How does cognitive behavior therapy for dissociative seizures work? A mediation analysis of the CODES trial.

BACKGROUND: We compared dissociative seizure specific cognitive behavior therapy (DS-CBT) plus standardized medical care (SMC) to SMC alone in a randomized controlled trial. DS-CBT resulted in better outcomes on several secondary trial outcome measures at the 12-month follow-up point. The purpose of this paper is to evaluate putative treatment mechanisms. METHODS: We carried out a secondary mediation analysis of the CODES trial. 368 participants were recruited from the National Health Service in secondary / tertiary care in England, Scotland, and Wales. Sixteen mediation hypotheses corresponding to combinations of important trial outcomes and putative mediators were assessed. Twelve-month trial outcomes considered were final-month seizure frequency, Work and Social Adjustment Scale (WSAS), and the SF-12v2, a quality-of-life measure providing physical (PCS) and mental component summary (MCS) scores. Mediators chosen for analysis at six months (broadly corresponding to completion of DS-CBT) included: (a) beliefs about emotions, (b) a measure of avoidance behavior, (c) anxiety and (d) depression. RESULTS: All putative mediator variables except beliefs about emotions were found to be improved by DS-CBT. We found evidence for DS-CBT effect mediation for the outcome variables dissociative seizures (DS), WSAS and SF-12v2 MCS scores by improvements in target variables avoidance behavior, anxiety, and depression. The only variable to mediate the DS-CBT effect on the SF-12v2 PCS score was avoidance behavior. CONCLUSIONS: Our findings largely confirmed the logic model underlying the development of CBT for patients with DS. Interventions could be additionally developed to specifically address beliefs about emotions to assess whether it improves outcomes.

Brivaracetam efficacy and tolerability in clinical practice: A UK-based retrospective multicenter service evaluation.

PURPOSE: This multicenter service evaluation explores the efficacy and tolerability of brivaracetam (BRV) in an unselected, consecutive population in 'real-life' clinical settings. METHOD: We retrospectively collected data from patient records at 11 UK hospitals and epilepsy centers. Consecutive patients prescribed BRV with at least 3 months of follow-up (FU) were included. Apart from reporting effectiveness and tolerability of BRV across the whole cohort, we compared treatment outcomes depending on previous levetiracetam use (LEV+ versus LEV-), comorbid learning disability (LD+ versus LD-), and epilepsy syndrome (focal versus generalized epilepsy). RESULTS: Two hundred and ninety patients (46% male, median age: 38 years, range: 15 to 77) with ≥3 months of FU were included. The median duration of BRV exposure was 12 months (range: 1 day to 72 months). Overall BRV retention was 71.1%. While 56.1% of patients improved in terms of seizure frequency category (daily, weekly, monthly, yearly seizures), 23.1% did not improve on this measure and 20.8% deteriorated. In terms of seizure frequency, 21% of patients experienced a ≥50% reduction, with 7.0% of all patients becoming seizure-free. Treatment-emergent adverse events (AEs) were reported by 107 (36.9%) patients, but there were no serious AEs. The commonest AEs were sedation/fatigue (18.3%), mood changes (9.0%), and irritability/aggression (4.8%). There were no significant differences in drug retention, seizure frequency outcomes, or AEs between the LEV+ and LEV- subgroups, or between patients with generalized or focal epilepsies. Although 15.5% of patients in the LD+ group achieved a ≥50% reduction, this rate was lower than in the LD- group. CONCLUSIONS: This 'real-life' evaluation suggests that reductions in seizure frequency can be achieved with BRV in patients with highly refractory epilepsy. Brivaracetam may be a useful treatment option in patients who have previously failed to respond to or tolerate LEV, those with LD, or (off-label) those with generalized epilepsies.

The incidence and prevalence of epilepsy in the United Kingdom 2013-2018: A retrospective cohort study of UK primary care data.

PURPOSE: The aim of this study was to update overall incidence and prevalence calculations for epilepsy of the United Kingdom (UK) and its constituent nations (England, Northern Ireland, Scotland, and Wales). METHODS: We used data from primary care practices contributing to the Clinical Practice Research Datalink (CRPD), based on the electronic health records of 14 million patients, representing approximately 20% of the population. CPRD contains data from two different health record systems: the Vision clinical system (CPRD GOLD database) and the EMIS Web® clinical system (CPRD Aurum database). We calculated incidence and prevalence rates with 95% confidence intervals (CIs). Data were stratified by age, gender, deprivation, country (England, Scotland, Wales and Northern Ireland) and region (England only). RESULTS: In the UK, the estimated overall point prevalence for epilepsy was 9.37 per 1000 persons / year (95% CI 9.34-9.40) and the overall estimated incidence rate was 42.68 per 100,000 person-years (95% 42.18-43.18) using the CPRD GOLD database. In England, the estimated incidence (37.41 (95% CI 36.96-37.83)) and prevalence (8.85 (95% CI 8.83-8.87)) was lower (combined databases) compared to figures for Scotland (incidence 47.76 (95% CI 46.15-49.42)); prevalence 10.13 (95% CI 10.06-10.20)) (CPRD GOLD only), Wales (incidence 54.84 (95% CI 52.79-56.95); prevalence 11.40 (95% CI 11.31-11.49)) (CPRD GOLD only) and Northern Ireland (incidence 46.18 (95% CI 43.13-49.90); prevalence 12.08 (95% CI 11.93-12.23))(combined databases). Prevalence and incidence were higher in more deprived regions. CONCLUSION: The prevalence and incidence of epilepsy in the UK is broadly in line with other high income countries, showing the usual pattern of high incidence in the young and the old, with a nadir in middle age. The prevalence of epilepsy has fallen slightly since 2011. There is significant geographical variation (between countries and between regions), and a suggestion of a relationship between deprivation and epilepsy which needs further investigation.

Functional (conversion) neurological symptoms: research since the millennium.

Functional neurological symptoms (FNS) are commonly encountered but have engendered remarkably little academic interest. 'UK-Functional Neurological Symptoms (UK-FNS)' was an informal inaugural meeting of UK based clinicians in March 2011 with a variety of research and clinical interests in the field. This narrative review reflects the content of the meeting, and our opinion of key findings in the field since the turn of the millennium.

Short-term outcome of psychogenic non-epileptic seizures after communication of the diagnosis.

We previously described a communication strategy for the delivery of the diagnosis of psychogenic non-epileptic seizures (PNES) that was acceptable and effective at communicating the psychological cause of PNES. This prospective multicenter study describes the short-term seizure and psychosocial outcomes after the communication of the diagnosis and with no additional treatment. Participants completed self-report measures at baseline, two and six months after the diagnosis (seizure frequency, HRQoL, health care utilization, activity levels, symptom attributions and levels of functioning). Thirty-six participants completed the self-report questionnaires. A further eight provided seizure frequency data. After six months, the median seizure frequency had dropped from 10 to 7.5 per month (p=0.9), 7/44 participants (16%) were seizure-free, and an additional 10/44 (23%) showed greater than 50% improvement in seizure frequency. Baseline questionnaire measures demonstrated high levels of impairment, which had not improved at follow-up. The lack of change in self-report measures illustrates the need for further interventions in this patient group.

Shame in patients with psychogenic nonepileptic seizure: A narrative review.

Psychogenic Nonepileptic Seizures (PNES) have been linked to dysregulated emotions and arousal. However, the question which emotions may be most relevant has received much less attention. In this multidisciplinary narrative review, we argue that the self-conscious emotion of shame is likely to be of particular importance for PNES. We summarize current concepts of the development of shame processing and its relationship with other emotional states. We demonstrate the potential of acute shame to cause a sudden disruption of normal cognitive function and trigger powerful behavioral, cognitive, physiological and secondary emotional responses which closely resemble key components of PNES. These responses may lead to the development of shame avoidance strategies which can become disabling in themselves. We discuss how excessive shame proneness and shame dysregulation are linked to several psychopathologies often associated with PNES (including depression and PTSD) and how they may predispose to, precipitate and perpetuate PNES disorders, not least by interacting with stigma. We consider current knowledge of the neurobiological underpinnings of shame and PNES. We explore how shame could be the link between PNES and a heterogeneous range of possible etiological factors, and how it may link historical aversive experiences with individual PNES events occurring much later and without apparent external trigger. We argue that, in view of the potential direct links between shame and PNES, the well-documented associations of shame with common comorbidities of this seizure disorder and the well-characterized relationship between chronic shame and stigma, there is a compelling case to pay greater attention to shame in relation to PNES. Its role in the treatment of patients with PNES is discussed in a separate, linked review incorporating case vignettes to highlight the complex interactions of different but interlinked shame-related issues in individual patients.

Moderators of cognitive behavioural therapy treatment effects and predictors of outcome in the CODES randomised controlled trial for adults with dissociative seizures.

OBJECTIVE: We explored moderators of cognitive behavioural therapy (CBT) treatment effects and predictors of outcome at 12-month follow-up in the CODES Trial (N = 368) comparing CBT plus standardised medical care (SMC) vs SMC-alone for dissociative seizures (DS). METHODS: We undertook moderator analyses of baseline characteristics to determine who had benefited from being offered CBT 12 months post-randomisation. Outcomes included: monthly DS frequency, psychosocial functioning (Work and Social Adjustment Scale - WSAS), and health-related quality of life (Mental Component Summary (MCS) and Physical Component Summary (PCS) SF-12v2 scores). When moderating effects were absent, we tested whether baseline variables predicted change irrespective of treatment allocation. RESULTS: Moderator analyses revealed greater benefits (p < 0.05) of CBT on DS frequency for participants with more (≥22) symptoms (Modified PHQ-15) or ≥ 1 current (M.I.N.I.-confirmed) comorbid psychiatric diagnosis at baseline. The effect of CBT on PCS scores was moderated by gender; women did better than men in the CBT + SMC group. Predictors of improved outcome included: not receiving disability benefits, lower anxiety and/or depression scores (PCS, MCS, WSAS); shorter duration, younger age at DS onset, employment, fewer symptoms and higher educational qualification (PCS, WSAS); stronger belief in the diagnosis and in CBT as a "logical" treatment (MCS). Some variables that clinically might be expected to moderate/predict outcome (e.g., maladaptive personality traits, confidence in treatment) were not shown to be relevant. CONCLUSION: Patient complexity interacted with treatment. CBT was more likely to reduce DS frequency in those with greater comorbidity. Other patient characteristics predicted outcome regardless of the received intervention.

Epilepsy, anti-seizure medication, intellectual disability and challenging behaviour - Everyone's business, no one's priority.

PURPOSE: People with Intellectual Disability (ID) and epilepsy are more likely to experience psychiatric conditions, challenging behaviour (CB), treatment resistance and adverse effects of anti-seizure medications (ASM) than those without. This population receives care from various professionals, depending on local care pathways. This study evaluates the training status, confidence, reported assessment and management practices of different professional groups involved in caring for people with ID, epilepsy and CB. METHODS: A cross sectional survey using a questionnaire developed by expert consensus which measured self-reported training status, confidence, and approaches to assessment and management of CB in people with ID and epilepsy was distributed to practitioners involved in epilepsy and/or ID. RESULTS: Of the 83 respondents, the majority had either a psychiatry/ID (n = 39), or Neurology/epileptology background (n = 31). Psychiatry/ID and Neurology/epileptology had similar confidence in assessing CB in ID-epilepsy cases, but Psychiatry/ID exhibited higher self-rated confidence in the management of these cases. While assessing and managing CB, Psychiatry/ID appeared more likely to consider mental health aspects, while Neurology/epileptology typically focused on ASM. CONCLUSION: Psychiatry/ID and Neurology/epileptology professionals had varying training levels in epilepsy, ID and CB, had differing confidence levels in managing this patient population, and considered different factors when approaching assessment and management. As such, training opportunities in ID should be offered to neurology professionals, and vice versa. Based on the findings, a best practice checklist is presented, which aims to provide clinicians with a structured framework to consider causal explanations for CB in this population.

Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride.

The antihistaminic over-the-counter drug methapyrilene hydrochloride, mixed with food at a concentration of 0.1 percent, was administered to 50 male and 50 female Fischer rats. A second group of 50 male and 50 female rats was given the same treatment together with 0.2 percent of sodium nitrite added to the food. Almost all of the rats in both groups developed liver neoplasms, mainly hepatocellular carcinomas and cholangiocarcinomas. The first rat died with a liver neoplasm at the 43rd week. Over 50 percent of the rats in both groups had metastases from the carcinomas of the liver to distant organs. Control rats treated with nitrite only, or untreated, did not develop liver neoplasms. There was no discernible effect of nitrite on the carcinogenicity of methapyrilene hydrochloride.

Which patients become seizure free with antiepileptic drugs? An observational study in 821 patients with epilepsy.

OBJECTIVES: Analysis of factors influencing seizure outcome in antiepileptic drug treatment of epilepsy. PATIENTS AND METHODS: Retrospective analysis of 500 patients with complete seizure control and 321 patients with refractory epilepsy (mean ages 33.3 and 32.1 years respectively). RESULTS: The seizure-free group consisted of 377 patients with symptomatic/cryptogenic epilepsy (SCE; mean seizure control 45 months) and 123 patients with idiopathic generalized epilepsy (IGE; mean seizure control 61 months) (P = 0.02). Of the patients with SCE, 35.7% had achieved seizure control with monotherapy (MT), 29.6% with >or=2 AEDs. No single AED was superior in MT. Of the patients with IGE, 35.9% had become seizure free with MT, 15.6% on combination therapy (CT). Valproate MT was more commonly associated with seizure freedom than lamotrigine (P < 0.05). CONCLUSIONS: The results indicate that, in SCE, seizures can be controlled with carefully selected CT more commonly than suggested by previous studies. The seizure prognosis of patients with IGE presenting to a specialist in epilepsy may be worse than previously thought.

Audit of healthcare provision for UK prisoners with suspected epilepsy.

PURPOSE: To describe the prevalence and nature of epileptic seizure disorders in a typical UK prison and compare the care offered to prisoners to the recommendations of the National Institute for Clinical Excellence (NICE). METHODS: Over a 14-month period, all prisoners identified as having epilepsy were registered by prison primary healthcare services at a category 'C' prison holding 640 male adults. Prison and National Health Service health records were reviewed, prisoners were re-assessed by members of a specialist secondary care service based in the local general hospital NHS. RESULTS: Twenty-six prisoners were thought to have epilepsy. 61.5% of diagnoses had not been made by epilepsy specialists, 73.1% had uncontrolled seizures, only 19.2% had had computed tomography, none magnetic resonance imaging. At review, 30.8% of prisoners were thought to require neuroimaging, 19.2% cardiac investigations. The diagnosis of epilepsy was confirmed in only 57.9% of those prisoners considered to have the condition by prison healthcare services. 53.8% of those prisoners confirmed as having epilepsy had not had a medical review in the past 12 months; 63.2% required a change in their antiepileptic drugs (AEDs). CONCLUSION: Although the prevalence of epilepsy in this prison population appeared high at first sight, a critical review of the diagnoses reduced the difference to the prevalence of epilepsy in the population at large. Fewer prisoners than expected achieved seizure control. Collaboration with specialist epilepsy services was poor. There were significant discrepancies between the healthcare provision in prison and the NICE epilepsy guidelines.

Examining a community model of epilepsy care for people with learning disabilities.

PURPOSE: To assess the use of specialised medical epilepsy services by people with learning disabilities (LD) and epilepsy in a community healthcare setting, to compare medical epilepsy care in this group to current management guidelines, and to contrast important outcomes with those achieved in different healthcare settings. METHODS: Postal survey with a carer completed questionnaire addressed to all adults with epilepsy registered on an LD register in Sheffield, UK (n=442). RESULTS: An analysis based on 225 returned questionnaires revealed that 22.7% of individuals with LD and epilepsy had been free of seizures for over 1 year. 95.1% were taking antiepileptic drugs (AEDs), 46.2% had had an EEG, and 41.3% a brain scan. 53.3% of diagnoses had been made by epilepsy experts, 38.7% of individuals with LD and epilepsy were under specialist review. Although patients with more severe epilepsy were more likely to be under specialist care, 60.6% of patients with ongoing seizures, 57.9% with major seizures and 68.7% of individuals taken to hospital with prolonged had no access to specialist advice. CONCLUSION: The proportion of people with LD who achieved seizure-control in the described population was lower than in all previously reported studies of LD patient groups. The poor outcome in terms of seizure-control, the lack of access to the epilepsy specialist service, and the apparent under-utilisation of investigations indicate that there are grounds for serious concern about this community model of medical epilepsy care for people with LD.

Panic symptoms in transient loss of consciousness: Frequency and diagnostic value in psychogenic nonepileptic seizures, epilepsy and syncope.

PURPOSE: Previous studies suggest that ictal panic symptoms are common in patients with psychogenic nonepileptic seizures (PNES). This study investigates the frequency of panic symptoms in PNES and if panic symptoms, just before or during episodes, can help distinguish PNES from the other common causes of transient loss of consciousness (TLOC), syncope and epilepsy. METHODS: Patients with secure diagnoses of PNES (n=98), epilepsy (n=95) and syncope (n=100) were identified using clinical databases from three United Kingdom hospitals. Patients self-reported the frequency with which they experienced seven symptoms of panic disorder in association with their episodes. A composite panic symptom score was calculated on the basis of the frequency of symptoms. RESULTS: 8.2% of patients with PNES reported "never" experiencing any of the seven panic symptoms in their episodes of TLOC. Patients with PNES reported more frequent panic symptoms in their attacks than those with epilepsy (p<0.001) or syncope (p<0.001), however, patients with PNES were more likely "rarely" or "never" to report five of the seven-ictal panic symptoms than "frequently" or "always" (45-69% versus 13-29%). A receiver operating characteristic analysis demonstrated that the composite panic symptom score distinguished patients with PNES from the other groups (sensitivity 71.1%, specificity 71.2%), but not epilepsy from syncope. CONCLUSIONS: Patients with PNES report TLOC associated panic symptoms more commonly than those with epilepsy or syncope. Although panic symptoms are reported infrequently by most patients with PNES, a composite symptom score may contribute to the differentiation between PNES and the other two common causes of TLOC.

Epilepsy and Pregnancy: For healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group.

Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy-related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene - Golden Moments of opportunities for improving outcomes -Which Key Groups have a role in making change -When - 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries.

Histopathology of preneoplastic and neoplastic lesions of the esophagus in BUF rats ingesting diethylnitrosamine.

Carcinomas developed in the mucosa of the esophagus in BUF strain rats ingesting diethylnitrosamine in the diet. The stages of hyperplasia, hyperplastic nodules, small carcinomas, and large, well-developed carcinomas were observed. Carcinomas, which were well differentiated, poorly differentiated, or undifferentiated, invaded the adjacent tissue but did not metastasize.

Leiomyomas and leiomyosarcomas of the kidney in 4-day-old BUF rats given methylazoxymethanol acetate intraperitoneally.

The effect of age and sex on the development of renal tumors was studied in inbred BUF male and female rats 4 days, 5, 8, 12, 24, or 52 weeks old. Methylazoxymethanol (MAM) acetate was injected ip (20 mg/kg body wt) once weekly for 9 weeks. Animals 52 weeks old died from hepatic and/or renal necrosis; however, animals of other ages survived 24-42 weeks. Female rats 4 days old were susceptible to the development of leiomyomas and leiomyosarcomas of the kidney, whereas 4-day-old male rats had a few leiomyomas. Adenomas and carcinomas of the kidney and nephroblastomas were not observed. It was concluded that the aglycone of cycasin, MAM, is important in the induction of leiomyosarcomas of the kidneys in 4-day-old rats.

Various degrees of susceptibility of different stocks of rats to N-2-fluorenyldiacetamide hepatic carcinogenesis.

Outbred Osborne Mendel, Japanese, Wistar, NIH Black, and Sorague-Dawley male rats 12 weeks of age ingested 0.025% N-2-fluorenyldiacetamide in a semisynthetic diet Sprague-Daeley and NIH Black male rats were most susceptible to the development of carcinomas and cirrhosis of the liver and also had the highest incidence of metastases. More and larger carcinomas per liver and more poorly differentiated and undifferentiated carcinomas were found, as well as more advanced cirrhosis, Japanese and Wistar male rats were susceptible, but less so, to hepatic carcinogenesis and cirrhosis. These rats had fewer and smaller hepatic carcinomas per liver, and the neoplasms were well differentiated. By contrast, Osborne Mendel male rats were least susceptible to hepatic carcinogenesis and cirrhosis.

Hyperplastic and neoplastic lesions of the kidney in Buffalo rats of varying ages ingesting N-4-(4'-flurobiphenyl)acetamide.

Inbred Buffalo male and female rats 4, 12, 24, and 52 weeks of age ingested 0.04% N-4(4'-fluorobiphenyl)acetamide in a semisynthetic diet for 36 weeks. Animals were killed 12 weeks later. Male rats 24 weeks old were more susceptible to the development of carcinomas of the kidney than were female rats of the same age or younger or older animals of both sexes. Rats with renal cell carcinomas either did not have hepatic carcinomas or had small ones.

Histopathology of liver carcinomas in (C57BL/6N X C3H/HeN)F1 mice ingesting chlordane.

(C57BL/6N X C3H/HeN)F1 male mice that ingested 30 or 56 ppm chlordane and female mice that ingested 30 or 64 ppm chlordane in the diet had highly significant incidences of carcinomas of the liver. The carcinomas varied from well differentiated to poorly differentiated and undifferentiated and were capable of invasion and metastasis. They were more poorly differentiated in mice receiving chlordane than in controls.

Carcinogenicity of deuterium-labeled N-nitroso-N-methylcyclohexylamine in rats.

F344 rats were treated with both unlabeled N-nitroso-N-methylcyclohexylamine (NMC) and deuterium-labeled NMC (NMC-d3) in the methyl group. Both compounds were administered in the drinking water at concentrations of 50 and 12.5 mg/liter. The NMC-d3 was not less carcinogenic than the unlabeled NMC, which suggested that oxidation of the methyl group is not a rate-limiting step in the induction of esophageal tumors.