Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy.

OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.

Scoping review and expert-based consensus recommendations for assessment and management of psychogenic non-epileptic (functional) seizures (PNES) in children: A report from the Pediatric Psychiatric Issues Task Force of the International League Against Epilepsy.

Limited guidance exists regarding the assessment and management of psychogenic non-epileptic seizures (PNES) in children. Our aim was to develop consensus-based recommendations to fill this gap. The members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment-There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a "probable" diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management-There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities-There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.

Impact of psychiatric comorbidities on the treatment of epilepsies in adults.

INTRODUCTION: Epilepsy is often accompanied by psychiatric comorbidities and the management of epilepsy in these patients presents unique challenges due to the interplay between the underlying neurological condition and the psychiatric symptoms and the combined use of multiple medications. AREAS COVERED: This paper aims to explore the complexities associated with managing epilepsy in the presence of psychiatric comorbidities, focusing on the impact of psychiatric disorders on epilepsy treatment strategies and the challenges posed by the simultaneous administration of multiple medications. EXPERT OPINION: Patients with epilepsy and psychiatric comorbidities seem to present with a more severe form of epilepsy that is resistant to drug treatments and burdened by an increased morbidity and mortality. Whether prompt treatment of psychiatric disorders can influence the long-term prognosis of the epilepsy is still unclear as well as the role of specific treatment strategies, such as neuromodulation, in this group of patients. Clinical practice recommendations and guidelines will prompt the development of new models of integrated care to be implemented.

Changes in the heartbeat-evoked potential are associated with functional seizures.

BACKGROUND: Patients with functional seizures (FS) can experience dissociation (depersonalisation) before their seizures. Depersonalisation reflects disembodiment, which may be related to changes in interoceptive processing. The heartbeat-evoked potential (HEP) is an electroencephalogram (EEG) marker of interoceptive processing. AIM: To assess whether alterations in interoceptive processing indexed by HEP occur prior to FS and compare this with epileptic seizures (ES). METHODS: HEP amplitudes were calculated from EEG during video-EEG monitoring in 25 patients with FS and 19 patients with ES, and were compared between interictal and preictal states. HEP amplitude difference was calculated as preictal HEP amplitude minus interictal HEP amplitude. A receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of HEP amplitude difference in discriminating FS from ES. RESULTS: The FS group demonstrated a significant reduction in HEP amplitude between interictal and preictal states at F8 (effect size rB=0.612, false discovery rate (FDR)-corrected q=0.030) and C4 (rB=0.600, FDR-corrected q=0.035). No differences in HEP amplitude were found between states in the ES group. Between diagnostic groups, HEP amplitude difference differed between the FS and ES groups at F8 (rB=0.423, FDR-corrected q=0.085) and C4 (rB=0.457, FDR-corrected q=0.085). Using HEP amplitude difference at frontal and central electrodes plus sex, we found that the ROC curve demonstrated an area under the curve of 0.893, with sensitivity=0.840 and specificity=0.842. CONCLUSION: Our data support the notion that aberrant interoception occurs prior to FS. Changes in HEP amplitude may reflect a neurophysiological biomarker of FS and may have diagnostic utility in differentiating FS and ES.

Is there a hierarchy in mental health stigma?

People with mental illness fight not just against their condition but also against stigma, discrimination and inequalities. Research into stigma in mental illness has increased over time, but data on transdiagnostic stigma are still very limited. This commentary focuses on this topic alongside a recently published article in BJPsych Open.

Current and future pharmacotherapy options for drug-resistant epilepsy.

INTRODUCTION: Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide. AREAS COVERED: The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies. EXPERT OPINION: Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

Neuropsychiatric and Cognitive Comorbidities in Epilepsy.

PURPOSE OF REVIEW: This article discusses psychiatric and cognitive comorbidities of epilepsy over the lifespan and illustrates opportunities to improve the quality of care of children and adults with epilepsy. RECENT FINDINGS: One in 3 people with epilepsy have a lifetime history of psychiatric disorders, and they represent an important prognostic marker of epilepsy. Contributors are diverse and display a complex relationship. Cognitive comorbidities are also common among those living with epilepsy and are increasingly recognized as a reflection of changes to underlying brain networks. Among the cognitive comorbidities, intellectual disability and dementia are common and can complicate the diagnostic process when cognitive and/or behavioral features resemble seizures. SUMMARY: Comorbidities require consideration from the first point of contact with a patient because they can determine the presentation of symptoms, responsiveness to treatment, and the patient's day-to-day functioning and quality of life. In epilepsy, psychiatric and cognitive comorbidities may prove a greater source of disability for the patient and family than the seizures themselves, and in the case of essential comorbidities, they are regarded as core to the disorder in terms of etiology, diagnosis, and treatment.

Suicidality and antiepileptic drugs in people with epilepsy: an update.

INTRODUCTION: Almost 15 years after the Food and Drug Administration (FDA) issued an alert about an increased suicidality risk with antiseizure medications (ASMs), there is still considerable debate on this subject. AREAS COVERED: This is a review of the role of ASMs in the context of suicide in epilepsy. EXPERT OPINION: After an explosion of research shortly after the FDA warning was released, only a limited number of studies were published in more recent years, and they did not overcome the limitations of previous studies. Overall, available literature does not support an obvious causal relationship between ASMs and suicide. On the contrary, studies are highlighting the complex relationship between suicide and epilepsy, strengthening the bidirectional relationship and the multifactorial origin.

ILAE clinical practice recommendations for the medical treatment of depression in adults with epilepsy.

The aim of this document is to provide evidence-based recommendations for the medical treatment of depression in adults with epilepsy. The working group consisted of members of an ad hoc Task Force of the International League Against Epilepsy (ILAE) Commission on Psychiatry, ILAE Executive and the International Bureau for Epilepsy (IBE) representatives. The development of these recommendations is based on a systematic review of studies on the treatment of depression in adults with epilepsy, and a formal adaptation process of existing guidelines and recommendations of treatment of depression outside epilepsy using the ADAPTE process. The systematic review identified 11 studies on drug treatments (788 participants, class of evidence III and IV); 13 studies on psychological treatments (998 participants, class of evidence II, III and IV); and 2 studies comparing sertraline with cognitive behavioral therapy (CBT; 155 participants, class of evidence I and IV). The ADAPTE process identified the World Federation of Societies of Biological Psychiatry guidelines for the biological treatment of unipolar depression as the starting point for the adaptation process. This document focuses on first-line drug treatment, inadequate response to first-line antidepressant treatment, and duration of such treatment and augmentation strategies within the broader context of electroconvulsive therapy, psychological, and other treatments. For mild depressive episodes, psychological interventions are first-line treatments, and where medication is used, selective serotonin reuptake inhibitors (SSRIs) are first-choice medications (Level B). SSRIs remain the first-choice medications (Level B) for moderate to severe depressive episodes; however, in patients who are partially or non-responding to first-line treatment, switching to venlafaxine appears legitimate (Level C). Antidepressant treatment should be maintained for at least 6 months following remission from a first depressive episode but it should be prolonged to 9 months in patients with a history of previous episodes and should continue even longer in severe depression or in cases of residual symptomatology until such symptoms have subsided.

Psychiatric Comorbidities in People With Epilepsy.

PURPOSE OF REVIEW: To review the latest evidence concerning the epidemiology, clinical implications, and management of psychiatric disorders in epilepsy. RECENT FINDINGS: People with epilepsy have a 2-5 times increased risk of developing any psychiatric disorder, and 1 in 3 patients with epilepsy have a lifetime psychiatric diagnosis. Psychiatric comorbidities represent a poor prognostic marker as they have been associated with a poor response to treatment (drugs and surgery), increased morbidity, and mortality. Validated screening instruments are available for mood and anxiety disorders in adults as well as attention-deficit hyperactivity disorder in children with epilepsy. SUMMARY: All patients with epilepsy should be routinely screened for psychiatric disorder at the onset and at least once a year. Patients with epilepsy and their relatives should be informed of the risk of mental health problems and the implications.

Demographic and clinical phenotypic differences between people with dissociative seizures and those with other psychiatric disorders.

BACKGROUND: A large amount of literature surrounds the differences between dissociative neurological symptom disorder with non-epileptic seizures (DNSD-S) and epilepsy. AIMS: To explore the research gap on phenotypic differences between DNSD-S and other psychiatric disorders. METHOD: We conducted a case-control study of 1860 patients (620 patients with DNSD-S and 1240 controls with other psychiatric disorders) seen at the South London and Maudsley Hospital NHS Trust between 2007 and 2019. RESULTS: Compared with the controls, the patients with DNSD-S were more likely to be female (76 v. 47%, P < 0.001), of White ethnicity (77 v. 60%, P < 0.001), married (34 v. 14%, P < 0.001) and living in areas of lower socioeconomic status (-3.79, 95% CI -2.62 to -4.96, P < 0.001). Two peaks for age at diagnosis were observed for DNSD-S: the early 20s and late 40s. After 31 years of age, men's chance of being diagnosed with DNSD-S increased from 19 to 28% (P = 0.009). People with DNSD-S presented more commonly with a history of a neurological episodic or paroxysmal disorder (OR = 12, 95% CI 7.82-20.26), another dissociative disorder (OR = 10, 95% CI 1.64- 65.95) or unclassified signs or symptoms (OR = 4, 95% CI 2.61-6.43). Neither anxiety, depression nor other somatoform disorders predicted subsequent diagnosis of DNSD-S, and controls had a larger proportion of preceding psychiatric diagnoses than patients with DNSD-S (65 v. 49%, P < 0.001). CONCLUSIONS: This is the first study comparing demographic and phenotypic correlates of patients with DNSD-S against a large cohort of psychiatric patients. These data will inform development and drive service needs in psychiatry for people with DNSD-S.

Pharmacological treatment of focal epilepsy in adults: an evidence based approach.

INTRODUCTION: Focal seizures represent the most common seizure type and focal epilepsies the most common epilepsy type. Anti-seizure medications (ASMs) still represent the main form of treatment for epilepsy. AREAS COVERED: The aim of this review article is to provide an overview of available evidence about current and upcoming pharmacological options and strategies for adults with focal epilepsy focusing on the last 5 years. EXPERT OPINION: Seventeen drugs are currently approved for the treatment of focal seizures including cenobamate as the very latest option. Ten of these drugs are also licensed for monotherapy. Level A evidence for initial monotherapy is available for seven drugs with no robust data supporting that one drug is superior to the other. Safety, tolerability as well as pharmacoeconomic reasons would then drive treatment decisions. Data on adjunctive treatment are available for 13 ASMs showing again no obvious difference in terms of efficacy. Evidence on specific drug combinations is almost non-existent and the final decision of combining specific drugs is based on the experience of the individual clinician rather than on robust evidence. Current outcome measures do not consider number of previously failed drugs and the observation period is often too short.

A systematic review of neuroimaging studies of depression in adults with epilepsy.

OBJECTIVE: Depression is a relatively common comorbidity in people with epilepsy with a lifetime history identified in 1 in 4 individuals. In this paper, we aimed to provide a systematic review of structural and functional brain region-specific group differences of adults with epilepsy and depression and to discuss existing evidence as compared to that in people with depression. METHODS: We undertook a systematic review of neuroimaging studies of depression in adults with epilepsy through MEDLINE/PubMed, Embase and PsycInfo searches until June 2020. RESULTS: A total of 44 studies were included in the qualitative synthesis: 21 on structural neuroimaging, 9 on functional, and 14 on pharmaco/metabolic neuroimaging. Almost all studies focused on temporal lobe epilepsy (TLE). Patterns of changes in the hippocampi and subcortical structures seem to be different from those reported in depression outside epilepsy. Cortical changes are grossly similar as well as the lack of any laterality effect. Serotonin dysfunction seems to be due to different mechanisms with reduced synaptic availability for depression in epilepsy as compared to reduced 5HT1 receptor density outside epilepsy. Depressive symptoms seem to correlate with a dysfunction in temporolimbic structures contralateral to the epileptogenic zone especially in patients with de novo postsurgical depression. CONCLUSIONS: Depression, at least in TLE, seems to be associated with a different pattern of brain changes as compared to major depression, potentially supporting the notion of phenomenological peculiarities of depression in epilepsy.

Double stigma in mental health: epilepsy and mental illness.

BACKGROUND: Epilepsy and mental illness share similar problems in terms of stigma, as a result of centuries of superstition, ignorance and misbeliefs. Stigma leads not only to discrimination and civil and human rights violations but also to poor access to healthcare and non-adherence or decreased adherence to treatment, ultimately increasing morbidity and mortality. Despite continuous efforts in fighting stigma in these conditions, there is very limited knowledge on the phenomenon of double stigma, meaning the impact of having two stigmatised conditions at the same time. AIMS: To discuss double stigma in mental health with special reference to epilepsy. METHOD: Articles were identified through searches in PubMed up to 31 October 2019 using the search terms 'epilepsy', 'psychiatric disorders', 'stigma' and additional material was identified from the authors' own files and from chosen bibliographies. RESULTS: Double stigma is gaining attention for other stigmatised medical conditions, such as HIV, however, the literature on epilepsy is almost non-existent and this is quite astonishing given that one in three people with epilepsy have a lifetime diagnosis of a psychiatric condition. Felt (perceived) stigma and psychiatric disorders, particularly depression, create a vicious circle in epilepsy maintaining both, as depression correlates with stigma and vice versa as well as epilepsy and depression serving as bidirectional risk factors. This phenomenon has no geographical and economic boundaries as similar data have been reported for low-income and high-income countries. CONCLUSIONS: Governments and policymakers as well as health services, patients' organisations, families and the general public need to be aware of the phenomenon of double stigma in order to develop campaigns and interventions tailored for these patients.

Trait and state interoceptive abnormalities are associated with dissociation and seizure frequency in patients with functional seizures.

OBJECTIVE: Dissociative traits represent a disturbance in selfhood that may predispose to, and trigger, functional seizures (FSs). The predictive representation and control of the internal physiological state of the body (interoception) are proposed to underpin the integrity of the sense of self ("minimal selfhood"). Therefore, discrepancies between objective and subjective aspects of interoception may relate to symptom expression in patients with FSs. Here, we tested whether individual differences in trait measures of interoception relate to dissociative symptoms, and whether state interoceptive deficits predict FS occurrence. METHODS: Forty-one participants with FSs and 30 controls completed questionnaire ratings of dissociation, and measures of (1) interoceptive accuracy (IA)-objective performance on heartbeat detection tasks; (2) trait interoceptive sensibility-subjective sensitivity to internal sensations (using the Porges Body Perception Questionnaire); and (3) state interoceptive sensibility-subjective trial-by-trial measures of confidence in heartbeat detection. Interoceptive trait prediction error (ITPE) was calculated from the discrepancy between IA and trait sensibility, and interoceptive state prediction error (ISPE) from the discrepancy between IA and state sensibility. RESULTS: Patients with FSs had significantly lower IA and greater trait interoceptive sensibility than healthy controls. ITPE was the strongest predictor of dissociation after controlling for trait anxiety and depression in a regression model. ISPE correlated significantly with FS frequency after controlling for state anxiety. SIGNIFICANCE: Patients with FSs have disturbances in interoceptive processing that predict both dissociative traits reflecting the disrupted integrity of self-representation, and the expression of FSs. These findings provide insight into the pathophysiology of functional neurological disorder, and could lead to novel diagnostic and therapeutic approaches.