jun 25.

Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom. Electronic address:

Limited research exists exploring the experiences of psychological therapy providers (PTPs) working with people with dissociative seizures (DS). PTPs play a key role in the treatment of DS, yet sit at the end of a long, often ineffective process of diagnosis and waiting before treatment can commence. This qualitative study was undertaken involving 12 PTPs from specialist DS services throughout England and Scotland. Semi-structured interviews were carried out, using thematic analysis to evaluate the data. Four key themes were identified, "neurological to psychological", "putting the person with DS at the center", "treatment process", and "issues and impact of therapy with patients with DS". The findings showed that an unclear and uncomprehended diagnosis, together with waiting times had a detrimental impact on patients at the starting point of therapy. People with DS were perceived as a heterogeneous group whose treatment needed to be individualized, using the PTPs' full 'toolkit' of modalities and techniques, with a focus on improving quality of life, rather than reducing seizures. The study highlighted the complexity for PTPs of working with major but also accumulated minor traumas, compounded by the impact of DS on both PTPs and treatment. The desire of PTPs to be totally patient-focused meant that individualized treatment was considered essential and meant that participants were doubtful about the possibility of compiling an effective manual for the psychological treatment for DS.
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http://dx.doi.org/10.1016/j.yebeh.2021.108156DOI Listing
September 2021

Feasibility of using an automated analysis of formulation effort in patients' spoken seizure descriptions in the differential diagnosis of epileptic and nonepileptic seizures.

Seizure 2021 Oct 13;91:141-145. Epub 2021 Jun 13.

Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield, United Kingdom.

Objective: There are three common causes of Transient Loss of Consciousness (TLOC), syncope, epileptic and psychogenic nonepileptic seizures (PNES). Many individuals who have experienced TLOC initially receive an incorrect diagnosis and inappropriate treatment. Whereas syncope can be distinguished relatively easily with a small number of "yes"/"no" questions, the differentiation of the other two causes of TLOC is more challenging. Previous qualitative research based on the methodology of Conversation Analysis has demonstrated that the descriptions of epileptic seizures contain more formulation effort than accounts of PNES. This research investigates whether features likely to reflect the level of formulation effort can be automatically elicited from audio recordings and transcripts of speech and used to differentiate between epileptic and nonepileptic seizures.

Method: Verbatim transcripts of conversations between patients and neurologists were manually produced from video and audio recordings of 45 interactions (21 epilepsy and 24 PNES). The subsection of each transcript containing the person's account of their first seizure was manually extracted for the analysis. Seven automatically detectable features were designed as markers of formulation effort. These features were used to train a Random Forest machine learning classifier.

Result: There were significantly more hesitations and repetitions in descriptions of epileptic than nonepileptic seizures. Using a nested leave-one-out cross validation approach, 71% of seizures were correctly classified by the Random Forest classifier.

Discussion: This pilot study provides proof of principle that linguistic features that have been automatically extracted from audio recordings and transcripts could be used to distinguish between epileptic seizures and PNES and thereby contribute to the differential diagnosis of TLOC. Future research should explore whether additional observations can be incorporated into a diagnostic stratification tool and compare the performance of these features when they are combined with additional information provided by patients and witnesses about seizure manifestations and medical history.
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http://dx.doi.org/10.1016/j.seizure.2021.06.009DOI Listing
October 2021

Validation of the PHQ-9 in adults with dissociative seizures.

J Psychosom Res 2021 07 8;146:110487. Epub 2021 Apr 8.

Academic Neurology Unit, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK.

Background: The PHQ-9 is a self-administered depression screening instrument. Little is known about its utility and accuracy in detecting depression in adults with dissociative seizures (DS).

Objectives: Using the Mini - International Neuropsychiatric Interview as a reference, we evaluated the diagnostic accuracy of the PHQ-9 in adults with DS, and examined its convergent and discriminant validity and uniformity.

Methods: Our sample comprised 368 people with DS who completed the pre-randomisation assessment of the CODES trial. The uniformity of the PHQ-9 was determined using factor analysis for categorical data. Optimal cut-offs were determined using the area under the curve (AUC), Youden Index, and diagnostic odds ratio (DOR). Convergent and discriminant validity were assessed against pre-randomisation measures.

Results: Internal consistency of the PHQ-9 was high (α = 0.87). While the diagnostic odds ratio suggested that a cut-off of ≥10 had the best predictive performance (DOR = 14.7), specificity at this cut off was only 0.49. AUC (0.74) and Youden Index (0.48) suggested a ≥ 13 cut-off would yield an optimal sensitivity (0.81) and specificity (0.67) balance. However, a cut-off score of ≥20 would be required to match specificity resulting from a cut-off of ≥13 in other medical conditions. We found good convergent and discriminant validity and one main factor for the PHQ-9.

Conclusions: In terms of internal consistency and structure, our findings were consistent with previous validation studies but indicated that a higher cut-off would be required to identify DS patients with depression with similar specificity achieved with PHQ-9 screening in different clinical and non-clinical populations.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110487DOI Listing
July 2021

Evidence of objective sleep impairment in nonepileptic attack disorder: A naturalistic prospective controlled study using actigraphy and daily sleep diaries over six nights.

Epilepsy Behav 2021 04 5;117:107867. Epub 2021 Mar 5.

Department of Psychology, Queen's University Belfast, David Keir Building, Belfast, Northern Ireland, UK. Electronic address:

Poor sleep is reported by many with nonepileptic attack disorder (NEAD) with correlations evident between self-reported sleep quality and mood and functional impairment. However, it is contended that self-reported sleep impairment in NEAD is a subjective phenomenon, which represents a general tendency to over-report symptoms or misinterpret bodily states in those with NEAD. The present study was therefore designed to investigate the extent of subjective and objective sleep impairments in those with NEAD. Over six nights we prospectively recorded comparable nightly objective (actigraphy) and subjective (consensus sleep diary) sleep parameters in a sample of 17 people with NEAD, and an age- and gender-matched normative control group (N = 20). Participants recorded daily measures of attacks, dissociation, and mood. Alongside higher subjective sleep impairment, the NEAD group had significantly worse objective sleep on several metrics compared to the normative controls, characterized by disrupted sleep (frequent awakenings and wake after sleep onset, low efficiency). Exploratory analyses using mixed effects models showed that attacks were more likely to occur on days preceded by longer, more restful sleep. This study, which had good ecological validity, evidences the presence of objective sleep impairment in NEAD, suggesting that in patient reports of problems with sleep should be given careful consideration in clinical practice.
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http://dx.doi.org/10.1016/j.yebeh.2021.107867DOI Listing
April 2021

Managing depression and anxiety in people with epilepsy: A survey of epilepsy health professionals by the ILAE Psychology Task Force.

Epilepsia Open 2021 03 8;6(1):127-139. Epub 2021 Feb 8.

Department of Neurology Gemeinschaftskrankenhaus Herdecke University of Witten/Herdecke Herdecke Germany.

Objectives: The Psychology Task Force of the Medical Therapies Commission of the International League Against Epilepsy (ILAE) has been charged with taking steps to improve global mental health care for people with epilepsy. This study aimed to inform the direction and priorities of the Task Force by examining epilepsy healthcare providers' current practical experiences, barriers, and unmet needs around addressing depression and anxiety in their patients.

Methods: A voluntary 27-item online survey was distributed via ILAE chapters and networks. It assessed practices in the areas of screening, referral, management, and psychological care for depression and anxiety. A total of 445 participants, from 67 countries (68% high income), commenced the survey, with 87% completing all components. Most respondents (80%) were either neurologists or epileptologists.

Results: Less than half of respondents felt adequately resourced to manage depression and anxiety. There was a lack of consensus about which health professionals were responsible for screening and management of these comorbidities. About a third only assessed for depression and anxiety following spontaneous report and lack of time was a common barrier (>50%). Routine referrals to psychiatrists (>55%) and psychologists (>41%) were common, but approximately one third relied on watchful waiting. A lack of both trained mental health specialists (>55%) and standardized procedures (>38%) was common barriers to referral practices. The majority (>75%) of respondents' patients identified with depression or anxiety had previously accessed psychotropic medications or psychological treatments. However, multiple barriers to psychological treatments were endorsed, including accessibility difficulties (52%).

Significance: The findings suggest that while the importance of managing depression and anxiety in patients with epilepsy is being recognized, there are ongoing barriers to effective mental health care. Key future directions include the need for updated protocols in this area and the integration of mental health professionals within epilepsy settings.
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http://dx.doi.org/10.1002/epi4.12455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918327PMC
March 2021

Neurologists' perceptions of utilising tele-neurology to practice remotely during the COVID-19 pandemic.

Patient Educ Couns 2021 03 2;104(3):452-459. Epub 2021 Jan 2.

Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, South Yorkshire S10 2JF, UK. Electronic address:

Objectives: The COVID-19 pandemic enforced an almost complete switch from face-to-face clinical work to tele-neurology. This study explores neurologists' perceptions of telephone and videophone remote consultations.

Methods: Semi-structured interviews were conducted with neurologists and a GP with a specialist interest (n = 22). Interviews were conducted remotely via Zoom®, audio-recorded, transcribed verbatim and analysed using the principles of thematic analysis.

Results: Four main themes emerged: 'unknown unknowns (risks/uncertainties)', 'better service', 'challenges', and 'beyond the pandemic'. Thematic saturation was achieved by interview 19. Participants highlighted a number of benefits of remote consultations but over 80% also complained of a reduction in work satisfaction.

Conclusion: The sudden introduction of tele-neurology is unlikely to be fully reversed when pandemic-related restrictions have been lifted. However, this study confirms tele-neurology cannot completely replace face-to-face consultations. Some patient groups and consultation types require direct contact. Moreover, significant administrative and infrastructural investment will be required to develop the full potential of tele-neurology.

Practice Implications: Tele-medicine is capable of improving access and efficiency of specialist neurology services, but limited by lack of non-verbal communication and technical problems. It could enhance service provision with sufficient infrastructural and administrative investment, but may reduce neurologists' job statisfaction.
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http://dx.doi.org/10.1016/j.pec.2020.12.027DOI Listing
March 2021

Interoception and stress in patients with Functional Neurological Symptom Disorder.

Cogn Neuropsychiatry 2021 03 29;26(2):75-94. Epub 2020 Dec 29.

Department of Psychology, The University of Sheffield, Sheffield, UK.

Introduction: Research suggests that patients with Functional Neurological Symptom Disorder (pwFND) struggle to identify their own emotions and associated physiological cues (interoceptive sensitivity, IS). However, it is not known how this deficit interacts with stress. This study aimed to assess IS in pwFND at baseline and following stress induction, and relate the findings to self-reported emotion processing difficulties.

Methods: Twenty-six pwFND and 27 healthy controls performed the Heart Beat Detection Task pre- and post-stress induction with the Cold Pressor Test. Participants also completed questionnaires assessing anxiety (GAD-7) and depressive symptomology (PHQ-9), as well as emotion processing (EPS-25).

Results: Patients reported deficits in emotion processing (< . 001) and had lower IS ( = .032) than healthy controls. IS improved following stress induction across both groups ( = .003) but patients' IS was lower than that of healthy controls' pre-and post-stress induction. Exploratory analyses revealed that patients reporting sensory symptoms had lower IS at baseline than patients who did not.

Conclusion: Our findings suggest that pwFND are relatively impaired in the identification of their emotions at baseline and following stress induction. This may be related to the experience of functional sensory symptoms and has implications for the psychological treatment of emotion dysregulation in this population.
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http://dx.doi.org/10.1080/13546805.2020.1865895DOI Listing
March 2021

Food for thought: Opinions on the past, present and future of carbamazepine.

Authors:
Markus Reuber

Seizure 2020 Dec 14;83:242. Epub 2020 Dec 14.

Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.10.023DOI Listing
December 2020

Fully automated cognitive screening tool based on assessment of speech and language.

J Neurol Neurosurg Psychiatry 2020 Nov 20. Epub 2020 Nov 20.

Neuroscience, The University of Sheffield, Sheffield, Sheffield, UK

Introduction: Recent years have seen an almost sevenfold rise in referrals to specialist memory clinics. This has been associated with an increased proportion of patients referred with functional cognitive disorder (FCD), that is, non-progressive cognitive complaints. These patients are likely to benefit from a range of interventions (eg, psychotherapy) distinct from the requirements of patients with neurodegenerative cognitive disorders. We have developed a fully automated system, 'CognoSpeak', which enables risk stratification at the primary-secondary care interface and ongoing monitoring of patients with memory concerns.

Methods: We recruited 15 participants to each of four groups: Alzheimer's disease (AD), mild cognitive impairment (MCI), FCD and healthy controls. Participants responded to 12 questions posed by a computer-presented talking head. Automatic analysis of the audio and speech data involved speaker segmentation, automatic speech recognition and machine learning classification.

Results: CognoSpeak could distinguish between participants in the AD or MCI groups and those in the FCD or healthy control groups with a sensitivity of 86.7%. Patients with MCI were identified with a sensitivity of 80%.

Discussion: Our fully automated system achieved levels of accuracy comparable to currently available, manually administered assessments. Greater accuracy should be achievable through further system training with a greater number of users, the inclusion of verbal fluency tasks and repeat assessments. The current data supports CognoSpeak's promise as a screening and monitoring tool for patients with MCI. Pending confirmation of these findings, it may allow clinicians to offer patients at low risk of dementia earlier reassurance and relieve pressures on specialist memory services.
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http://dx.doi.org/10.1136/jnnp-2019-322517DOI Listing
November 2020

Catastrophising and repetitive negative thinking tendencies in patients with psychogenic non-epileptic seizures or epilepsy.

Seizure 2020 Dec 17;83:57-62. Epub 2020 Oct 17.

Academic Neurology Unit, University of Sheffield, United Kingdom.

Purpose: Previous research suggests that catastrophisation and perseverative, or repetitive negative thinking (RNT) could play an important role in the aetiology of Psychogenic Nonepileptic Seizures (PNES). This study was designed to explore whether these cognitive tendencies are more prevalent in patients with PNES than those with epilepsy and to examine the relationship between these cognitions, depression, anxiety, seizure frequency and diagnosis.

Methods: 26 patients with PNES (PWPNES) and 29 with epilepsy (PWE) self-reported RNT (Perseverative Thinking Questionnaire), catastrophisation tendencies (modified Safety Behaviors and Catastrophizing Scale), symptoms of anxiety (Generalised Anxiety Disorder Assessment 7) and depression (Primary Health Questionnaire 9) as well as seizure frequency.

Results: RNT and catastrophic thinking were highly correlated with each other and more prevalent in PWPNES than PWE. Positive correlations were also found between all other self-report measures and seizure frequency. The PNES diagnosis predicted RNT (perseverative thinking) independently of catastrophic thinking, anxiety, depression and seizure frequency.

Conclusion: PWPNES exhibit greater negative perseverative and catastrophising cognitive tendencies than PWE. PNES as a diagnosis independently predicted RNT. Hence, RNT and catastrophisation should be considered as possible specific targets for psychological interventions in patients with PNES.
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http://dx.doi.org/10.1016/j.seizure.2020.09.034DOI Listing
December 2020

Driving a motor vehicle and psychogenic nonepileptic seizures: ILAE Report by the Task Force on Psychogenic Nonepileptic Seizures.

Epilepsia Open 2020 Sep 9;5(3):371-385. Epub 2020 Jun 9.

Academic Department of Neurosciences University of Sheffield Royal Hallamshire Hospital Sheffield UK.

Objectives: This International League Against Epilepsy (ILAE) Report: (a) summarizes the literature about "driving and psychogenic nonepileptic seizures (PNES)"; (b) presents the views of international experts; and (c) proposes an approach to assessing the ability of persons with PNES (PwPNES) to drive.

Methods: Phase 1: Systematic literature review. Phase 2: Collection of international expert opinion using SurveyMonkey®. Experts included the members of the ILAE PNES Task Force and individuals with relevant publications since 2000. Phase 3: Joint analysis of the findings and refinement of conclusions by all participants using email. As an ILAE Report, the resulting text was reviewed by the Psychiatry Commission, the ILAE Task Force on Driving Guidelines, and Executive Committee.

Results: Eight studies identified by the systematic review process failed to provide a firm evidence base for PNES-related driving regulations, but suggest that most health professionals think restrictions are appropriate. Twenty-six experts responded to the survey. Most held the view that decisions about driving privileges should consider individual patient and PNES characteristics and take account of whether permits are sought for private or commercial driving. Most felt that those with active PNES should not be allowed to drive unless certain criteria were met and that PNES should be thought of as "active" if the last psychogenic seizure had occurred within 6 months.

Significance: Recommendations on whether PwPNES can drive should be made at the individual patient level. Until future research has determined the risk of accidents in PwPNES a proposed algorithm may guide decisions about driving advice.
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http://dx.doi.org/10.1002/epi4.12408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469780PMC
September 2020

Valproate prescribing practices for women with intellectual disability across Europe.

Acta Neurol Scand 2021 Jan 6;143(1):56-61. Epub 2020 Sep 6.

Cornwall Partnership NHS Foundation Trust, Truro, UK.

Background: Valproate (VPA) is a known teratogen associated with greater risk of major congenital malformations and other neurodevelopmental sequelae than all other licensed antiepileptic medicines. To reduce the potential for VPA-related teratogenicity, the European Medicines Agency issued recommendations in 2018. Over two-thirds of women/girls with intellectual disability (ID) may have treatment-resistant epilepsy that could benefit from VPA treatment.

Aims: This investigation compared VPA prescribing practice for women/girls with ID between European countries, specifically evaluating the practice in the UK with that in other countries.

Methods: An expert working group with representation from key stake-holding organizations developed a survey for dissemination to relevant professionals across Europe.

Results: Seventy one responses were received (27 UK, 44 Europe). Clinicians in the UK were more likely to report that they are working to mandatory regulations compared with European respondents (P = .015). European respondents were less likely to be aware of user-independent contraception options (P = .06). In The UK, VPA regulations were more likely to be applied to women with ID than in Europe (P = .024).

Conclusion: There is heterogeneity in the application of VPA regulations across Europe for women/girls with ID. In both the UK and Europe, the regulations lack suitable adjustments for specific ID-related factors.
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http://dx.doi.org/10.1111/ane.13337DOI Listing
January 2021

Functional cognitive disorder: dementia's blind spot.

Brain 2020 10;143(10):2895-2903

Centre for Clinical Brain Sciences, The University of Edinburgh, EH16 4SB, UK.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.
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http://dx.doi.org/10.1093/brain/awaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586080PMC
October 2020

A European questionnaire survey on epilepsy monitoring units' current practice for postoperative psychogenic nonepileptic seizures' detection.

Epilepsy Behav 2020 11 31;112:107355. Epub 2020 Jul 31.

National Institute of Psychiatry and Neurology, Department of Neurology, University of Pécs, Budapest, Hungary.

Background: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES.

Methods: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project.

Results: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 ( ± 19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 ± 7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project.

Conclusion: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.
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http://dx.doi.org/10.1016/j.yebeh.2020.107355DOI Listing
November 2020

The experience of trial participation, treatment approaches and perceptions of change among participants with dissociative seizures within the CODES randomized controlled trial: A qualitative study.

Epilepsy Behav 2020 10 5;111:107230. Epub 2020 Jul 5.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK. Electronic address:

Background: Nested within a large, multicenter randomized controlled trial (RCT) for people with dissociative seizures (DS), the study used purposive sampling to explore participants' experience of participating in an RCT, their experience of DS-specific cognitive behavioral therapy (CBT) and another component of the RCT, Standardized Medical Care (SMC) and their perceptions of and reflections on seizure management and change.

Methods: A qualitative study using semistructured interviews was conducted with 30 participants in an RCT (the COgnitive behavioral therapy vs standardized medical care for adults with Dissociative non-Epileptic Seizures (CODES) Trial) investigating the effectiveness of two treatments for DS. Key themes and subthemes were identified using thematic framework analysis (TFA).

Results: Analysis yielded three overarching themes: taking part in a treatment trial - "the only thing out there", the experience of treatment techniques that were perceived to help with seizure management, and reflections on an "unpredictable recovery".

Conclusions: People with DS are amenable to participating in a psychotherapy RCT and described a largely positive experience. They also described the applicability of aspects of DS-specific CBT and SMC in the management of their DS, received within the confines of the CODES trial. Factors that appeared to account for the variability in response to treatment delivery included individual preferences for the nature of sessions, the nature of therapeutic relationships, readiness to discuss trauma, other aspects of emotional avoidance, and whether therapy provided something new.
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http://dx.doi.org/10.1016/j.yebeh.2020.107230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581898PMC
October 2020

Characterising spoken responses to an intelligent virtual agent by persons with mild cognitive impairment.

Clin Linguist Phon 2021 03 19;35(3):237-252. Epub 2020 Jun 19.

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield , Sheffield, UK.

The diagnosis of Mild Cognitive Impairment (MCI) characterises patients at risk of dementia and may provide an opportunity for disease-modifying interventions. Identifying persons with MCI (PwMCI) from adults of a similar age without cognitive complaints is a significant challenge. The main aims of this study were to determine whether generic speech differences were evident between PwMCI and healthy controls (HC), whether such differences were identifiable in responses to recent or remote memory questions, and to determine which speech variables showed the clearest between-group differences. This study analysed recordings of 8 PwMCI (5 females, 3 males) and 14 HC of a similar age (8 females, 6 males). Participants were recorded interacting with an intelligent virtual agent: a computer-generated talking head on a computer screen which asks pre-recorded questions when prompted by the interviewee through pressing the next key on a computer keyboard. Responses to recent and remote memory questions were analysed. Mann-Whitney U tests were used to test for statistically significant differences between PwMCI and HC on each of 12 speech variables, relating to temporal characteristics, number of words produced and pitch. It was found that compared to HC, PwMCI produce speech for less time and in shorter chunks, they pause more often and for longer, take longer to begin speaking and produce fewer words in their answers. It was also found that the PwMCI and HC were more alike when responding to remote memory questions than when responding to recent memory questions. These findings show great promise and suggest that detailed speech analysis can make an important contribution to diagnostic and stratification systems in patients with memory complaints.
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http://dx.doi.org/10.1080/02699206.2020.1777586DOI Listing
March 2021

Psychogenic nonepileptic seizures in Latin America: A survey describing current practices.

Epilepsy Behav 2021 01 2;114(Pt A):107150. Epub 2020 Jun 2.

Saskatchewan Epilepsy Program, Department of Medicine, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Electronic address:

Objective: Psychogenic nonepileptic seizures (PNES) are one of the most common differential diagnoses of epilepsy. This study provides an overview of diagnostic and treatment services for patients with PNES across Latin America.

Methods: In 2017-2018, clinicians practicing in Latin America with responsibilities for patients with PNES were contacted to respond to a survey regarding the management of this disorder developed by the International League Against Epilepsy (ILAE) PNES Task Force.

Results: Three hundred and sixty responses from 17 Latin American countries were analyzed. Most respondents were neurologists (81%) under 40 years of age (61%). Fifty-seven percent of professionals stated that they personally diagnose PNES, but only 33% stated that they provide follow-up, and only 20% that they recommend treatment. Many participants (54%) characterized themselves as either unfamiliar with the diagnosis or inexperienced in arranging treatment. Most respondents reported having access to brain magnetic resonance imaging (MRI; 88%) and routine electroencephalogram (EEG; 71%), 64% have the access to video-EEG longer than 8 h, and 54% of professionals performed video-EEG to confirm PNES diagnoses. Although cognitive-behavioral therapy was recognized as the treatment of choice (by 82% of respondents), there was little access to it (60%). In contrast, a high proportion of respondents reported using antidepressant (67%), antiseizure (57%), and antipsychotic medications (54%) as treatments for PNES.

Significance: This study reveals several deficiencies in the diagnosis and treatment of patients with PNES in Latin America. The barriers are reinforced by lack of knowledge among the specialists and poor healthcare system support. There is inadequate access to prolonged video-EEG and psychotherapy. An inappropriate use of antiseizure medicines seems commonplace, and there are low follow-up rates by neurologists after the diagnosis. Multidisciplinary guidelines are required to improve the approach of patients with PNES.
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http://dx.doi.org/10.1016/j.yebeh.2020.107150DOI Listing
January 2021

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

Lancet Psychiatry 2020 06 20;7(6):491-505. Epub 2020 May 20.

Department of Psychological Medicine, King's College London, London, UK.

Background: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency.

Methods: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544.

Findings: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the 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 [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events.

Interpretation: CBT 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. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach.

Funding: National Institute for Health Research, Health Technology Assessment programme.
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http://dx.doi.org/10.1016/S2215-0366(20)30128-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242906PMC
June 2020

Psychological and demographic characteristics of 368 patients with dissociative seizures: data from the CODES cohort.

Psychol Med 2021 Oct 11;51(14):2433-2445. Epub 2020 May 11.

South London and Maudsley NHS Foundation Trust, London, UK.

Background: We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and explored differences associated with age at onset of DS, gender, and DS semiology.

Methods: Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic).

Results: Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men.

Conclusions: Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.
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http://dx.doi.org/10.1017/S0033291720001051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506352PMC
October 2021

The impact and challenges of the 2018 MHRA statement on the use of sodium valproate in women of childbearing age during the first year of implementation, in a UK epilepsy centre.

Seizure 2020 Jul 17;79:8-13. Epub 2020 Apr 17.

Neurology Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Electronic address:

Purpose: On 24/04/2018, the United Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA) clarified previous policies by issuing a statement, that the use of sodium valproate is contraindicated in women of childbearing potential unless the conditions of a pregnancy prevention programme are met, and only if other treatments are ineffective or not tolerated. We evaluated the impact of this over the first year of implementation in a tertiary epilepsy centre.

Methods: Cross-sectional study of all women under active follow up, or newly referred, of childbearing age (16-55 years), taking valproate for the treatment of epilepsy, over 12 months from 01/05/2018.

Results: We identified 125 cases, with 31 newly referred in response to MHRA regulations. 9.6% of patients did not attend their appointment, 35.2% had a learning disability (LD), which in 19.2% was sufficiently severe that they could not consent to a sexual relationship. Patients with LD prescribed valproate were significantly younger, and more likely to have a focal or uncharacterised epilepsy than patients without LD. In 46.4% of patients, MHRA regulations were followed: women were already using highly active contraception (HAC), HAC was started, or valproate withdrawn. In 24.8% of cases, women elected to continue valproate, and were not willing to use HAC.

Conclusions: In 53.6% of cases, MHRA regulations contraindicating the use valproate in women of childbearing potential could not be followed fully, due to lack of patient attendance, lack of applicability in severe LD, or ethical concerns relating to patient choice.
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http://dx.doi.org/10.1016/j.seizure.2020.03.015DOI Listing
July 2020

Machine learning as a diagnostic decision aid for patients with transient loss of consciousness.

Neurol Clin Pract 2020 Apr;10(2):96-105

Sheffield Teaching Hospitals NHS Foundation Trust (AW, RAG, SJH, MR), Royal Hallamshire Hospital; Division of Psychiatry and Applied Psychology (JJ-K), University of Nottingham, Institute of Mental Health, Innovation Park; Mental Health Liaison Team (MB), Derbyshire Healthcare NHS Foundation Trust Hartington Unit, Chesterfield; School of Mathematics and Statistics (TJH), University of Sheffield; Department of Clinical and Experimental Epilepsy (MK, SS, MCW), University College London Queen Square Institute of Neurology; NIHR Newcastle Biomedical Research Centre and Institute of Cellular Medicine (SWP), Newcastle University, Newcastle upon Tyne; and Academic Neurology Unit (MR), University of Sheffield, Royal Hallamshire Hospital, United Kingdom.

Background: Transient loss of consciousness (TLOC) is a common reason for presentation to primary/emergency care; over 90% are because of epilepsy, syncope, or psychogenic non-epileptic seizures (PNES). Misdiagnoses are common, and there are currently no validated decision rules to aid diagnosis and management. We seek to explore the utility of machine-learning techniques to develop a short diagnostic instrument by extracting features with optimal discriminatory values from responses to detailed questionnaires about TLOC manifestations and comorbidities (86 questions to patients, 31 to TLOC witnesses).

Methods: Multi-center retrospective self- and witness-report questionnaire study in secondary care settings. Feature selection was performed by an iterative algorithm based on random forest analysis. Data were randomly divided in a 2:1 ratio into training and validation sets (163:86 for all data; 208:92 for analysis excluding witness reports).

Results: Three hundred patients with proven diagnoses (100 each: epilepsy, syncope and PNES) were recruited from epilepsy and syncope services. Two hundred forty-nine completed patient and witness questionnaires: 86 epilepsy (64 female), 84 PNES (61 female), and 79 syncope (59 female). Responses to 36 questions optimally predicted diagnoses. A classifier trained on these features classified 74/86 (86.0% [95% confidence interval 76.9%-92.6%]) of patients correctly in validation (100 [86.7%-100%] syncope, 85.7 [67.3%-96.0%] epilepsy, 75.0 [56.6%-88.5%] PNES). Excluding witness reports, 34 features provided optimal prediction (classifier accuracy of 72/92 [78.3 (68.4%-86.2%)] in validation, 83.8 [68.0%-93.8%] syncope, 81.5 [61.9%-93.7%] epilepsy, 67.9 [47.7%-84.1%] PNES).

Conclusions: A tool based on patient symptoms/comorbidities and witness reports separates well between syncope and other common causes of TLOC. It can help to differentiate epilepsy and PNES. Validated decision rules may improve diagnostic processes and reduce misdiagnosis rates.

Classification Of Evidence: This study provides Class III evidence that for patients with TLOC, patient and witness questionnaires discriminate between syncope, epilepsy and PNES.
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http://dx.doi.org/10.1212/CPJ.0000000000000726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156196PMC
April 2020

Peri-ictal responsiveness to the social environment is greater in psychogenic nonepileptic than epileptic seizures.

Epilepsia 2020 04 10;61(4):758-765. Epub 2020 Mar 10.

Sheffield Teaching Hospitals National Health Service Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.

Objective: To look for evidence of peri-ictal social interaction in psychogenic nonepileptic seizures (PNES) and epileptic seizures exploring the notion of PNES as a form of nonverbal communication.

Methods: Video recordings of typical seizures experienced by patients with epilepsy and PNES were obtained in a naturalistic social setting (residential epilepsy monitoring unit). Video analysis by three nonexpert clinicians identified 18 predefined semiological and interactional features indicative of apparent impairment of consciousness or of peri-ictal responsiveness to the social environment with assessment of interrater reliability using Fleiss κ. Features were compared between epileptic seizures and PNES.

Results: One hundred eighty-nine seizures from 50 participants (24 epilepsy, 18 PNES, eight combined) were analyzed. At least fair (κ > 0.20) interrater agreement was achieved for 14 features. The PNES and epileptic seizures compared were of similar severity in terms of ictal impairment of consciousness (κ = 0.34, odds ratio [OR] = 1.11, 95% confidence interval [CI] = 0.62-1.96) and responsiveness (κ = 0.52, OR = 1.01, 95% CI = 0.55-1.86). PNES were more likely to be preceded by attempts to alert others (κ = 0.52, OR = 12.4, 95% CI = 3.2-47.7, P < .001), to show intensity affected by the presence of others (κ = 0.44, OR = 199.4, 95% CI = 12.0-3309.9, P < .001), and to display postictal behavior affected by the presence of others (κ = 0.35, OR = 91.1, 95% CI = 17.2-482.1, P < .001).

Significance: Nonexpert raters can, with fair to moderate reliability, rate features characterizing ictal impairment of consciousness and responsivity in video recordings of seizures. PNES are associated with greater peri-ictal responsiveness to the social environment than epileptic seizures. These findings are consistent with a potential communicative function of PNES and could be of differential diagnostic significance.
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http://dx.doi.org/10.1111/epi.16471DOI Listing
April 2020

Outcome measurement in functional neurological disorder: a systematic review and recommendations.

J Neurol Neurosurg Psychiatry 2020 06 28;91(6):638-649. Epub 2020 Feb 28.

FND Hope International, Salmon, Idaho, USA.

Objectives: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes.

Methods: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group.

Results: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years).

Conclusions: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.
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http://dx.doi.org/10.1136/jnnp-2019-322180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279198PMC
June 2020
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