Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

PURPOSE: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). METHODS: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. RESULTS: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. CONCLUSION: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

OPTIMAL: An OPTimized Imaging Mass cytometry AnaLysis framework for benchmarking segmentation and data exploration.

Analysis of imaging mass cytometry (IMC) data and other low-resolution multiplexed tissue imaging technologies is often confounded by poor single-cell segmentation and suboptimal approaches for data visualization and exploration. This can lead to inaccurate identification of cell phenotypes, states, or spatial relationships compared to reference data from single-cell suspension technologies. To this end we have developed the "OPTimized Imaging Mass cytometry AnaLysis (OPTIMAL)" framework to benchmark any approaches for cell segmentation, parameter transformation, batch effect correction, data visualization/clustering, and spatial neighborhood analysis. Using a panel of 27 metal-tagged antibodies recognizing well-characterized phenotypic and functional markers to stain the same Formalin-Fixed Paraffin Embedded (FFPE) human tonsil sample tissue microarray over 12 temporally distinct batches we tested several cell segmentation models, a range of different arcsinh cofactor parameter transformation values, 5 different dimensionality reduction algorithms, and 2 clustering methods. Finally, we assessed the optimal approach for performing neighborhood analysis. We found that single-cell segmentation was improved by the use of an Ilastik-derived probability map but that issues with poor segmentation were only really evident after clustering and cell type/state identification and not always evident when using "classical" bivariate data display techniques. The optimal arcsinh cofactor for parameter transformation was 1 as it maximized the statistical separation between negative and positive signal distributions and a simple Z-score normalization step after arcsinh transformation eliminated batch effects. Of the five different dimensionality reduction approaches tested, PacMap gave the best data structure with FLOWSOM clustering out-performing phenograph in terms of cell type identification. We also found that neighborhood analysis was influenced by the method used for finding neighboring cells with a "disc" pixel expansion outperforming a "bounding box" approach combined with the need for filtering objects based on size and image-edge location. Importantly, OPTIMAL can be used to assess and integrate with any existing approach to IMC data analysis and, as it creates .FCS files from the segmentation output and allows for single-cell exploration to be conducted using a wide variety of accessible software and algorithms familiar to conventional flow cytometrists.

Elevated plasma neurofilament light and glial fibrillary acidic protein in epilepsy versus nonepileptic seizures and nonepileptic disorders.

OBJECTIVE: Research suggests that recurrent seizures may lead to neuronal injury. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) levels increase in cerebrospinal fluid and blood in response to neuroaxonal damage, and they have been hypothesized as potential biomarkers for epilepsy. We examined plasma NfL and GFAP levels and their diagnostic utility in differentiating patients with epilepsy from those with psychogenic nonepileptic seizures (PNES) and other nonepileptic disorders. METHODS: We recruited consecutive adults admitted for video-electroencephalographic monitoring and formal neuropsychiatric assessment. NfL and GFAP levels were quantified and compared between different patient groups and an age-matched reference cohort (n = 1926) and correlated with clinical variables in patients with epilepsy. RESULTS: A total of 138 patients were included, of whom 104 were diagnosed with epilepsy, 22 with PNES, and 12 with other conditions. Plasma NfL and GFAP levels were elevated in patients with epilepsy compared to PNES, adjusted for age and sex (NfL p = .04, GFAP p = .04). A high proportion of patients with epilepsy (20%) had NfL levels above the 95th age-matched percentile compared to the reference cohort (5%). NfL levels above the 95th percentile of the reference cohort had a 95% positive predictive value for epilepsy. Patients with epilepsy who had NfL levels above the 95th percentile were younger than those with lower levels (37.5 vs. 43.8 years, p = .03). SIGNIFICANCE: An elevated NfL or GFAP level in an individual patient may support an underlying epilepsy diagnosis, particularly in younger adults, and cautions against a diagnosis of PNES alone. Further examination of the association between NfL and GFAP levels and specific epilepsy subtypes or seizure characteristics may provide valuable insights into disease heterogeneity and contribute to the refinement of diagnosis, understanding pathophysiological mechanisms, and formulating treatment approaches.

Australian Headache Epidemiology Data (AHEAD): a pilot study to assess sampling and engagement methodology for a nationwide population-based survey.

BACKGROUND: There are no robust population-based Australian data on prevalence and attributed burden of migraine and medication-overuse headache (MOH) data. In this pilot cross-sectional study, we aimed to capture the participation rate, preferred response method, and acceptability of self-report questionnaires to inform the conduct of a future nationwide migraine/MOH epidemiological study. METHODS: We developed a self-report questionnaire, available in hard-copy and online, including modules from the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, the Eq. 5D (quality of life), and enquiry into treatment gaps. Study invitations were mailed to 20,000 randomly selected households across Australia's two most populous states. The household member who most recently had a birthday and was aged ≥ 18 years was invited to participate, and could do so by returning a hard-copy questionnaire via reply-paid mail, or by entering responses directly into an online platform. RESULTS: The participation rate was 5.0% (N = 1,000). Participants' median age was 60 years (IQR 44-71 years), and 64.7% (n = 647) were female. Significantly more responses were received from areas with relatively older populations and middle-level socioeconomic status. Hard copy was the more commonly chosen response method (n = 736). Females and younger respondents were significantly more likely to respond online than via hard-copy. CONCLUSIONS: This pilot study indicates that alternative methodology is needed to achieve satisfactory engagement in a future nationwide migraine/MOH epidemiological study, for example through inclusion of migraine screening questions in well-resourced, interview-based national health surveys that are conducted regularly by government agencies. Meanwhile, additional future research directions include defining and addressing treatment gaps to improve migraine awareness, and minimise under-diagnosis and under-treatment.

Pharmacological treatment for older adults with epilepsy and comorbid neurodegenerative disorders.

PURPOSE OF REVIEW: An increased interest in epilepsy in older adults has emerged as the global population ages. The purpose of this article is to review the literature regarding the pharmacological treatment of epilepsy in older adults, highlighting issues specifically pertinent to those living with comorbid neurodegenerative disorders. RECENT FINDINGS: Although new original research remains sparse, in the last 5 years, there has been a growing number of studies addressing the relationship between epilepsy and neurodegenerative disorders. Accurate diagnosis is incredibly challenging with electroencephalogram findings often requiring circumspect interpretation. Older individuals are often excluded from or under-represented in clinical trials, and there are sparse guidelines offered on the management of these patients, with even less available in reference to those with neurodegenerative comorbidities. SUMMARY: We propose that seizures occurring earlier in the neurodegenerative process should be treated aggressively, with the goal to inhibit neuro-excitotoxicity and the associated neuronal loss. By strategically choosing newer antiseizure medications with less adverse effects and a holistic approach to treatment, a patient's time living independently can be conserved. In addition, we advocate for original, multinational collaborative research efforts.

Impact of epilepsy surgery on quality of life: Systematic review and meta-analysis.

Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug-resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta-analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre- and post-epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta-analysis assessed the postsurgery change in QoL. Meta-regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre- and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory-31 item (QOLIE-31) meta-analysis included six studies, and QOLIE-89 meta-analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE-31 (95% confidence interval [CI] = 10.9-30.1, I2 = 95.5) and 12.1 for QOLIE-89 (95% CI = 8.0-16.1, I2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta-regression demonstrated a higher postoperative QOLIE-31 score as well as change in pre- and postoperative QOLIE-31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an individual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between individual studies and high risk of bias.

Development and validation of a novel radiomics-clinical model for predicting post-stroke epilepsy after first-ever intracerebral haemorrhage.

OBJECTIVES: Post-stroke epilepsy (PSE) is associated with increased morbidity and mortality. This study aimed to develop and validate a novel prediction model combining clinical factors and radiomics features to accurately identify patients at high risk of developing PSE after intracerebral haemorrhage (ICH). METHODS: Researchers performed a retrospective medical chart review to extract derivation and validation cohorts of patients with first-ever ICH that attended two tertiary hospitals in China between 2010 and 2020. Clinical data were extracted from electronic medical records and supplemented by tele-interview. Predictive clinical variables were selected by multivariable logistic regression to build the clinical model. Predictive radiomics features were identified, and a Rad-score was calculated according to the coefficient of the selected feature. Both clinical variables and radiomic features were combined to build the radiomics-clinical model. Performances of the clinical, Rad-score, and combined models were compared. RESULTS: A total of 1571 patients were included in the analysis. Cortical involvement, early seizures within 7 days of ICH, NIHSS score, and ICH volume were included in the clinical model. Rad-score, instead of ICH volume, was included in the combined model. The combined model exhibited better discrimination ability and achieved an overall better benefit against threshold probability than the clinical model in the decision curve analysis (DCA). CONCLUSIONS: The combined radiomics-clinical model was better able to predict ICH-associated PSE compared to the clinical model. This can help clinicians better predict an individual patient's risk of PSE following a first-ever ICH and facilitate earlier PSE diagnosis and treatment. KEY POINTS: • Radiomics has not been used in predicting the risk of developing PSE. • Higher Rad-scores were associated with higher risk of developing PSE. • The combined model showed better performance of PSE prediction ability.

Making migraine easier to stomach: the role of the gut-brain-immune axis in headache disorders.

BACKGROUND AND PURPOSE: Headache disorders place a significant burden on the healthcare system, being the leading cause of disability in those under 50 years. Novel studies have interrogated the relationship between headache disorders and gastrointestinal dysfunction, suggesting a link between the gut-brain-immune (GBI) axis and headache pathogenesis. Although the exact mechanisms driving the complex relationship between the GBI axis and headache disorders remain unclear, there is a growing appreciation that a healthy and diverse microbiome is necessary for optimal brain health. METHODS: A literature search was performed through multiple reputable databases in search of Q1 journals within the field of headache disorders and gut microbiome research and were critically and appropriately evaluated to investigate and explore the following; the role of the GBI axis in dietary triggers of headache disorders and the evidence indicating that diet can be used to alleviate headache severity and frequency. The relationship between the GBI axis and post-traumatic headache is then synthesized. Finally, the scarcity of literature regarding paediatric headache disorders and the role that the GBI axis plays in mediating the relationship between sex hormones and headache disorders are highlighted. CONCLUSIONS: There is potential for novel therapeutic targets for headache disorders if understanding of the GBI axis in their aetiology, pathogenesis and recovery is increased.

Markov modelling of treatment response in a 30-year cohort study of newly diagnosed epilepsy.

People with epilepsy have variable and dynamic trajectories in response to antiseizure medications. Accurately modelling long-term treatment response will aid prognostication at the individual level and health resource planning at the societal level. Unfortunately, a robust model is lacking. We aimed to develop a Markov model to predict the probability of future seizure-freedom based on current seizure state and number of antiseizure medication regimens trialled. We included 1795 people with newly diagnosed epilepsy who attended a specialist clinic in Glasgow, Scotland, between July 1982 and October 2012. They were followed up until October 2014 or death. We developed a simple Markov model, based on current seizure state only, and a more detailed model, based on both current seizure state and number of antiseizure medication regimens trialled. Sensitivity analyses were performed for the regimen-based states model to examine the effect of regimen changes due to adverse effects. The model was externally validated in a separate cohort of 455 newly diagnosis epilepsy patients seen in Perth, Australia, between May 1999 and May 2016. Our models suggested that once seizure-freedom was achieved, it was likely to persist, regardless of the number of antiseizure medications trialled to reach that point. The likelihood of achieving long-term seizure-freedom was highest with the first antiseizure medication regimen, at approximately 50%. The chance of achieving seizure-freedom fell with subsequent regimens. Fluctuations between seizure-free and not seizure-free states were highest earlier on but decreased with chronicity of epilepsy. Seizure-freedom/recurrence risk tables were constructed with these probability data, similar to cardiovascular risk tables. Sensitivity analyses showed that the general trends and conclusions from the base model were maintained despite perturbing the model and input data with regimen changes due to adverse effects. Quantitative comparison with the external validation cohort showed excellent consistency at Year 1, good at Year 3 and moderate at Year 5. Quantitative models, as used in this study, can provide pertinent clinical insights that are not apparent from simple statistical analysis alone. Attaining seizure freedom at any time in a patient's epilepsy journey will confer durable benefit. Seizure-freedom risk tables may be used to individualize the prediction of future seizure control trajectory.

The effect of epilepsy surgery on productivity: A systematic review and meta-analysis.

OBJECTIVES: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. METHODS: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews - Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes. RESULTS: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07-1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15-0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90-0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94-0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies - of Interventions and was low for most variables except "measurement of exposure." SIGNIFICANCE: There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.

The prevalence of headache disorders in Postural Tachycardia Syndrome: A systematic review and meta-analysis of the literature.

BACKGROUND: Headache is a common presentation of postural tachycardia syndrome, yet robust prevalence data is lacking. OBJECTIVES: To undertake a systematic review and meta-analysis to estimate the prevalence of headache disorders in postural tachycardia syndrome, and to explore the potential shared pathophysiological mechanisms that underpin these conditions as well as treatment options. METHODS: Three databases were searched for publications evaluating prevalence of migraine (primary outcome) and general and orthostatic headache (secondary outcomes) in patients with postural tachycardia syndrome. Two independent reviewers selected studies and extracted data. A random-effects meta-analysis calculated the pooled prevalence of migraine in postural tachycardia syndrome. A narrative literature review explored the pathophysiology and treatment options for concurrent headache disorders and postural tachycardia syndrome. RESULTS: Twenty-three articles met inclusion criteria. Estimated pooled prevalence of migraine in postural tachycardia syndrome was 36.8% (95% CI 2.9-70.7%). Various shared pathophysiological pathways for these conditions, as well as proposed treatment strategies, were identified.Limitations: Heterogeneity of study design, populations, and methodology for identifying headache disorders and postural tachycardia syndrome limited the generalisability of results. CONCLUSIONS: Migraine is a commonly reported comorbidity in POTS, however the true prevalence cannot be determined from the current literature. Further studies are required to assess this comorbidity and investigate the underlying mechanisms, as well as identify effective treatment strategies.

Multidimensional psychopathological profile differences between patients with psychogenic nonepileptic seizures and epileptic seizure disorders.

OBJECTIVE: Early differential diagnosis of psychogenic nonepileptic seizures (PNES) and epileptic seizures (ES) remains difficult. Self-reported psychopathology is often elevated in patients with PNES, although relatively few studies have examined multiple measures of psychopathology simultaneously. This study aimed to identify differences in multidimensional psychopathology profiles between PNES and ES patient groups. METHOD: This was a retrospective case-control study involving patients admitted for video-EEG monitoring (VEM) over a two-year period. Clinicodemographic variables and psychometric measures of depression, anxiety, dissociation, childhood trauma, maladaptive personality traits, and cognition were recorded. Diagnosis of PNES or ES was determined by multidisciplinary assessment and consensus opinion. General linear mixed models (GLMMs) were used to investigate profile differences between diagnostic groups across psychometric measures. A general psychopathology factor was then computed using principal components analysis (PCA) and differences between groups in this 'p' factor were investigated. RESULTS: 261 patients (77 % with ES and 23 % with PNES) were included in the study. The PNES group endorsed greater symptomatology with GLMM demonstrating a significant main effect of group (η2p = 0.05) and group by measure interaction (η2p = 0.03). Simple effects analysis indicated that the PNES group had particularly elevated scores for childhood trauma (ß = 0.78), dissociation (ß = 0.70), and depression (ß = 0.60). There was a high correlation between psychopathology measures, with a single p factor generated to explain 60 % variance in the psychometric scores. The p factor was elevated in the PNES group (ß = 0.61). ROC curve analysis indicated that these psychometric measures had limited usefulness when considered individually (AUC range = 0.63-0.69). CONCLUSION: Multidimensional psychopathological profile differences exist between patients with PNES and ES. Patients with PNES report more psychopathology overall, with particular elevations in childhood trauma, dissociation, and depression. Although not suitable to be used as a standalone screening tool to differentiate PNES and ES, understanding of these profiles at a construct level might help triage patients and guide further psychiatric examination and enquiry.

CD4+ effector T cells accelerate Alzheimer's disease in mice.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aß) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. METHODS: In this report, we developed and characterized cloned lines of amyloid beta (Aß) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aß-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aß T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb-KLVFFAEDVGSNKGA) tetramer binding. Aß-Th1 and Aß-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. RESULTS: The propagated Aß-Th1 and Aß-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aß reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aß-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. CONCLUSIONS: These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aß reactive Tregs.

Clinical predictors of discordance between screening tests and psychiatric assessment for depressive and anxiety disorders among patients being evaluated for seizure disorders.

OBJECTIVE: This study was undertaken to identify factors that predict discordance between the screening instruments Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder scale (GAD-7), and diagnoses made by qualified psychiatrists among patients with seizure disorders. Importantly, this is not a validation study; rather, it investigates clinicodemographic predictors of discordance between screening tests and psychiatric assessment. METHODS: Adult patients admitted for inpatient video-electroencephalographic monitoring completed eight psychometric instruments, including the NDDI-E and GAD-7, and psychiatric assessment. Patients were grouped according to agreement between the screening instrument and psychiatrists' diagnoses. Screening was "discordant" if the outcome differed from the psychiatrist's diagnosis, including both false positive and false negative results. Bayesian statistical analyses were used to identify factors associated with discordance. RESULTS: A total of 411 patients met inclusion criteria; mean age was 39.6 years, and 55.5% (n = 228) were female. Depression screening was discordant in 33% of cases (n = 136/411), driven by false positives (n = 76/136, 56%) rather than false negatives (n = 60/136, 44%). Likewise, anxiety screening was discordant in one third of cases (n = 121/411, 29%) due to false positives (n = 60/121, 50%) and false negatives (n = 61/121, 50%). Seven clinical factors were predictive of discordant screening for both depression and anxiety: greater dissociative symptoms, greater patient-reported adverse events, subjective cognitive impairment, negative affect, detachment, disinhibition, and psychoticism. When the analyses were restricted to only patients with psychogenic nonepileptic seizures (PNES) or epilepsy, the rate of discordant depression screening was higher in the PNES group (n = 29, 47%) compared to the epilepsy group (n = 70, 30%, Bayes factor for the alternative hypothesis = 4.65). SIGNIFICANCE: Patients with seizure disorders who self-report a variety of psychiatric and other symptoms should be evaluated more thoroughly for depression and anxiety, regardless of screening test results, especially if they have PNES and not epilepsy. Clinical assessment by a qualified psychiatrist remains essential in diagnosing depressive and anxiety disorders among such patients.

Adverse events related to antiepileptic drugs.

OBJECTIVE: Adverse events (AEs) related to antiepileptic drugs (AEDs) may interfere with adequate dosing and patient adherence, leading to suboptimal seizure control, and relatedly, increased injuries, hospitalizations, and mortality. This study investigated the clinicodemographic factors associated with AEs related to AEDs as reported by the Liverpool Adverse Events Profile (LAEP), and explored the ability of LAEP to discriminate between epilepsy and psychogenic nonepileptic seizures (PNES). We hypothesized that female sex, mood disorders, AED-polytherapy, duration, and severity of epilepsy are associated with increased endorsement of AEs related to AEDs, and that endorsement of AEs related to AEDs would significantly differ between epilepsy and PNES patients. METHODS: We prospectively enrolled adult patients admitted to two inpatient video-electroencephalogram monitoring units. Clinicodemographic variables and psychometric measures of depression, anxiety, and cognitive function were recorded. Patient-reported AE endorsement was obtained using the LAEP, which was reduced to four latent domains using exploratory structural equation modeling. General linear models identified variables associated with each domain. Logistic regression determined the ability of LAEP scores to differentiate between epilepsy and PNES. RESULTS: 311 patients met inclusion criteria. Mean age was 38 years and 56% of patients were female. Network analysis demonstrated strong relationships between depression and anxiety with physical, sleep, psychiatric, and dermatological AE endorsement. Depression, female sex, and AED polytherapy were associated with greater AE endorsement. Epilepsy, compared to PNES, was associated with lower AE endorsement. Fewer prescribed AEDs and greater reported physical AE endorsement were associated with PNES diagnosis. SIGNIFICANCE: There is a strong relationship between patient-reported AEs and psychiatric symptomatology. Those with PNES paradoxically endorse greater physical AEs despite receiving fewer AEDs. Patients who endorse AEs in clinical practice should be screened for comorbid depression or anxiety and treated accordingly.

Development and validation of a screening questionnaire for psychogenic nonepileptic seizures.

OBJECTIVE: Epilepsy and psychogenic nonepileptic seizures (PNES) are serious conditions, associated with substantial morbidity and mortality. Although prompt diagnosis is essential, these conditions are frequently misdiagnosed, delaying appropriate treatment. We developed and validated the Anxiety, Abuse, and Somatization Questionnaire (AASQ), a quick and clinically practical tool to differentiate PNES from epilepsy. METHOD: We retrospectively identified psychological variables that differentiated epilepsy from PNES in a discovery cohort of patients admitted to a video-electroencephalography monitoring (VEM) unit from 2002 to 2017. From these findings, we developed the AASQ and prospectively validated it in an independent cohort of patients with gold-standard VEM diagnosis. RESULTS: One thousand two hundred ninety-one patients were included in the retrospective study; mean age was 39.5 years (range: 18-99), 58% were female, 67% had epilepsy, and 33% had PNES. Psychometric data for 192 instrument items were reviewed, receiver operating characteristic curves were computed, and a 20-item AASQ was created. Prospective validation in 74 patients showed that a one-point increase in the AASQ score was associated with 11 times increase in the odds of having PNES compared with epilepsy. Low scores on the AASQ were associated with a low probability of PNES with a negative predictive value of 95%. SIGNIFICANCE: The AASQ is quick, inexpensive, and clinically useful for workup of seizure disorders. The AASQ excludes PNES with a high degree of confidence and can predict PNES with significance when combined with basic clinicodemographic variables. Future research will investigate diagnostic performance of the AASQ in relevant clinical subgroups, such as patients with comorbid epilepsy and PNES.

Impact of a health marketing campaign on sugars intake by children aged 5-11 years and parental views on reducing children's consumption.

BACKGROUND: The association between Free Sugars intake and non-communicable diseases such as obesity and dental caries is well documented and several countries are taking measures to reduce sugars intakes. Public Health England (PHE) instigated a range of approaches to reduce sugars, including a national health marketing campaign (Sugar Smart). The campaign aimed to raise awareness of the amount of sugars in foods and drinks and to encourage parents to reduce their children's intake. The aim of this study was to determine whether the campaign was effective in altering dietary behaviour, by assessing any impact of the campaign on sugars intake among children aged 5-11 years. Parental perceptions of the campaign and barriers to reducing sugars intake were also explored. METHODS: Parents of 873 children aged 5-11 years, identified from an existing PHE database, were invited to take part. Dietary information was collected online using Intake24 before, during, and at 1, 10 and 12 months following the campaign. Change in sugars intake was assessed using mixed effects linear regression models. One-to-one telephone interviews were conducted with a purposive sample of parents to explore perceptions of the campaign and identify barriers and facilitators to reducing children's sugars intake. RESULTS: Completion rates for dietary assessment ranged from 61 to 72% across the follow up time points. Qualitative telephone interviews were conducted with 20 parents. Total sugars intake decreased on average by ~ 6.2 g/day (SD 43.8) at peak campaign and the percentage of energy from total sugars significantly decreased immediately and 1 year post campaign. The percentage of energy from Free Sugars significantly decreased across all time points with the exception of the long term follow up at 12-months post campaign. The percentage of energy intake from total fat increased. Parents expressed a willingness to reduce sugars intakes, however, identified barriers including time constraints, the normalisation of sugary treats, and confusing information. CONCLUSIONS: A health marketing campaign had a positive impact in reducing sugars intake but reductions in sugars were not sustained. Parents want to reduce their child's sugars intake but societal barriers and confusion over which sources of sugars to avoid hamper efforts to change.

Progressive 24-Hour Recall: Usability Study of Short Retention Intervals in Web-Based Dietary Assessment Surveys.

BACKGROUND: Under-reporting because of the limitations of human memory is one of the key challenges in dietary assessment surveys that use the multiple-pass 24-hour recall. Research indicates that shortening a retention interval (ie, the time between the eating event and recall) reduces the burden on memory and may increase the accuracy of the assessment. OBJECTIVE: This study aimed to explore the accuracy and acceptability of Web-based dietary assessment surveys based on a progressive recall, where a respondent is asked to record multiple recalls throughout a 24-hour period using the multiple-pass protocol and portion size estimation methods of the 24-hour recall. METHODS: The experiment was conducted with a dietary assessment system, Intake24, that typically implements the multiple-pass 24-hour recall method where respondents record all meals they had for the previous day on a single occasion. We modified the system to allow respondents to add multiple recalls throughout the day using the multiple-pass protocol and portion size estimation methods of the 24-hour recall (progressive recall). We conducted a dietary assessment survey with 33 participants, where they were asked to record dietary intake using both 24-hour and progressive recall methods for weekdays only. We compared mean retention intervals (ie, the time between eating event and recall) for the 2 methods. To examine accuracy, we compared mean energy estimates and the mean number of reported foods. Of these participants, 23 were interviewed to examine the acceptability of the progressive recall. RESULTS: Retention intervals were found to be, on average, 15.2 hours (SD 7.8) shorter during progressive recalls than those during 24-hour recalls. We found that the mean number of foods reported for evening meals for progressive recalls (5.2 foods) was significantly higher (P=.001) than that for 24-hour recalls (4.2 foods). The number of foods and the amount of energy reported for other meals remained similar across the 2 methods. In interviews, 65% (15/23) of participants said that the 24-hour recall is more convenient in terms of fitting in with their daily lifestyles, and 65% (15/23) of respondents indicated that they remembered meal content and portion sizes better with the progressive recall. CONCLUSIONS: The analysis of interviews and data from our study indicate that progressive recalls provide minor improvements to the accuracy of dietary assessment in Intake24. Additional work is needed to improve the acceptability of progressive recalls in this system.

Autotransplantation of a surgically removed canine using a customised 3D-printed surgical template.

Autotransplantation is a treatment option with high reported survival rates to replace failing teeth in the anterior maxilla. This treatment requires a multidisciplinary approach from orthodontists, paediatric dentists, restorative dentists, and oral and maxillofacial surgeons to achieve successful outcomes. Success is dependent on many factors including stage of root development, handling of the periodontal ligament, extra-alveolar time and splinting. This case report presents the novel use of digitally designed and three-dimensional (3D) printed surgical templates to aid intraoperatively and reduce the extra-alveolar time. A preoperative cone-beam computed tomography scan allowed digital planning and construction of surgical templates that replicated the exact root dimensions of impacted maxillary canines. These templates were subsequently 3D printed in resin, sterilised and utilised intraoperatively to aid socket preparation before the surgical autotransplantation.

First seizure presentations in adults: beyond assessment and treatment.

Almost 10% of people will experience at least one seizure over a lifetime. Although common, first seizures are serious events and warrant careful assessment and management. First seizures may be provoked by acute or remote symptomatic factors including life-threatening metabolic derangements, drug toxicity or structural brain lesions. An unprovoked first seizure may herald the onset of epilepsy and may be accompanied by medical and psychiatric illnesses. Accidents, injuries and death associated with first seizures are likely under-reported. The cognitive and emotional impact of first seizures is often neglected. Evaluation of a patient presenting with a first seizure requires careful history-taking and early specialist assessment, however optimal management strategies have not been extensively investigated. Further, advances in technology and the role of eHealth interventions such as telemedicine may be of value in the care of patients who have experienced a first seizure. This article reviews the impact and implications of first seizures beyond the scope provided in current guidelines which tend to focus on assessment and management. It examines the effect of first seizures on the well-being of patients; assesses morbidity and premature mortality in first seizures and discusses current and future directions to optimise safety and health of people with first seizures, with a focus on adult patients. Recognition of these issues is essential to provide adequate care for people with first seizures.