Psychiatric adverse effects of zonisamide in patients with epilepsy and mental disorder comorbidities

Over the last few years, zonisamide has been proposed as a potentially useful medication for patients with focal seizures, with or without secondary generalization. Since psychiatric adverse effects, including mania, psychosis, and suicidal ideation, have been associated with its use, it was suggested that the presence of antecedent psychiatric disorders is an important factor associated with the discontinuation of zonisamide therapy in patients with epilepsy. We, therefore, set out to assess the tolerability profile of zonisamide in a retrospective chart review of 23 patients with epilepsy and comorbid mental disorders, recruited from two specialist pediatric (n=11) and adult (n=12) neuropsychiatry clinics. All patients had a clinical diagnosis of treatment-refractory epilepsy after extensive neurophysiological and neuroimaging investigations. The vast majority of patients (n=22/23, 95.7%) had tried previous antiepileptic medications, and most adult patients (n=9/11, 81.8%) were on concomitant medication for epilepsy. In the majority of cases, the psychiatric adverse effects of zonisamide were not severe. Four patients (17.4%) discontinued zonisamide because of lack of efficacy, whereas only one patient (4.3%) discontinued it because of the severity of psychiatric adverse effects (major depressive disorder). The low discontinuation rate of zonisamide in a selected population of patients with epilepsy and neuropsychiatric comorbidity suggests that this medication is safe and reasonably well-tolerated for use in patients with treatment-refractory epilepsy. Given the limitations of the present study, including the relatively small sample size, further research is warranted to confirm this finding. © 2013 Elsevier Inc.

Factors determining disease duration in Alzheimer's disease:a postmortem study of 103 cases using the Kaplan-Meier estimator and Cox regression

Factors associated with duration of dementia in a consecutive series of 103 Alzheimer's disease (AD) cases were studied using the Kaplan-Meier estimator and Cox regression analysis (proportional hazard model). Mean disease duration was 7.1 years (range: 6 weeks-30 years, standard deviation = 5.18); 25% of cases died within four years, 50% within 6.9 years, and 75% within 10 years. Familial AD cases (FAD) had a longer duration than sporadic cases (SAD), especially cases linked to presenilin (PSEN) genes. No significant differences in duration were associated with age, sex, or apolipoprotein E (Apo E) genotype. Duration was reduced in cases with arterial hypertension. Cox regression analysis suggested longer duration was associated with an earlier disease onset and increased senile plaque (SP) and neurofibrillary tangle (NFT) pathology in the orbital gyrus (OrG), CA1 sector of the hippocampus, and nucleus basalis of Meynert (NBM). The data suggest shorter disease duration in SAD and in cases with hypertensive comorbidity. In addition, degree of neuropathology did not influence survival, but spread of SP/NFT pathology into the frontal lobe, hippocampus, and basal forebrain was associated with longer disease duration. © 2014 R. A. Armstrong.

The neural correlates of reading impairment in adults with developmental dyslexia:evidence from fMRI between group analyses and an fMRI multiple-case study

The goal of this project was to investigate the neural correlates of reading impairment in dyslexia as hypothesised by the main theories – the phonological deficit, visual magnocellular deficit and cerebellar deficit theories, with emphasis on individual differences. This research took a novel approach by: 1) contrasting the predictions in one sample of participants with dyslexia (DPs); 2) using a multiple-case study (and between-group comparisons) to investigate differences in BOLD between each DP and the controls (CPs); 3) demonstrating a possible relationship between reading impairment and its hypothesised neural correlates by using fMRI and a reading task. The multiple-case study revealed that the neural correlates of reading in dyslexia in all cases are not in agreement with the predictions of a single theory. The results show striking individual differences - even, where the neural correlates of reading in two DPs are consistent with the same theory, the areas can differ. A DP can exhibit under-engagement in an area in word, but not in pseudoword reading and vice versa, demonstrating that underactivation in that area cannot be interpreted as a ‘developmental lesion’. Additional analyses revealed complex results. Within-group analyses between behavioural measures and BOLD showed correlations in the predicted regions, areas outside ROI, and lack of correlations in some predicted areas. Comparisons of subgroups which differed on Orthography Composite supported the MDT, but only for Words. The results suggest that phonological scores are not a sufficient predictor of the under-engagement of phonological areas during reading. DPs and CPs exhibited correlations between Purdue Pegboard Composite and BOLD in cerebellar areas only for Pseudowords. Future research into reading in dyslexia should use a more holistic approach, involving genetic and environmental factors, gene by environment interaction, and comorbidity with other disorders. It is argued that multidisciplinary research, within the multiple-deficit model holds significant promise here.

Application of Naïve Bayesian sequential analysis to primary care optometry

The objective of this study was to investigate the effects of circularity, comorbidity, prevalence and presentation variation on the accuracy of differential diagnoses made in optometric primary care using a modified form of naïve Bayesian sequential analysis. No such investigation has ever been reported before. Data were collected for 1422 cases seen over one year. Positive test outcomes were recorded for case history (ethnicity, age, symptoms and ocular and medical history) and clinical signs in relation to each diagnosis. For this reason only positive likelihood ratios were used for this modified form of Bayesian analysis that was carried out with Laplacian correction and Chi-square filtration. Accuracy was expressed as the percentage of cases for which the diagnoses made by the clinician appeared at the top of a list generated by Bayesian analysis. Preliminary analyses were carried out on 10 diagnoses and 15 test outcomes. Accuracy of 100% was achieved in the absence of presentation variation but dropped by 6% when variation existed. Circularity artificially elevated accuracy by 0.5%. Surprisingly, removal of Chi-square filtering increased accuracy by 0.4%. Decision tree analysis showed that accuracy was influenced primarily by prevalence followed by presentation variation and comorbidity. Analysis of 35 diagnoses and 105 test outcomes followed. This explored the use of positive likelihood ratios, derived from the case history, to recommend signs to look for. Accuracy of 72% was achieved when all clinical signs were entered. The drop in accuracy, compared to the preliminary analysis, was attributed to the fact that some diagnoses lacked strong diagnostic signs; the accuracy increased by 1% when only recommended signs were entered. Chi-square filtering improved recommended test selection. Decision tree analysis showed that accuracy again influenced primarily by prevalence, followed by comorbidity and presentation variation. Future work will explore the use of likelihood ratios based on positive and negative test findings prior to considering naïve Bayesian analysis as a form of artificial intelligence in optometric practice.

Dyslexia research at the turn of the 21st century:behavioural, neuroimaging and genetic findings

Behavioural studies have shown that dyslexics are a heterogeneous population and between-group comparisons are thus inadequate. Some subjects do not develop dyslexia despite having a deficit implicated in this disorder, which points to protective factors. Dyslexia co-occurs with ADHD, DCD, SLI, and SSD, so that future behavioural studies will need to screen and/or statistically control for other disorders. Studies of multiple cases of DPs with other developmental disorders are necessary. Neuroimaging findings show structural and/or functional brain abnormalities in language areas, V5/MT and the cerebellum. Future neuroimaging studies need to investigate the whole reading network and multiple cases. Six dyslexia risk genes have been found, mostly involved in neural migration, which may suggest dyslexia is a deficit of neuronal migration. However, it is not clear how these genes can restrict migration to specific brain areas. As a complex and heterogeneous disorder, dyslexia is likely to be associated with several mutated genes. ADHD and SSD are characterised by genetic risk factors which are partially shared with dyslexia, resulting in comorbidity. Future genetic studies need to focus on identifying other risk genes and pleiotropic genes involved in comorbidities, and linking genotypes implicated in dyslexia with brain structure. Any theory of dyslexia needs to take into account a multitude of risk and protective factors across behavioural, neural and genetic domains.

Description and preliminary results from a structured specialist behavioural weight management group intervention:Specialist Lifestyle Management (SLiM) programme

Background -  Specialist Lifestyle Management (SLiM) is a structured patient education and self-management group weight management programme. Each session is run monthly over a 6-month period providing a less intensive long-term approach. The groups are patient-centred incorporating educational, motivational, behavioural and cognitive elements. The theoretical background, programme structure and preliminary results of SLiM are presented. Subjects/methods - The study was a pragmatic service evaluation of obese patients with a body mass index (BMI) ≥35 kg/m2 with comorbidity or ≥40 kg/m2 without comorbidity referred to a specialist weight management service in the West Midlands, UK. 828 patients were enrolled within SLiM over a 48-month period. Trained facilitators delivered the programme. Preliminary anonymised data were analysed using the intention-to-treat principle. The primary outcome measure was weight loss at 3 and 6 months with comparisons between completers and non-completers performed. The last observation carried forward was used for missing data. Results - Of the 828 enrolled within SLiM, 464 completed the programme (56%). The mean baseline weight was 135 kg (BMI=49.1 kg/m2) with 87.2% of patients having a BMI≥40 kg/m2 and 12.4% with BMI≥60 kg/m2. The mean weight change of all patients enrolled was −4.1 kg (95% CI −3.6 to −4.6 kg, p=0.0001) at the end of SLiM, with completers (n=464) achieving −5.5 kg (95% CI −4.2 to −6.2 kg, p=0.0001) and non-completers achieving −2.3 kg (p=0.0001). The majority (78.6%) who attended the 6-month programme achieved weight loss with 32.3% achieving a ≥5% weight loss. Conclusions - The SLiM programme is an effective group intervention for the management of severe and complex obesity.

Definitions and factors associated with subthreshold depressive conditions:a systematic review

BACKGROUND: Subthreshold depressive disorders (minor and subthrehold depression) have been defined in a wide range of forms, varying on the number of symptoms and duration required. Disability associated with these conditions has also been reported. Our aim was to review the different definitions and to determine factors associated with these conditions in order to clarify the nosological implications of these disorders. METHODS: A Medline search was conducted of the published literature between January 2001 and September 2011. Bibliographies of the retrieved papers were also analysed. RESULTS: There is a wide heterogeneity in the definition and diagnostic criteria of minor and subthreshold depression. Minor depression was defined according to DSM-IV criteria. Regarding subthreshold depression, also called subclinical depression or subsyndromal symptomatic depression, between 2 and 5 depressive symptoms were required for the diagnosis, and a minimum duration of 2 weeks. Significant impairment associated with subthreshold depressive conditions, as well as comorbidity with other mental disorders, has been described. CONCLUSIONS: Depression as a disorder is better explained as a spectrum rather than as a collection of discrete categories. Minor and subthreshold depression are common conditions and patients falling below the diagnostic threshold experience significant difficulties in functioning and a negative impact on their quality of life. Current diagnostic systems need to reexamine the thresholds for depressive disorders and distinguish them from ordinary feelings of sadness.

Work disability and depressive disorders:impact on the European population

OBJECTIVE: Our aim was to study the impact of depressive disorders on work disability to discover the determinants of depression for work disability in the European countries. DESIGN: The sample was composed of 31,126 individuals from 29 countries included in the 2002 World Health Survey of the World Health Organization. National representative samples of countries from all regions of Europe and with different levels of economic development and health coverage were selected. RESULTS: Estimates of people not working because of ill health did not differ among European countries in relation to levels of economic development or health coverage. Significant determinants of people with diagnosis of depression not working because of ill health (reference category) versus working were age (odds ratio = 0.97), female sex (odds ratio = 1.71), education (odds ratio = 1.11), marital status (being unmarried indicating less probability), lowest income level, and comorbidity with angina pectoris (odds ratio = 0.51). Moreover, according to previous studies, we found some determinants (comorbidity with other diseases, young age, and unemployment) impacting on health status. CONCLUSIONS: Depression is a substantial cause of work disability and it is a complex phenomenon that involves many variables. Investigation into this relationship should improve, focusing on the role of determinants.

Clinical characteristics of patients with epilepsy in a specialist neuropsychiatry service

Neuropsychiatry services provide specialist input into the assessment and management of behavioral symptoms associated with a range of neurological conditions, including epilepsy. Despite the centrality of epilepsy to neuropsychiatry and the recent expansion of neuropsychiatry service provision, little is known about the clinical characteristics of patients with epilepsy who are routinely seen by a specialist neuropsychiatry service. This retrospective study filled this gap by retrospectively evaluating a naturalistic series of 60 consecutive patients with epilepsy referred to and assessed within a neuropsychiatry setting. Fifty-two patients (86.7%) had active epilepsy and were under the ongoing care of the referring neurologist for seizure management. The majority of patients (N = 42; 70.0%) had a diagnosis of localization-related epilepsy, with temporal lobe epilepsy as the most common epilepsy type (N = 37; 61.7%). Following clinical assessment, 39 patients (65.0%) fulfilled formal diagnostic criteria for at least one psychiatric disorder; nonepileptic attack disorder (N = 37; 61.7%), major depression (N = 23; 38.3%), and generalized anxiety disorder (N = 16; 26.7%) were the most commonly diagnosed comorbidities. The clinical characteristics of patients seen in specialist neuropsychiatry settings are in line with the results from previous studies in neurology clinics in terms of both epilepsy and psychiatric comorbidity. Our findings confirm the need for the development and implementation of structured care pathways for the neuropsychiatric aspects of epilepsy, with focus on comorbid nonepileptic attacks and affective and anxiety symptoms. This is of particular importance in consideration of the impact of behavioral symptoms on patients' health-related quality of life.

Examining factors associated with excess mortality in older people (age ≥ 70 years) with diabetes - a 10-year cohort study of older people with and without diabetes

Aims: To compare all-cause mortality in older people with or without diabetes and consider the associated risk of comorbidity and polypharmacy. Methods: A 10-year cohort study using data from the Health Innovation Network database (2003-2013) comparing mortality in people aged ≥ 70 years with diabetes (DM cohort) (n = 35 717) and without diabetes (No DM cohort) (n = 307 918). Results: The mean age of the DM cohort was 78.1 ± 5.8 years vs. 79.0 ± 6.3 years in the No DM cohort. Mean diabetes duration was 8.2 ± 8.1 years, and 30% had diabetes for > 10 years. The DM cohort had a greater comorbidity load and people in this cohort were prescribed more therapies than the No DM cohort. The 5- and 10-year survival rates were lower in the DM cohort at 64% and 39%, respectively, compared with 72% and 50% in the No DM cohort. The excess mortality in the DM cohort was greatest in those aged <75 years with longer duration diabetes, the relative hazard for mortality was higher in females. Although comorbidity and polypharmacy were associated with increased mortality risk in the DM cohort, this risk was lower compared with the No DM cohort. The hazard ratios (95% confidence interval) for comorbidities > 4 and medicines ≥ 7 were 1.29 (1.19 to 1.41) and 1.34 (1.25 to 1.43) in the DM cohort and 1.63 (1.57 to 1.70) and 1.48 (1.40 to 1.56) in the No DM cohort, respectively. Conclusions: There is significant excess mortality in older people with diabetes, which is unexplained by comorbidity or polypharmacy. This excess is greatest in the younger old with longer disease duration, suggesting that it may be related to the effect of diabetes exposure.

Systemic inflammatory impact of periodontitis on acute coronary syndrome

Aim: A causative relationship between acute coronary syndrome (ACS) and periodontitis has yet to be defined. The aim of this study was to assess differences in levels of serum cytokines between individuals with or without ACS or periodontal comorbidity. Material and Methods: In a case–control study, individuals with ACS (78 individuals, 10.3% females) and matching healthy controls (78 individuals, 28.2% females) were included. Medical and dental examinations were performed to diagnose ACS and periodontitis. Serum levels of cytokines were assessed, using Luminex technology. Results: A diagnosis of periodontitis in the ACS and control group was diagnosed in 52.6% and 12.8% of the individuals, respectively. The unadjusted odds-ratio that individuals with ACS also had periodontitis was 7.5 (95% CI: 3.4, 16.8, p