The relationship between white matter architecture and language lateralisation in the healthy brain.

Interhemispheric anatomical differences have long been thought to be related to language lateralisation. Previous studies have explored whether asymmetries in the diffusion characteristics of white matter language tracts are consistent with language lateralisation. These studies, typically with smaller cohorts, yielded mixed results. This study investigated whether connectomic analysis of quantitative anisotropy (QA) and shape features of white matter tracts across the whole brain are associated with language lateralisation. We analysed 1040 healthy individuals (562 females) from the Human Connectome Project database. Hemispheric language dominance for each participant was quantified using a laterality quotient (LQ) derived from fMRI activation in regions of interest (ROIs) associated with a language comprehension task compared against a math task. A linear regression model was used to examine the relationship between structural asymmetry and functional lateralisation. Connectometry revealed a significant negative correlation between LQs and QA of corpus callosum tracts, indicating that higher QA in these regions is associated with bilateral and right-hemisphere language representation in frontal and temporal regions, respectively. Left language laterality in temporal lobe was significantly associated with longer right inferior fronto-occipital fasciculus (IFOF) and forceps minor tracts. These results suggest that diffusion measures of microstructural architecture as well as geometrical features of reconstructed white matter tracts play a role in language lateralisation. People with increased dependence on right or both frontal hemispheres for language processing may have more developed commissural fibres, which may support more efficient interhemispheric communication.Significance statement The left cerebral hemisphere is dominant for language functions in most people. In some healthy people, language functions are lateralised to the right hemisphere or distributed across both hemispheres. The anatomy underlying patterns of hemispheric language dominance are not well established. Emerging evidence suggests that white matter connectivity and architecture is an important feature of cortical functional organisation. In this work, we report that people who have language functions distributed across both hemispheres have greater inter-hemispheric connectivity compared to lateralised people. Our findings provide further insights into the anatomical basis of language function and may have wider clinical implications.

Hypothyroidism.

Hypothyroidism, the deficiency of thyroid hormone, is a common condition worldwide. It affects almost all body systems and has a wide variety of clinical presentations from being asymptomatic to, in rare cases, life threatening. The classic symptoms of hypothyroidism include fatigue, lethargy, weight gain, and cold intolerance; however, these symptoms are non-specific and the diagnosis is typically made on biochemical grounds through serum thyroid function tests. The most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's thyroiditis), although other causes, including drugs (such as amiodarone, lithium, and immune checkpoint inhibitors), radioactive-iodine treatment, and thyroid surgery, are frequent. Historically, severe iodine deficiency was the most common cause. Reference ranges for thyroid function tests are based on fixed percentiles of the population distribution, but there is increasing awareness of the need for more individualised reference intervals based on key factors such as age, sex, and special circumstances such as pregnancy. Levothyroxine monotherapy is the standard treatment for hypothyroidism; it is safe and inexpensive, restores thyroid function tests to within the reference range, and improves symptoms in the majority of patients. However, 10% of patients have persistent symptoms of ill health despite normalisation of thyroid function tests biochemically and a substantial proportion of patients on levothyroxine have thyroid-stimulating hormone concentrations outside the reference range. Ongoing symptoms despite levothyroxine treatment has led to some patients using liothyronine or desiccated thyroid extract. Taken together, these factors have led to intense debate around the treatment thresholds and treatment strategies for hypothyroidism. In this Seminar, we review the epidemiology, genetic determinants, causes, and presentation of hypothyroidism; highlight key considerations and controversies in its diagnosis and management; and provide future directions for research.

Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK.

BACKGROUND: A rise in the incidence of some autoimmune disorders has been described. However, contemporary estimates of the overall incidence of autoimmune diseases and trends over time are scarce and inconsistent. We aimed to investigate the incidence and prevalence of 19 of the most common autoimmune diseases in the UK, assess trends over time, and by sex, age, socioeconomic status, season, and region, and we examine rates of co-occurrence among autoimmune diseases. METHODS: In this UK population-based study, we used linked primary and secondary electronic health records from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex and ethnicity. Eligible participants were men and women (no age restriction) with acceptable records, approved for Hospital Episodes Statistics and Office of National Statistics linkage, and registered with their general practice for at least 12 months during the study period. We calculated age and sex standardised incidence and prevalence of 19 autoimmune disorders from 2000 to 2019 and used negative binomial regression models to investigate temporal trends and variation by age, sex, socioeconomic status, season of onset, and geographical region in England. To characterise co-occurrence of autoimmune diseases, we calculated incidence rate ratios (IRRs), comparing incidence rates of comorbid autoimmune disease among individuals with a first (index) autoimmune disease with incidence rates in the general population, using negative binomial regression models, adjusted for age and sex. FINDINGS: Among the 22 009 375 individuals included in the study, 978 872 had a new diagnosis of at least one autoimmune disease between Jan 1, 2000, and June 30, 2019 (mean age 54·0 years [SD 21·4]). 625 879 (63·9%) of these diagnosed individuals were female and 352 993 (36·1%) were male. Over the study period, age and sex standardised incidence rates of any autoimmune diseases increased (IRR 2017-19 vs 2000-02 1·04 [95% CI 1·00-1·09]). The largest increases were seen in coeliac disease (2·19 [2·05-2·35]), Sjogren's syndrome (2·09 [1·84-2·37]), and Graves' disease (2·07 [1·92-2·22]); pernicious anaemia (0·79 [0·72-0·86]) and Hashimoto's thyroiditis (0·81 [0·75-0·86]) significantly decreased in incidence. Together, the 19 autoimmune disorders examined affected 10·2% of the population over the study period (1 912 200 [13·1%] women and 668 264 [7·4%] men). A socioeconomic gradient was evident across several diseases, including pernicious anaemia (most vs least deprived area IRR 1·72 [1·64-1·81]), rheumatoid arthritis (1·52 [1·45-1·59]), Graves' disease (1·36 [1·30-1·43]), and systemic lupus erythematosus (1·35 [1·25-1·46]). Seasonal variations were observed for childhood-onset type 1 diabetes (more commonly diagnosed in winter) and vitiligo (more commonly diagnosed in summer), and regional variations were observed for a range of conditions. Autoimmune disorders were commonly associated with each other, particularly Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison's disease (IRR 26·5 [95% CI 17·3-40·7]), coeliac disease (28·4 [25·2-32·0]), and thyroid disease (Hashimoto's thyroiditis 13·3 [11·8-14·9] and Graves' disease 6·7 [5·1-8·5]), and multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases. INTERPRETATION: Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases. The socioeconomic, seasonal, and regional disparities observed among several autoimmune disorders in our study suggest environmental factors in disease pathogenesis. The inter-relations between autoimmune diseases are commensurate with shared pathogenetic mechanisms or predisposing factors, particularly among connective tissue diseases and among endocrine diseases. FUNDING: Research Foundation Flanders.

Vagus nerve stimulation for epilepsy: A narrative review of factors predictive of response.

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality-specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1-weighted MRI morphometrics and EEG may provide better strategies for treatment optimization.

Incomplete resection of the intracranial electroencephalographic seizure onset zone is not associated with postsurgical outcomes.

Delineation of seizure onset regions using intracranial electroencephalography (icEEG) is vital in the surgical workup of drug-resistant epilepsy cases. However, it is unknown whether the complete resection of these regions is necessary for seizure freedom, or whether postsurgical seizure recurrence can be attributed to the incomplete removal of seizure onset regions. To address this gap, we retrospectively analyzed icEEG recordings from 63 subjects, identifying seizure onset regions visually and algorithmically. We assessed onset region resection and correlated this with postsurgical seizure control. The majority of subjects had more than half of their onset regions resected (82.46% and 80.65% of subjects using visual and algorithmic methods, respectively). There was no association between the proportion of the seizure onset zone (SOZ) that was subsequently resected and better surgical outcomes (area under the receiver operating characteristic curve [AUC] < .7). Investigating the spatial extent of onset regions, we found no substantial evidence of an association with postsurgical seizure control (all AUC < .7). Although seizure onset regions are typically resected completely or in large part, incomplete resection is not associated with worse postsurgical outcomes. We conclude that postsurgical seizure recurrence cannot be attributed to an incomplete resection of the icEEG SOZ alone. Other network mechanisms beyond icEEG seizure onset likely contribute.

Thalamostriatal disconnection underpins long-term seizure freedom in frontal lobe epilepsy surgery.

Around 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure free post-operatively; however, only about 30% of patients remain seizure free in the long-term. Early seizure recurrence is likely to be caused by partial resection of the epileptogenic lesion, whilst delayed seizure recurrence can occur even if the epileptogenic lesion has been completely excised. This suggests a coexistent epileptogenic network facilitating ictogenesis in close or distant dormant epileptic foci. As thalamic and striatal dysregulation can support epileptogenesis and disconnection of cortico-thalamostriatal pathways through hemispherotomy or neuromodulation can improve seizure outcome regardless of focality, we hypothesize that projections from the striatum and the thalamus to the cortex may contribute to this common epileptogenic network. To this end, we retrospectively reviewed a series of 47 consecutive individuals who underwent surgery for drug-resistant frontal lobe epilepsy. We performed voxel-based and tractography disconnectome analyses to investigate shared patterns of disconnection associated with long-term seizure freedom. Seizure freedom after 3 and 5 years was independently associated with disconnection of the anterior thalamic radiation and anterior cortico-striatal projections. This was also confirmed in a subgroup of 29 patients with complete resections, suggesting these pathways may play a critical role in supporting the development of novel epileptic networks. Our study indicates that network dysfunction in frontal lobe epilepsy may extend beyond the resection and putative epileptogenic zone. This may be critical in the pathogenesis of delayed seizure recurrence as thalamic and striatal networks may promote epileptogenesis and disconnection may underpin long-term seizure freedom.

Status epilepticus and thinning of the entorhinal cortex.

Status epilepticus (SE) carries risks of morbidity and mortality. Experimental studies have implicated the entorhinal cortex in prolonged seizures; however, studies in large human cohorts are limited. We hypothesised that individuals with temporal lobe epilepsy (TLE) and a history of SE would have more severe entorhinal atrophy compared to others with TLE and no history of SE. 357 individuals with drug resistant temporal lobe epilepsy (TLE) and 100 healthy controls were scanned on a 3T MRI. For all subjects, the cortex was segmented, parcellated, and the thickness calculated from the T1-weighted anatomical scan. Subcortical volumes were derived similarly. Cohen's d and Wilcoxon rank-sum tests respectively were used to capture effect sizes and significance. Individuals with TLE and SE had reduced entorhinal thickness compared to those with TLE and no history of SE. The entorhinal cortex was more atrophic ipsilaterally (d = 0.51, p < 0.001) than contralaterally (d = 0.37, p = 0.01). Reductions in ipsilateral entorhinal thickness were present in both left TLE (n = 22:176, d = 0.78, p < 0.001), and right TLE (n = 19:140, d = 0.31, p = 0.04), albeit with a smaller effect size in right TLE. Several other regions exhibited atrophy in individuals with TLE, but these did not relate to a history of SE. These findings suggest potential involvement or susceptibility of the entorhinal cortex in prolonged seizures.

MEG abnormalities and mechanisms of surgical failure in neocortical epilepsy.

OBJECTIVE: Epilepsy surgery fails to achieve seizure freedom in 30%-40% of cases. It is not fully understood why some surgeries are unsuccessful. By comparing interictal magnetoencephalography (MEG) band power from patient data to normative maps, which describe healthy spatial and population variability, we identify patient-specific abnormalities relating to surgical failure. We propose three mechanisms contributing to poor surgical outcome: (1) not resecting the epileptogenic abnormalities (mislocalization), (2) failing to remove all epileptogenic abnormalities (partial resection), and (3) insufficiently impacting the overall cortical abnormality. Herein we develop markers of these mechanisms, validating them against patient outcomes. METHODS: Resting-state MEG recordings were acquired for 70 healthy controls and 32 patients with refractory neocortical epilepsy. Relative band-power spatial maps were computed using source-localized recordings. Patient and region-specific band-power abnormalities were estimated as the maximum absolute z-score across five frequency bands using healthy data as a baseline. Resected regions were identified using postoperative magnetic resonance imaging (MRI). We hypothesized that our mechanistically interpretable markers would discriminate patients with and without postoperative seizure freedom. RESULTS: Our markers discriminated surgical outcome groups (abnormalities not targeted: area under the curve [AUC] = 0.80, p = .003; partial resection of epileptogenic zone: AUC = 0.68, p = .053; and insufficient cortical abnormality impact: AUC = 0.64, p = .096). Furthermore, 95% of those patients who were not seizure-free had markers of surgical failure for at least one of the three proposed mechanisms. In contrast, of those patients without markers for any mechanism, 80% were ultimately seizure-free. SIGNIFICANCE: The mapping of abnormalities across the brain is important for a wide range of neurological conditions. Here we have demonstrated that interictal MEG band-power mapping has merit for the localization of pathology and improving our mechanistic understanding of epilepsy. Our markers for mechanisms of surgical failure could be used in the future to construct predictive models of surgical outcome, aiding clinical teams during patient pre-surgical evaluations.

Temporal stability of intracranial electroencephalographic abnormality maps for localizing epileptogenic tissue.

OBJECTIVE: Identifying abnormalities on interictal intracranial electroencephalogram (iEEG), by comparing patient data to a normative map, has shown promise for the localization of epileptogenic tissue and prediction of outcome. The approach typically uses short interictal segments of approximately 1 min. However, the temporal stability of findings has not been established. METHODS: Here, we generated a normative map of iEEG in nonpathological brain tissue from 249 patients. We computed regional band power abnormalities in a separate cohort of 39 patients for the duration of their monitoring period (.92-8.62 days of iEEG data, mean = 4.58 days per patient, >4800 hours recording). To assess the localizing value of band power abnormality, we computed D RS -a measure of how different the surgically resected and spared tissue was in terms of band power abnormalities-over time. RESULTS: In each patient, the D RS value was relatively consistent over time. The median D RS of the entire recording period separated seizure-free (International League Against Epilepsy [ILAE] = 1) and not-seizure-free (ILAE > 1) patients well (area under the curve [AUC] = .69). This effect was similar interictally (AUC = .69) and peri-ictally (AUC = .71). SIGNIFICANCE: Our results suggest that band power abnormality D_RS, as a predictor of outcomes from epilepsy surgery, is a relatively robust metric over time. These findings add further support for abnormality mapping of neurophysiology data during presurgical evaluation.

A library of quantitative markers of seizure severity.

OBJECTIVE: Understanding fluctuations in seizure severity within individuals is important for determining treatment outcomes and responses to therapy, as well as assessing novel treatments for epilepsy. Current methods for grading seizure severity rely on qualitative interpretations from patients and clinicians. Quantitative measures of seizure severity would complement existing approaches to electroencephalographic (EEG) monitoring, outcome monitoring, and seizure prediction. Therefore, we developed a library of quantitative EEG markers that assess the spread and intensity of abnormal electrical activity during and after seizures. METHODS: We analyzed intracranial EEG (iEEG) recordings of 1009 seizures from 63 patients. For each seizure, we computed 16 markers of seizure severity that capture the signal magnitude, spread, duration, and postictal suppression of seizures. RESULTS: Quantitative EEG markers of seizure severity distinguished focal versus subclinical seizures across patients. In individual patients, 53% had a moderate to large difference (rank sum r > .3 , p < .05 ) between focal and subclinical seizures in three or more markers. Circadian and longer term changes in severity were found for the majority of patients. SIGNIFICANCE: We demonstrate the feasibility of using quantitative iEEG markers to measure seizure severity. Our quantitative markers distinguish between seizure types and are therefore sensitive to established qualitative differences in seizure severity. Our results also suggest that seizure severity is modulated over different timescales. We envisage that our proposed seizure severity library will be expanded and updated in collaboration with the epilepsy research community to include more measures and modalities.

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond.

Midbrain structure volume, estimated myelin and functional connectivity in idiopathic generalised epilepsy.

BACKGROUND: Structural and functional neuroimaging studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired T1-weighted scans. Here, we acquired T1-weighted, T2-weighted, and resting-state fMRI scans to investigate differences in volume, estimated myelin content and functional connectivity of the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN) of the midbrain in IGE. METHODS: Thirty-three patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex-matched healthy controls underwent MR imaging. Midbrain structures were automatically segmented from T2-weighted images and structural volumes were calculated. The estimated myelin content for each structure was determined using a T1-weighted/T2-weighted ratio method. Resting-state functional connectivity analysis of midbrain structures (seed-based) was performed using the CONN toolbox. RESULTS: An increased volume of the right RN was found in IGE and structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. However, no volume findings survived corrections for multiple comparisons. No myelin alterations of midbrain structures were found for any subject groups. We found functional connectivity alterations including significantly decreased connectivity between the left SN and the thalamus and significantly increased connectivity between the right SubTN and the superior frontal gyrus in IGE. CONCLUSIONS: We report volumetric and functional connectivity alterations of the midbrain in patients with IGE. We postulate that potential increases in structural volumes are due to increased iron deposition that impacts T2-weighted contrast. These findings are consistent with previous studies demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy.

Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy.

Personalized medicine requires that treatments adapt to not only the patient but also changing factors within each individual. Although epilepsy is a dynamic disorder characterized by pathological fluctuations in brain state, surprisingly little is known about whether and how seizures vary in the same patient. We quantitatively compared within-patient seizure network evolutions using intracranial electroencephalographic (iEEG) recordings of over 500 seizures from 31 patients with focal epilepsy (mean 16.5 seizures per patient). In all patients, we found variability in seizure paths through the space of possible network dynamics. Seizures with similar pathways tended to occur closer together in time, and a simple model suggested that seizure pathways change on circadian and/or slower timescales in the majority of patients. These temporal relationships occurred independent of whether the patient underwent antiepileptic medication reduction. Our results suggest that various modulatory processes, operating at different timescales, shape within-patient seizure evolutions, leading to variable seizure pathways that may require tailored treatment approaches.

Fluctuations in EEG band power at subject-specific timescales over minutes to days explain changes in seizure evolutions.

Epilepsy is recognised as a dynamic disease, where both seizure susceptibility and seizure characteristics themselves change over time. Specifically, we recently quantified the variable electrographic spatio-temporal seizure evolutions that exist within individual patients. This variability appears to follow subject-specific circadian, or longer, timescale modulations. It is therefore important to know whether continuously recorded interictaliEEG features can capture signatures of these modulations over different timescales. In this study, we analyse continuous intracranial electroencephalographic (iEEG) recordings from video-telemetry units and find fluctuations in iEEG band power over timescales ranging from minutes up to 12 days. As expected and in agreement with previous studies, we find that all subjects show a circadian fluctuation in their iEEG band power. We additionally detect other fluctuations of similar magnitude on subject-specific timescales. Importantly, we find that a combination of these fluctuations on different timescales can explain changes in seizure evolutions in most subjects above chance level. These results suggest that subject-specific fluctuations in iEEG band power over timescales of minutes to days may serve as markers of seizure modulating processes. We hope that future study can link these detected fluctuations to their biological driver(s). There is a critical need to better understand seizure modulating processes, as this will enable the development of novel treatment strategies that could minimise the seizure spread, duration or severity and therefore the clinical impact of seizures.

Late offspring effects of antenatal thyroid screening.

BACKGROUND: Thyroid dysfunction in pregnancy is associated with adverse offspring outcomes and recent birth-cohort studies suggest that even mild degrees of thyroid dysfunction may be linked with a range of late cognitive and behavioural effects in childhood and adolescence. SOURCES OF DATA: This review summarizes recent literature of observational studies and critically appraises randomized controlled trials (RCTs) of antenatal thyroid screening and Levothyroxine intervention. AREAS OF AGREEMENT: Overt hypothyroidism and hyperthyroidism carry significant risks for unfavourable offspring outcomes and should be appropriately corrected in pregnancy. AREAS OF CONTROVERSY: The significance of subclinical hypothyroidism and hypothyroxinaemia is still unclear. Meta-analyses of birth-cohort studies show associations of maternal subclinical hypothyroidism and hypothyroxinaemia with intellectual deficits, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders, while hyperthyroidism and high-normal FT4 were linked with ADHD. RCTs have shown no benefits of screening on neurodevelopmental outcomes although Levothyroxine could have been initiated too late in pregnancy in these trials. GROWING POINTS: A small number of studies have shown inconsistent associations of maternal thyroid dysfunction with offspring cardiometabolic indices including blood pressure and body weight. Correction of maternal thyroid dysfunction was, however, associated with favourable long-term metabolic profiles in mothers, including lipid profiles, fat mass and body mass index. Antenatal thyroid screening may therefore present opportunities for optimizing a wider range of outcomes than envisaged. AREAS FOR DEVELOPING RESEARCH: Future trials with early antenatal thyroid screening and intervention are necessary to clarify the impact of screening on late offspring and maternal effects.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis.

OBJECTIVES: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy. METHODS: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity. RESULTS: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up. CONCLUSIONS: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

Prescribing costs of hypoglycaemic agents and associations with metabolic control in Wales; a national analysis of primary care data.

AIMS: There has been a dramatic increase in hypoglycaemic agent expenditure. We assessed the variability in prescribing costs at the practice level and the relationship between expenditure and the proportion of patients achieving target glycaemic control. METHODS: We utilized national prescribing data from 406 general practices in Wales. This was compared against glycaemic control (percentage of patients achieving a HbA1c level < 59 mmol/mol in the preceding 12 months). Analyses were adjusted for the number of patients with diabetes in each general practice and the Welsh Index of Multiple Deprivation. RESULTS: There was considerable heterogeneity in hypoglycaemic agent spend per patient with diabetes, Median = £289 (IQR 247-343) range £31.1-£1713. Higher total expenditure was not associated with improved glycaemic control B(std)  = -0.01 (95%CI -0.01, 0.002) p = 0.13. High-spend practices spent more on SGLT2 inhibitors (16 vs. 9% p < 0.001) and GLP-1 agonists (13 vs. 11% p < 0.001) and less on insulin (34 vs. 42% p < 0.001), biguanides (9 vs. 11% p = 0.001) and sulphonylureas (2 vs. 3% p < 0.001) than low spend practices. There were no differences in the pattern of drug prescribing between high spend practices with better glycaemic control (mean 68% of patients HbA1c <59 mmol/mol) and those with less good metabolic control (mean 58% of patients HbA1c <59 mmol/mol). CONCLUSIONS: Spend on hypoglycaemic agents is highly variable between practices and increased expenditure per patient is not associated with better glycaemic control. Whilst newer, more expensive agents have additional benefits, in individuals where these advantages are more marginal widespread use of these agents has important cost implications.

Independent components of human brain morphology.

Quantification of brain morphology has become an important cornerstone in understanding brain structure. Measures of cortical morphology such as thickness and surface area are frequently used to compare groups of subjects or characterise longitudinal changes. However, such measures are often treated as independent from each other. A recently described scaling law, derived from a statistical physics model of cortical folding, demonstrates that there is a tight covariance between three commonly used cortical morphology measures: cortical thickness, total surface area, and exposed surface area. We show that assuming the independence of cortical morphology measures can hide features and potentially lead to misinterpretations. Using the scaling law, we account for the covariance between cortical morphology measures and derive novel independent measures of cortical morphology. By applying these new measures, we show that new information can be gained; in our example we show that distinct morphological alterations underlie healthy ageing compared to temporal lobe epilepsy, even on the coarse level of a whole hemisphere. We thus provide a conceptual framework for characterising cortical morphology in a statistically valid and interpretable manner, based on theoretical reasoning about the shape of the cortex.

Multivariate white matter alterations are associated with epilepsy duration.

Previous studies investigating associations between white matter alterations and duration of temporal lobe epilepsy (TLE) have shown differing results, and were typically limited to univariate analyses of tracts in isolation. In this study, we apply a multivariate measure (the Mahalanobis distance), which captures the distinct ways white matter may differ in individual patients, and relate this to epilepsy duration. Diffusion MRI, from a cohort of 94 subjects (28 healthy controls, 33 left-TLE and 33 right-TLE), was used to assess the association between tract fractional anisotropy (FA) and epilepsy duration. Using ten white matter tracts, we analysed associations using the traditional univariate analysis (z-scores) and a complementary multivariate approach (Mahalanobis distance), incorporating multiple white matter tracts into a single unified analysis. For patients with right-TLE, FA was not significantly associated with epilepsy duration for any tract studied in isolation. For patients with left-TLE, the FA of two limbic tracts (ipsilateral fornix, contralateral cingulum gyrus) were significantly negatively associated with epilepsy duration (Bonferonni corrected p < .05). Using a multivariate approach we found significant ipsilateral positive associations with duration in both left, and right-TLE cohorts (left-TLE: Spearman's ρ = 0.487, right-TLE: Spearman's ρ = 0.422). Extrapolating our multivariate results to duration equals zero (i.e., at onset) we found no significant difference between patients and controls. Associations using the multivariate approach were more robust than univariate methods. The multivariate Mahalanobis distance measure provides non-overlapping and more robust results than traditional univariate analyses. Future studies should consider adopting both frameworks into their analysis in order to ascertain a more complete understanding of epilepsy progression, regardless of laterality.

Focal to bilateral tonic-clonic seizures are associated with widespread network abnormality in temporal lobe epilepsy.

OBJECTIVE: Our objective was to identify whether the whole-brain structural network alterations in patients with temporal lobe epilepsy (TLE) and focal to bilateral tonic-clonic seizures (FBTCS) differ from alterations in patients without FBTCS. METHODS: We dichotomized a cohort of 83 drug-resistant patients with TLE into those with and without FBTCS and compared each group to 29 healthy controls. For each subject, we used diffusion-weighted magnetic resonance imaging to construct whole-brain structural networks. First, we measured the extent of alterations by performing FBTCS-negative (FBTCS-) versus control and FBTCS-positive (FBTCS+) versus control comparisons, thereby delineating altered subnetworks of the whole-brain structural network. Second, by standardizing each patient's networks using control networks, we measured the subject-specific abnormality at every brain region in the network, thereby quantifying the spatial localization and the amount of abnormality in every patient. RESULTS: Both FBTCS+ and FBTCS- patient groups had altered subnetworks with reduced fractional anisotropy and increased mean diffusivity compared to controls. The altered subnetwork in FBTCS+ patients was more widespread than in FBTCS- patients (441 connections altered at t > 3, p < .001 in FBTCS+ compared to 21 connections altered at t > 3, p = .01 in FBTCS-). Significantly greater abnormalities-aggregated over the entire brain network as well as assessed at the resolution of individual brain areas-were present in FBTCS+ patients (p < .001, d = .82, 95% confidence interval = .32-1.3). In contrast, the fewer abnormalities present in FBTCS- patients were mainly localized to the temporal and frontal areas. SIGNIFICANCE: The whole-brain structural network is altered to a greater and more widespread extent in patients with TLE and FBTCS. We suggest that these abnormal networks may serve as an underlying structural basis or consequence of the greater seizure spread observed in FBTCS.