Christopher P. Cheyne

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs

The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option.

IQ at 6 years after in utero exposure to antiepileptic drugs A controlled cohort study

Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. Methods: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] −4.9 to −14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5–19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (−5.6, 95% CI −11.1 to −0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4–18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (−4.2, 95% CI −0.6 to −7.8; p = 0.02) and increased frequency of IQ <85. Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

In utero exposure to levetiracetam vs valproate Development and language at 3 years of age

Objective: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. Methods: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. Results: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] −24.5 to −7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI −11.0 to −1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI −14.7 to −4.4, p < 0.001). Conclusion: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on womens preferred choice of antiepileptic drug.

Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate

Objective: To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning. Methods: This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses. Results: In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (−10.6, 95% confidence interval [CI] −16.3 to −5.0, p < 0.001), verbal abilities (−11.2, 95% CI −16.8 to −5.5, p < 0.001), nonverbal abilities (−11.1, 95% CI −17.3 to −4.9, p < 0.001), and expressive language ability (−2.3, 95% CI −3.4 to −1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate. Conclusions: Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

The effect of handedness on academic ability: A multivariate linear mixed model approach

In recent years questions have arisen about whether there are any links between handedness and academic abilities as well as other factors. In this study we investigate the effects of gender, writing hand, relative hand skill, and UK region on mathematics and reading test scores by applying a multivariate linear mixed-effects model. A data sample based on 11,847 11-year-old pupils across the UK from the National Child Development Study was considered for the analysis. Our results show that pupils who write with one hand while having better skill with their other hand (i.e., inconsistent writing hand and superior hand) obtained lower test scores in both reading and mathematics than pupils with consistent writing hand and superior hand. Furthermore, we confirm previous findings that degree of relative hand skill has a significant effect on both reading and maths scores and that this association is not linear. We also found higher scores of reading in children from the south of England, and of mathematics in children from the south of England and Scotland, when compared to other UK regions.

Health state utility values for diabetic retinopathy: protocol for a systematic review and meta-analysis

BackgroundPeople with diabetic retinopathy tend to have lower levels of health-related quality of life than individuals with no retinopathy. Strategies for screening and treatment have been shown to be cost-effective. In order to reduce the bias in cost-effectiveness estimates, systematic reviews of health state utility values (HSUVs) are crucial for health technology assessment and the development of decision analytic models. A review and synthesis of HSUVs for the different stages of disease progression in diabetic retinopathy has not previously been conducted.Methods/DesignWe will conduct a systematic review of the available literature that reports HSUVs for people with diabetic retinopathy, in correspondence with current stage of disease progression and/or visual acuity. We will search Medline, EMBASE, Web of Science, Cost-Effectiveness Analysis Registry, Centre for Reviews and Dissemination Database, and EconLit to identify relevant English-language articles. Data will subsequently be synthesized using linear mixed effects modeling meta-regression. Additionally, reported disease severity classifications will be mapped to a four-level grading scale for diabetic retinopathy.DiscussionThe systematic review and meta-analysis will provide important evidence for future model-based economic evaluations of technologies for diabetic retinopathy. The meta-regression will enable the estimation of utility values at different disease stages for patients with particular characteristics and will also highlight where the design of the study and HSUV instrument have influenced the reported utility values. We believe this protocol to be the first of its kind to be published.Systematic review registrationPROSPERO CRD42014012891

Detection of Visual Field Loss in Pituitary Disease: Peripheral Kinetic Versus Central Static

Abstract Visual field assessment is an important clinical evaluation for eye disease and neurological injury. We evaluated Octopus semi-automated kinetic peripheral perimetry (SKP) and Humphrey static automated central perimetry for detection of neurological visual field loss in patients with pituitary disease. We carried out a prospective cross-sectional diagnostic accuracy study comparing Humphrey central 30-2 SITA threshold programme with a screening protocol for SKP on Octopus perimetry. Humphrey 24-2 data were extracted from 30-2 results. Results were independently graded for presence/absence of field defect plus severity of defect. Fifty patients (100 eyes) were recruited (25 males and 25 females), with mean age of 52.4 years (SD = 15.7). Order of perimeter assessment (Humphrey/Octopus first) and order of eye tested (right/left first) were randomised. The 30-2 programme detected visual field loss in 85%, the 24-2 programme in 80%, and the Octopus combined kinetic/static strategy in 100% of eyes. Peripheral visual field loss was missed by central threshold assessment. Qualitative comparison of type of visual field defect demonstrated a match between Humphrey and Octopus results in 58%, with a match for severity of defect in 50%. Tests duration was 9.34 minutes (SD = 2.02) for Humphrey 30-2 versus 10.79 minutes (SD = 4.06) for Octopus perimetry. Octopus semi-automated kinetic perimetry was found to be superior to central static testing for detection of pituitary disease-related visual field loss. Where reliant on Humphrey central static perimetry, the 30-2 programme is recommended over the 24-2 programme. Where kinetic perimetry is available, this is preferable to central static programmes for increased detection of peripheral visual field loss.

Personalized risk-based screening for diabetic retinopathy: a multivariate approach vs. the use of stratification rules.

To evaluate our proposed multivariate approach to identify patients who will develop sight‐threatening diabetic retinopathy (STDR) within a 1‐year screen interval, and explore the impact of simple stratification rules on prediction.

A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology

Objectives To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. Methods The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. Results Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. Conclusions This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis.