Altered cortical thickness following prenatal sodium valproate exposure

Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy

PurposeThe association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status.MethodsParticipants were 105 Australian children aged 6–8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).ResultsEleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores.SignificanceUsing direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child

Neurological consequences of diabetic ketoacidosis at initial presentation of type 1 diabetes in a prospective cohort study of children

OBJECTIVE To investigate the impact of new-onset diabetic ketoacidosis (DKA) during child- hood on brain morphology and function. RESEARCH DESIGN AND METHODS Patients aged 6–18 years with and without DKA at diagnosis were studied at four time points: <48 h, 5 days, 28 days, and 6 months postdiagnosis. Patients under- went magnetic resonance imaging (MRI) and spectroscopy with cognitive assess- ment at each time point. Relationships between clinical characteristics at presentation and MRI and neurologic outcomes were examined using multiple linear regression, repeated-measures, and ANCOVA analyses. RESULTS Thirty-six DKA and 59 non-DKA patients were recruited between 2004 and 2009. With DKA, cerebral white matter showed the greatest alterations with increased total white matter volume and higher mean diffusivity in the frontal, temporal, and parietal white matter. Total white matter volume decreased over the first 6 months. For gray matter in DKA patients, total volume was lower at baseline and increased over 6 months. Lower levels of N-acetylaspartate were noted at base- line in the frontal gray matter and basal ganglia. Mental state scores were lower at baseline and at 5 days. Of note, although changes in total and regional brain volumes over the first 5 days resolved, they were associated with poorer delayed memory recall and poorer sustained and divided attention at 6 months. Age at time of presentation and pH level were predictors of neuroimaging and functional outcomes. CONCLUSIONS DKA at type 1 diabetes diagnosis results in morphologic and functional brain changes. These changes are associated with adverse neurocognitive outcomes in the medium term

Management of Victoria's visual landscape resources within the government legal and administrative structure

Thesis (MUP) -- University of Melbourne, Faculty of Architecture, Building and Town & Regional Planning, 197

Shear wave elastography in the assessment of liver fibrosis

© 2018 Dr. David NadebaumThe accurate quantification of liver fibrosis is essential to the prognostication and clinical management of patients with chronic liver disease (CLD). Whilst liver biopsy remains the gold standard for fibrosis assessment, it has a number of limitations which have seen its use become increasingly substituted by non-invasive techniques. Ultrasound shear wave elastography (SWE) includes some of the most widely used non-invasive technologies in clinical practice. This work evaluates two ultrasound SWE devices which are in differing stages of clinical development and use; the first being a well-validated point SWE technique from Siemens called Acoustic Radiation Force Impulse elastography or ‘ARFI’ and the second a new 2D-SWE platform by Toshiba. The differing study aims for the two technologies were assessed in separate patient cohorts. Hence the thesis is divided in two. ARFI (Siemens): Background: Acoustic Radiation Force Impulse elastography or ‘ARFI’ is a point shear wave elastography (SWE) technique that is in broad clinical use for the quantification of liver fibrosis. Whilst well validated, questions remain for a number of areas of ARFI performance. This includes the magnitude and likely mechanism of obesity’s impact on ARFI performance, the impact of hepatosteatosis on ARFI reliability and whether ARFI performance is dependent on operator experience. There is also conflicting information as to whether ARFI liver stiffness measurements (LSMs) correlate with cirrhosis severity and the presence of cirrhotic complications. Finally, clinicians have limited facility to gauge the validity of obtained ARFI measurements beyond the IQR/Median criteria. An additional study aim was therefore to develop new strategies to aid ARFI reliability assessment; specifically whether inter-operator disagreement predicts the presence of unreliable ARFI measurements. Method: ARFI performance was assessed amongst a cohort of 943 patients with diffuse CLD of mixed aetiology, who had ARFI LSMs taken as part of clinical fibrosis assessment. Patients were scanned independently by either two or three operators, with ARFI results analysed in the context of patient demographic and CLD information obtained from medical records. Anthropometric measures including body mass index (BMI) was recorded at the time of scanning, and the distance from the skin surface to liver capsule (SLD) was measured from ARFI screenshots as a marker of central adiposity. The cumulative number of scans completed by individual operators and the institution overall was recorded. Assessed performance measures included IQR/Median and inter-operator agreement. ARFI accuracy was also assessed amongst a subcohort of 55 patients who had undergone a liver biopsy within 6 months of ARFI. The performance of ARFI in assessing cirrhosis severity was assessed amongst a further subcohort of 186 patients with clinically diagnosed cirrhosis. The presence of cirrhotic complications was determined retrospectively from medical records and endoscopy reports. Prognostic indices including Child Pugh and Model for End stage Liver Disease (MELD) scores were calculated using bloods tests where available. Results: ARFI showed modest accuracy in assessing liver fibrosis, demonstrating an AUROC of 0.67, 0.76 and 0.70 at discriminating the F01/ F2, F2/ F3 and F3/F4 cut-offs, respectively. ARFI showed good sensitivity (80.0 – 88.9%) and NPV (70.6 – 95.3%), but relatively poor specificity (42.9 – 66.3%) and PPV (27.9 – 56.2%) at the three cut-offs. Body habitus, particularly skin-to-liver capsule distance or ’SLD’, was found to be the primary determinant of ARFI performance in multi-regression analyses. SLD had the strongest relationship with ARFI accuracy (R2 = 0.543) followed by necroinflammatory change (R2 = 0.167), whilst all other patient factors, including hepatosteatosis, failed to show an independent association. Patients with a SLD >2.5cm (indicating significant central adiposity) showed particularly poor ARFI performance and was associated with higher IQR/Median ratios (median = 0.363 vs. 0.187, p<0.001), greater deviation between operators (29.8% vs. 15.9%, p<0.001) and poorer correlation with biopsy (rho = -0.242 vs. 0.493) than those with a SLD ≤2.5cm. Individual operator experience showed a weak relationship with ARFI performance, with operators of <25 scans experience having similar median IQR/Median ratios (0.170 vs. 0.165, p=0.13), slightly greater deviation between operators (14.3% vs. 11.06%, p=0.014) and greater deviation from the biopsy reference range (mean deviation = 0.588 vs. 0.279m/s, p=0.004) than more experienced colleagues. There also appeared to be a similarly weak association between overall institutional experience and ARFI performance, with reliability being slightly reduced amongst the first 150 scans performed in the institution. In patients in whom both operators had concordant F score results, ARFI LSM showed greater correlation with biopsy (rho = 0.392) than in cases of inter-operator disagreement (rho = 0.010). When scanned by three operators, patients with three-way operator agreement showed even stronger correlation with histopathology (rho = 0.571). Amongst cirrhotic patients, ARFI showed a moderately strong correlation with prognostic scores of liver function, including both MELD score (rho = 0.342, p<0.001) and Child- Pugh Score (rho = 0.363, p<0.001). ARFI LSMs showed modest accuracy in predicting the presence of ascites (AUROC = 0.58), encephalopathy (AUROC = 0.60) and oesophageal varices (AUROC = 0.69). Conclusion: ARFI showed moderate performance in quantifying liver fibrosis in a clinical Australian setting. The technology’s strength appears to be in the exclusion of liver fibrosis, however the tool is prone to false positive results. Body habitus was found to be the primary determinant of ARFI performance, with necroinflammatory change and operator experience showing a weaker impact on scan reliability. Central adiposity, as indicated by SLD, showed a particularly strong relationship with ARFI performance and the routine measurement and reporting of SLD should be considered to help clinicians gauge the reliability of ARFI results. Scanning patients with multiple independent operators also showed value as a reliability indicator, with inter-operator discordance being a predictor of poor ARFI performance. 2D-SWE (Toshiba): Background: The second technology assessed is a new 2D-SWE platform from Toshiba, which has a number of technical innovations and theoretical advantages over Siemens’ ARFI system. The technology is in the early clinical phases of testing and therefore data on this new technique remains limited. Our study aim was therefore to evaluate specific technical parameters to help assist in the formation of acquisition guidelines. This included assessing the measurement variability of Toshiba 2D-SWE (i.e. IQR/Median), the number of measurements required per patient to yield a precise LSM estimate and whether the uniformity of shear wave velocities within the measurement ROI (i.e. ROI SD/Speed ratio) could be used to assess the reliability of individual 2D-SWE measurements. Method: 2D-SWE was assessed amongst fifty-five patients with mixed aetiology CLD using the Toshiba Aplio 500 ultrasound system. Ten measurements were obtained per patient by an operator blinded to all preceding readings. Measurement variability (i.e. IQR/Median) and the number of measurements required per patient to achieve a LSM estimate within 5% of the existing method using 10 samples was assessed. Results were analysed against scan and clinical information including CLD aetiology, BMI, SLD, presence and severity of hepatosteatosis and measurement depth within the liver. The ratio of the standard deviation of shear wave velocities within the measurement ROI to overall shear wave velocity (i.e. ROI SD/Speed) was calculated for each individual measurement, and its relationship with measurement consistency (i.e. deviation of the measurement from the set’s median) was assessed. Results: The median IQR/Median ratio for 2D-SWE was 0.131 (q1-q3: 0.089–0.174). Five readings provided an approximation within 0.11m/s or 4.2% of the median velocity of ten measurements. Factors associated with increased measurement variability included increasing BMI (rho=0.388, p=0.003), SLD (rho=0.426, p=0.002) and measurements taken within 1.5cm of the liver capsule (p0.15) showed greater deviation from the set’s median velocity than those with a ROI SD/Speed ≤0.15 (0.421 vs. 0.219 m/s, p=0.0001). Conclusion: 2D-SWE showed low overall measurement variability, with a minimum of five readings providing equivalent precision to the existing method using 10 samples. Obesity (i.e. BMI>30kg/m2), increasing abdominal wall thickness (i.e. SLD), sub-capsular measurements and a ROI SD/Speed >0.15 were all associated with increased measurement variability. ROI SD/Speed warrants further evaluation as a quality assessment metric, as it may allow objective operator assessment of individual 2D-SWE measurement reliability in real-time

Cognitive and behavioural outcomes of school aged children exposed prenatally to antiepileptic drugs

Although antiepileptic drug (AED) use during pregnancy is common, our understanding of the longer term impact of prenatal AED exposure remains incomplete. Although most women with epilepsy give birth to healthy babies, some AEDs are known to increase the risk of birth defects and other abnormalities. Despite this, pharmacotherapy is typically continued throughout pregnancy because of the increased risk of complications due to recurrent seizures. Some AEDs appear to carry greater risk of negative cognitive or behavioural sequelae than others. Previous studies have suggested that, in particular, prenatal exposure to valproate or polytherapy may result in impaired Verbal IQ. This research aimed to improve our understanding of the nature of the intellectual deficits of children prenatally exposed to VPA and polytherapy. Verbal intellectual abilities, working memory, language and autistic traits were identified as factors that may contribute to children’s performance on measures of Verbal IQ. These factors were investigated through standardised assessment of a prospectively recruited cohort of AED-exposed children. The sample included 23 children exposed to valproate monotherapy, 15 to polytherapy with valproate and 19 to polytherapy without valproate. Results were consistent with previous findings that intellectual abilities, and particularly verbal intellectual abilities, are negatively affected by exposure to valproate and polytherapy. In addition, valproate exposure was associated with poorer performance on tests of language and working memory, and was also associated with elevated rates of autistic traits. There was evidence for a dose-response relationship, with higher valproate doses being associated with poorer outcomes. Analyses further suggested that intellectual abilities may be affected at lower doses than are required to cause major malformations. In comparison, polytherapy per se (i.e. once the effects of valproate were controlled for) appeared to have a relatively modest impact, with the predominant effects identified in this research being on higher level intellectual skills and processing speed. The risks associated with prenatal exposure to valproate and polytherapy need to be carefully considered when prescribing AEDs to women of childbearing age. Women with epilepsy should be advised of the potential risks that may accompany AED treatment during pregnancy, and exposed children should be monitored from birth into the school-aged years to enable early identification and intervention for at-risk children. In any decision to change drug or dose, the adverse consequences of AED exposure need to be weighed against the risks that may accompany inadequate seizure or disease control. The findings of this research may also be relevant to the growing number of women taking AEDs for conditions other than epilepsy, such as pain and psychiatric disorders. Further research is needed to better understand the effects of valproate and polytherapy, improve identification and intervention for at-risk children, and to explain the underlying mechanisms