[This corrects the article DOI: 10.1162/IMAG.a.997.].

BACKGROUND:Herpes simplex virus (HSV) encephalitis is characterised by inflammation and swelling of the brain, resulting in death or severe neurocognitive sequelae. HSV encephalitis is treated with the antiviral aciclovir but still has substantial mortality and morbidity. Adjunct corticosteroids are sometimes used, but whether they improve the outcome is unclear. We aimed to establish the safety and efficacy of adjunct corticosteroids in HSV encephalitis. METHODS:In this multicentre, observer-blind, randomised, phase 3 trial, adults with HSV encephalitis admitted to 53 hospitals in the UK were randomly assigned to receive intravenous dexamethasone (10 mg/kg, four times daily for 4 days) plus intravenous aciclovir (10 mg/kg three times daily for at least 14 days; dexamethasone group), or intravenous aciclovir alone (control group). Eligible patients aged 16 years or older had suspected encephalitis (a febrile illness with new onset seizure, new focal neurological signs or alteration in consciousness, cognition, personality, or behaviour), with positive HSV type 1 or type 2 PCR test in CSF. Participants were randomly assigned by the trial team at the recruiting site, using a secure web-based randomisation programme. The primary outcome was verbal memory score at 26 weeks, measured by the Wechsler Memory Scale (WMS)-IV auditory memory index. Analyses of primary and secondary outcomes were performed according to the modified intention-to-treat principle, and safety analyses were based on whether participants received at least one dose of the study drug. Trial neuropsychologists assessing the primary outcome, and statisticians involved in the study's primary outcome, were masked to treatment group allocation. The trial is registered with the International Standard Randomised Controlled Trial Number Registry, ISRCTN11774734, and EudraCT, EudraCT2016-004835-19, and is completed. FINDINGS:Between Sept 22, 2016, and Feb 2, 2022, 94 patients with HSV encephalitis were recruited, 47 (20 [43%] female and 27 [57%] male) to the dexamethasone group, and 47 (24 [51%] female and 23 [49%] male) to the control group. Dexamethasone was initiated a median 7 (IQR 4-8) days after hospital admission. Seven patients withdrew consent, and six were lost to follow-up. Thus, 81 were included in the modified intention-to-treat analysis (39 in the treatment group and 42 in the control group). The primary outcome, verbal memory score at 26 weeks, did not differ significantly between the groups (71 [SD 26] in the dexamethasone group, and 69 [SD 25] in the control group; adjusted difference 1·77 [95% CI -9·57 to 13·12; p=0·76). There were 27 adverse events involving 18 (38%) participants in the control group, and 25 adverse events involving 18 (40%) participants in the dexamethasone group. The most common serious adverse events were seizures requiring readmission to hospital (affecting one [2%] patient in the dexamethasone group and one [2%] patient in the control group) and thrombotic events, including deep vein thrombosis (affecting one [2%] patient in the dexamethasone group) and pulmonary embolism (affecting one [2%]patient in the dexamethasone group). There were no treatment-related deaths. INTERPRETATION:In adults with HSV encephalitis, dexamethasone plus aciclovir had a satisfactory safety profile but did not improve verbal memory score compared with aciclovir alone. Given the established role of corticosteroids in other inflammatory encephalitides, our findings suggest that their early use in suspected encephalitis is unlikely to be harmful. Future studies should assess more targeted immunomodulatory approaches in HSV encephalitis. FUNDING:National Institute for Health and Care Research.

Structural neuroimaging analyses require "research quality" images, procured with costly MRI acquisitions. Isotropic (3D-T1) images are desirable for quantitative analyses, however, a routine compromise in the clinical setting is to acquire anisotropic (2D-T1) analogues for qualitative visual inspection. ML (machine learning-based) software have shown promise in addressing some of the limitations of 2D-T1 scans in research applications, yet their efficacy in quantitative research is generally poorly understood. Quantitative morphometric analyses have previously identified pathology-related abnormalities of the subcortical structures in idiopathic generalised epilepsy (IGE), which have been overlooked based on visual inspection. As such, IGE biomarkers present a suitable model in which to evaluate the applicability of image preprocessing methods. This study, therefore, explores subcortical structural biomarkers of IGE, first in our "silver standard" 3D-T1 scans, then in 2D-T1 scans that were either untransformed, resampled using a classical interpolation approach, or synthesised with a resolution and contrast agnostic ML model. 2D-T1 and 3D-T1 MRI scans were acquired during the same scanning session for 33 individuals with drug-sensitive IGE (age mean 32.16 ± SD = 14.20, male n = 14) and 42 individuals with drug-resistant IGE (31.76 ± 11.12, 17), all diagnosed at the Walton Centre NHS Foundation Trust Liverpool, alongside 39 age- and sex-matched healthy controls (32.32 ± 8.65, 16). The untransformed 2D-T1 scans were resampled into isotropic images using NiBabel (res-T1), and preprocessed into synthetic isotropic images using SynthSR (syn-T1). For the 3D-T1, 2D-T1, res-T1, and syn-T1 images, the recon-all command from FreeSurfer 8.0.0 was used to create parcellations of 174 anatomical regions (equivalent to the 174 regional parcellations provided as part of the DL+DiReCT pipeline), defined by the aseg and Destrieux atlases, and FSL run_first_all was used to segment subcortical surface shapes. The new ML FreeSurfer pipeline, recon-all-clinical, was also tested in the 2D-T1, 3D-T1, and res-T1 images. As a model comparison for SynthSR, the DL+DiReCT pipeline was used to provide segmentations of the 2D-T1 and res-T1 images, including estimates of regional volume and thickness. Spatial overlap and intraclass correlations between the morphometrics of the eight resulting parcellations were first determined, then subcortical surface shape abnormalities associated with IGE were identified by comparing the FSL run_first_all outputs of patients with controls. When standardised to the metrics derived from the 3D-T1 scans, cortical volume and thickness estimates trended lower for the 2D-T1, res-T1, syn-T1, and DL+DiReCT outputs, whereas subcortical volume estimates were more coherent. Dice coefficients revealed an acceptable spatial similarity between the cortices of the 3D-T1 scans and the other images overall, and was higher in the subcortical structures. Intraclass correlation coefficients were consistently lowest when metrics were computed for model-derived inputs, and estimates of thickness were less similar to the ground truth than those of volume. For the people with epilepsy, the 3D-T1 scans showed significant surface deflations across various subcortical structures when compared with those of healthy controls. Analysis of the 2D-T1 scans enabled the reliable detection of a subset of subcortical abnormalities, whereas analyses of the res-T1 and syn-T1 images were more prone to false-positive results. Resampling and ML image synthesis methods do not currently attenuate partial volume effects resulting from low through plane resolution in anisotropic MRI scans, instead quantitative analyses using 2D-T1 scans should be interpreted with caution, and researchers should consider the potential implications of preprocessing. The recon-all-clinical pipeline is promising, but requires further evaluation, especially when considered as an alternative to the classical pipeline.

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.

Objectives Encephalitis, brain inflammation and swelling, most often caused by an infection or the body’s immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical predictors of different types of encephalitis to help clinicians consider earlier treatment. Methods We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes. Results 341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had HSV, 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1st dose of aciclovir for those with HSV was 14 hours (IQR 5–50); time to 1st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45–250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x106/L, but they were less likely to have a febrile illness. Conclusions Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy.

Background Brain metastases are the most common intracranial tumors with an increasing incidence. They are an important cause of morbidity and mortality in patients with solid organ cancer and a focus of recent clinical research and experimental interest. Immune checkpoint inhibitors are being increasingly used to treat solid organ cancers. Methods To determine whether immune checkpoint inhibitors were biologically effective in the brain, we compared melanoma brain metastasis samples where treatment with ipilimumab had occurred preoperatively to those who had not received any immune modulating therapy and looked for histopathological (invasion, vascularity, metastasis inducing proteins, matrix metalloproteinases, immune cell infiltration, tissue architecture) and advanced MRI differences (diffusion weighted imaging). Results Co-localized tissue samples from the same regions as MRI regions of interest showed significantly lower vascularity (density of CD34 + vessels) in the core and higher T-cell infiltration (CD3 + cells) in the leading edge for ipilimumab-treated brain metastasis samples than for untreated cases and this correlated with a higher tumor ADC signal at post-treatment/preoperative MRI brain. Conclusions Treatment of a melanoma brain metastasis with ipilimumab appears to cause measurable biological changes in the tumor that can be correlated with post-treatment diffusion weighted MRI imaging, suggesting both a mechanism of action and a possible surrogate marker of efficacy.

supplementary data on IHC stains and image files

Introduction A first unprovoked seizure is a common presentation, reliably identifying those that will have recurrent seizures is a challenge. This study will be the first to explore the combined utility of serum biomarkers, quantitative electroencephalogram (EEG) and quantitative MRI to predict seizure recurrence. This will inform patient stratification for counselling and the inclusion of high-risk patients in clinical trials of disease-modifying agents in early epilepsy. Methods and analysis 100 patients with first unprovoked seizure will be recruited from a tertiary neuroscience centre and baseline assessments will include structural MRI, EEG and a blood sample. As part of a nested pilot study, a subset of 40 patients will have advanced MRI sequences performed that are usually reserved for patients with refractory chronic epilepsy. The remaining 60 patients will have standard clinical MRI sequences. Patients will be followed up every 6 months for a 24-month period to assess seizure recurrence. Connectivity and network-based analyses of EEG and MRI data will be carried out and examined in relation to seizure recurrence. Patient outcomes will also be investigated with respect to analysis of high-mobility group box-1 from blood serum samples. Ethics and dissemination This study was approved by North East—Tyne & Wear South Research Ethics Committee (20/NE/0078) and funded by an Association of British Neurologists and Guarantors of Brain clinical research training fellowship. Findings will be presented at national and international meetings published in peer-reviewed journals. Trial registration number NIHR Clinical Research Network's (CRN) Central Portfolio Management System (CPMS)—44976.

genetics: geneticsMismatch repair deficiency (MMRD) causes a rapid accumulation of genomic mutations during replication, leading to aggressive cancers that are difficult to treat with conventional chemotherapies. Accurately and efficiently diagnosing somatic and/or germline MMRD is critical for the therapeutic management in patients with the cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). However, current diagnostic tools are burdensome, expensive, and inconsistent in differentiating true drivers from passenger mutations in MMR genes. Consequently, an affordable and robust tool for MMRD detection in normal and cancer cells is critically needed. In a study conducted on behalf of the International Replication Repair Deficiency Consortium, researchers used a well-annotated dataset of childhood cancers and patients with cancer predisposition syndromes to generate a new tool to detect replication repair deficiency in cancerous and normal tissues. The findings were published in the Journal of Clinical Oncology (2022; doi: 10.1200/JCO.21.02873). It is well-established that that accumulation of microsatellite indels or instability (MSI) is a unique characteristic of MMRD cancers and has traditionally been used to diagnose such tumors. Here, the researchers hypothesized that since the human genome harbors >23 million microsatellites, incorporating a larger number of microsatellites may achiever better sensitivity and specificity. Accordingly, the team developed a low-pass genomic instability characterization (LOGIC) tool which utilizes low-pass whole-genome analysis to identify MSI and diagnose germline MMRD in a large cohort of pediatric cases. To test the efficacy of LOGIC as a diagnostic tool, the researchers compared the novel tools' performance against current clinically approved assays for replication repair deficiency diagnosis, including tumor mutational burden, immunohistochemistry, and the MSI panel. LOGIC was then employed to various normal tissues with CMMRD with thorough clinical data, including age of cancer presentation. The findings revealed that the functional genomic tool performs substantially better than used screening assays. Specifically, LOGIC achieved 100 percent sensitivity and specificity in detecting MMRD in childhood cancers (N=376). LOGIC was more sensitive than tumor mutational burden (80%, P=9.1 × 10−4), immunohistochemistry (86%, P=4.6 × 10−3), or the MSI panel (14%, P=4.3 × 10−12). Moreover, using blood and saliva, LOGIC was able to differentiate CMMRD from other cancer predisposition syndromes (P<.0001, n= 277). Furthermore, increased MMRDness score was linked with younger age of first cancer presentation in individuals with CMMRD (P=2.2 × 10−5). The researchers also noted that, in normal cells, MMRDness scores varied between tissues (GI >blood >brain), increased over time in the same individual, and revealed valuable genotype-phenotype associations between different mutations within the mismatch repair genes. Oncology Times chatted with corresponding study author, Uri Tabori, MD, for additional insights into the study. He is Section Head of Neuro-Oncology in the Division of Hematology/Oncology at The Hospital for Sick Children in Toronto. He participates in the development of systems for early detection and intervention in individuals determined to be at high risk of developing brain tumors, including those with mismatch repair genes. Oncology Times: Why is the diagnosis of mismatch repair deficiency (MMRD) so critical for tumor management? What are the current methodologies used to diagnosis MMRD? Tabori: “MMRD may be somatic (in the tumor only) or in every cell of the patient's body, leading to a rare but aggressive cancer predisposition syndrome known as constitutional MMRD syndrome (CMMRD). LOGIC can detect MMRD in both tumor and normal (non-tumor) tissues, like blood or saliva. The diagnosis of MMRD in a tumor is crucial for treatment, as these tumors are resistant to the established chemoradiation-based therapies. They instead respond well to a novel form of therapy called immune checkpoint inhibitors, which have shown remarkable effects in reducing the tumor volume and improving survival in individuals with MMRD cancers.Uri Tabori, MD: Uri Tabori, MD“Diagnosis of the germline syndrome, CMMRD, by screening normal tissues is critical to patient management, as these individuals are predisposed to developing a multitude of cancer types in childhood. It also allows clinicians to follow an established surveillance protocol to potentially catch cancers early when they can be easily and less aggressively managed. Until now, there are no functional assays to determine constitutional MMRD in normal tissues such as blood. “The current methodologies used to diagnosis MMRD in cancer include microsatellite instability (MSI) testing (which is only 15% sensitive in childhood cancer), immunohistochemistry (which is 80-85% sensitive), and tumor sequencing for tumor mutational burden (which has similar sensitivity but is extremely expensive).” Oncology Times: Based on the study findings, what are the advantages of the LOGIC assay over current established tests when it comes to diagnosing somatic and/or germline MMRD? Tabori: “Altogether, current tools are less robust and expensive. LOGIC is an inexpensive, sensitive, and specific assay to detect MMRD in both tumor and in the germline, shown in our study to display 100 percent specificity and sensitivity. The advantages include a robust rapid, high-throughput assay that can be done on paraffin blocks and on all types of normal samples, including buccal swabs, with high accuracy and potential feasibility in most countries including low- and middle-income countries. Globally, this could be a single assay to replace several cascade assays and at a lower cost. This saves several steps in the diagnosis of MMRD in cancer and germline, which can save time and significant funds per patient. “LOGIC can also simplify the diagnostic workflow with [fewer] steps compared to current established tests for MMRD diagnosis, and with the ability to analyze both tumor and germline tissues without the need for a matched sample (or control). It also costs about $100 per sample—about one-tenth the price of other testing, in which one sample can cost over $1,000 to test. This enables LOGIC to be a tool that can be widely adopted in centers globally, including low- and middle-income countries. It can also be utilized as a screening tool for MMRD, which is not possible with other established tools due to cost and turnaround time. This makes LOGIC a unique tool that can enable us to better understand how prevalent MMRD really is in the general population and investigate more ways to better treat and manage these patients.” Oncology Times: What are some of the biologic and clinical implications of the LOGIC assay to further quantify the extent of microsatellite instability in normal tissues? Tabori: “The clinical implications are quite straightforward. We observed that normal gastrointestinal tissues have a higher level of microsatellite instability than other tissues, making it a good candidate for biopsy in individuals where the diagnosis cannot be clearly made. Additionally, we have been using other normal tissues that are less invasive to make the assay more accessible in low- and middle-income countries and for children, such as taking saliva samples and using LOGIC to determine their microsatellite instability levels. Biologically, we can determine the correlation of tissue cell renewal and microsatellite mutations, which have been shown to be related using models, but we can show it in real human tissues. Also, as for the basis of LOGIC, we observed that tissues without mismatch repair actually acquire variations that are characteristic/unique, as in there are patterns of these variations that can be identified. Using these patterns, which we call mutational signatures, we have been able to parse out how different mechanisms can result in different microsatellite variations, which can imply that there is a determinable biological process that controls the repair process of these regions.” Oncology Times: In terms of next steps for the LOGIC assay, what additional questions are you looking forward to investigating? Tabori: “We are currently working with major centers in Ontario to validate our LOGIC tool for clinical use. We are looking to not only identify MMRD in pediatric samples, but in adulthood cases as well. We are also incorporating other variation signatures that can be inferred from the low-pass whole genome sequencing so that our tool not only captures MMRD, but also other cancer driver mutations and mechanisms. Overall, we are looking forward to expanding LOGIC to be used to diagnose and characterize a wide variety of cancer types to deliver the right type of therapy and cancer management to patients. As the low-pass genome can detect copy number alterations and mutational burden, LOGIC can be expanded to other aspects of cancer management on top of MMRD detection.” Dibash Kumar Das is a contributing writer.

Background Seizures can occur unpredictably in patients with acute encephalitis syndrome (AES), and many suffer from poor long-term neurological sequelae. Establishing factors associated with acute seizures risk and poor outcomes could support clinical care. We aimed to conduct regional and volumetric analysis of cerebral oedema on magnetic resonance imaging (MRI) in patients with AES. We assessed the relationship of brain oedema with acute seizure activity and long-term neurological outcome. Methods In a multi-centre cohort study, adults and children presenting with an AES were recruited in the UK. The clinical and brain MRI data were retrospectively reviewed. The outcomes variables were inpatient acute seizure activity and neurological disability at six-months post-discharge. A poor outcome was defined as a Glasgow outcome score (GOS) of 1–3. We quantified regional brain oedema on MRI through stereological examination of T2-weighted images using established methodology by independent and blinded assessors. Clinical and neuroimaging variables were analysed by multivariate logistic regression to assess for correlation with acute seizure activity and outcome. Results The study cohort comprised 69 patients (mean age 31.8 years; 53.6% female), of whom 41 (59.4%) had acute seizures as inpatients. A higher Glasgow coma scale (GCS) score on admission was a negative predictor of seizures (OR 0.61 [0.46–0.83], p = 0.001). Even correcting for GCS on admission, the presence of cortical oedema was a significant risk factor for acute seizure activity (OR 5.48 [1.62–18.51], p = 0.006) and greater volume of cerebral oedema in these cortical structures increased the risk of acute seizures (OR 1.90 [1.12–3.21], p = 0.017). At six-month post-discharge, 21 (30.4%) had a poor neurological outcome. Herpes simplex virus encephalitis was associated with higher risk of poor outcomes in univariate analysis (OR 3.92 [1.08–14.20], p = 0.038). When controlling for aetiology, increased volume of cerebral oedema was an independent risk factor for adverse neurological outcome at 6 months (OR 1.73 [1.06–2.83], p = 0.027). Conclusions Both the presence and degree of cerebral oedema on MRIs of patients with AES may help identify patients at risk of acute seizure activity and subsequent long-term morbidity.

Introduction: Idiopathic generalized epilepsy (IGE) is a collection of generalized nonlesional epileptic network disorders. Around 20-40% of patients with IGE are refractory to antiseizure medication, and mechanisms underlying refractoriness are poorly understood. Here, we characterize structural brain network alterations and determine whether network alterations differ between patients with refractory and nonrefractory IGE.Methods: Thirty-three patients with IGE (10 nonrefractory and 23 refractory) and 39 age- and sex-matched healthy controls were studied. Network nodes were segmented from T1-weighted images, while connections between these nodes (edges) were reconstructed from diffusion magnetic resonance imaging (MRI). Diffusion networks of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and streamline count (Count) were studied. Differences between all patients, refractory, nonrefractory, and control groups were computed using network-based statistics. Nodal volume differences between groups were computed using Cohen's d effect size calculation.Results: Patients had significantly decreased bihemispheric FA and Count networks and increased MD and RD networks compared with controls. Alterations in network architecture, with respect to controls, differed depending on treatment outcome, including predominant FA network alterations in refractory IGE and increased nodal volume in nonrefractory IGE. Diffusion MRI networks were not influenced by nodal volume.Discussion: Although a nonlesional disorder, patients with IGE have bihemispheric structural network alterations that may differ between patients with refractory and nonrefractory IGE. Given that distinct nodal volume and FA network alterations were observed between treatment outcome groups, a multifaceted network analysis may be useful for identifying imaging biomarkers of refractory IGE. Impact statementAlthough it is accepted that epilepsy is a network disorder, few studies have prospectively recruited patients with clear refractory and nonrefractory idiopathic generalized epilepsy (IGE) with a goal to identify magnetic resonance imaging (MRI) markers of pharmacoresistance. By showing that patients with refractory and nonrefractory IGE have different patterns of diffusion MRI networks and nodal volume alterations with respect to controls, we suggest that imaging analysis of structural networks may have the potential to identify unique biomarkers of treatment outcome. Reliable imaging markers of pharmacoresistance could inform the treatment pathway for many patients with epilepsy.

Most techniques used for automatic segmentation of subcortical brain regions are developed for three-dimensional (3D) MR images. MRIs obtained in non-specialist hospitals may be non-isotropic and two-dimensional (2D). Automatic segmentation of 2D images may be challenging and represents a lost opportunity to perform quantitative image analysis. We determine the performance of a modified subcortical segmentation technique applied to 2D images in patients with idiopathic generalised epilepsy (IGE). Volume estimates were derived from 2D (0.4 × 0.4 × 3 mm) and 3D (1 × 1x1mm) T1-weighted acquisitions in 31 patients with IGE and 39 healthy controls. 2D image segmentation was performed using a modified FSL FIRST (FMRIB Integrated Registration and Segmentation Tool) pipeline requiring additional image reorientation, cropping, interpolation and brain extraction prior to conventional FIRST segmentation. Consistency between segmentations was assessed using Dice coefficients and volumes across both approaches were compared between patients and controls. The influence of slice thickness on consistency was further assessed using 2D images with slice thickness increased to 6 mm. All average Dice coefficients showed excellent agreement between 2 and 3D images across subcortical structures (0.86–0.96). Most 2D volumes were consistently slightly lower compared to 3D volumes. 2D images with increased slice thickness showed lower agreement with 3D images with lower Dice coefficients (0.55–0.83). Significant volume reduction of the left and right thalamus and putamen was observed in patients relative to controls across 2D and 3D images. Automated subcortical volume estimation of 2D images with a resolution of 0.4 × 0.4x3mm using a modified FIRST pipeline is consistent with volumes derived from 3D images, although this consistency decreases with an increased slice thickness. Thalamic and putamen atrophy has previously been reported in patients with IGE. Automated subcortical volume estimation from 2D images is feasible and most reliable at using in-plane acquisitions greater than 1 mm x 1 mm and provides an opportunity to perform quantitative image analysis studies in clinical trials.

Despite an expanding literature on brain alterations in patients with longstanding epilepsy, few neuroimaging studies investigate patients with newly diagnosed focal epilepsy (NDfE). Understanding brain network impairments at diagnosis is necessary to elucidate whether or not brain abnormalities are principally due to the chronicity of the disorder and to develop prognostic markers of treatment outcome. Most adults with NDfE do not have MRI-identifiable lesions and the reasons for seizure onset and refractoriness are unknown. We applied structural connectomics to T1-weighted and multi-shell diffusion MRI data with generalized q-sampling image reconstruction using Network Based Statistics (NBS). We scanned 27 patients within an average of 3.7 (SD = 2.9) months of diagnosis and anti-epileptic drug treatment outcomes were collected 24 months after diagnosis. Seven patients were excluded due to lesional NDfE and outcome data was available in 17 patients. Compared to 29 healthy controls, patients with non-lesional NDfE had connectomes with significantly decreased quantitative anisotropy in edges connecting right temporal, frontal and thalamic nodes and increased diffusivity in edges between bilateral temporal, frontal, occipital and parietal nodes. Compared to controls, patients with persistent seizures showed the largest effect size (|d|>=1) for decreased anisotropy in right parietal edges and increased diffusivity in edges between left thalamus and left parietal nodes. Compared to controls, patients who were rendered seizure-free showed the largest effect size for decreased anisotropy in the edge connecting the left thalamus and right temporal nodes and increased diffusivity in edges connecting right frontal nodes. As demonstrated by large effect sizes, connectomes with decreased anisotropy (edge between right frontal and left insular nodes) and increased diffusivity (edge between right thalamus and left parietal nodes) were found in patients with persistent seizures compared to patients who became seizure-free. Patients who had persistent seizures showed larger effect sizes in all network metrics than patients who became seizure-free when compared to each other and compared to controls. Furthermore, patients with focal-to-bilateral tonic-clonic seizures (FBTCS, N = 11) had decreased quantitative anisotropy in a bilateral network involving edges between temporal, parietal and frontal nodes with greater effect sizes than those of patients without FBTCS (N = 9). NBS findings between patients and controls indicated that structural network changes are not necessarily a consequence of longstanding refractory epilepsy and instead are present at the time of diagnosis. Computed effect sizes suggest that there may be structural network MRI-markers of future pharmacoresistance and seizure severity in patients with a new diagnosis of focal epilepsy.

It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic nuclei and how nuclear‐specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non‐refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting‐state functional magnetic resonance imaging (MRI) in patients with refractory and non‐refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed‐to‐voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non‐refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non‐refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting‐state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE.

Despite an increasing number of drug treatment options for people with idiopathic generalized epilepsy (IGE), drug resistance remains a significant issue and the mechanisms underlying it remain poorly understood. Previous studies have largely focused on potential cellular or genetic explanations for drug resistance. However, epilepsy is understood to be a network disorder and there is a growing body of literature suggesting altered topology of large-scale resting networks in people with epilepsy compared with controls. We hypothesize that network alterations may also play a role in seizure control. The aim of this study was to compare resting state functional network structure between well-controlled IGE (WC-IGE), drug resistant IGE (DR-IGE) and healthy controls. Thirty-three participants with IGE (10 with WC-IGE and 23 with DR-IGE) and 34 controls were included. Resting state functional MRI networks were constructed using the Functional Connectivity Toolbox (CONN). Global graph theoretic network measures of average node strength (an equivalent measure to mean degree in a network that is fully connected), node strength distribution variance, characteristic path length, average clustering coefficient, small-world index and average betweenness centrality were computed. Graphs were constructed separately for positively weighted connections and for absolute values. Individual nodal values of strength and betweenness centrality were also measured and 'hub nodes' were compared between groups. Outcome measures were assessed across the three groups and between both groups with IGE and controls. The IGE group as a whole had a higher average node strength, characteristic path length and average betweenness centrality. There were no clear differences between groups according to seizure control. Outcome metrics were sensitive to whether negatively correlated connections were included in network construction. There were no clear differences in the location of 'hub nodes' between groups. The results suggest that, irrespective of seizure control, IGE interictal network topology is more regular and has a higher global connectivity compared to controls, with no alteration in hub node locations. These alterations may produce a resting state network that is more vulnerable to transitioning to the seizure state. It is possible that the lack of apparent influence of seizure control on network topology is limited by challenges in classifying drug response. It is also demonstrated that network topological features are influenced by the sign of connectivity weights and therefore future methodological work is warranted to account for anticorrelations in graph theoretic studies.

INTRODUCTION:Herpes simplex virus (HSV) encephalitis is a rare severe form of brain inflammation that commonly leaves survivors and their families with devastating long-term consequences. The virus particularly targets the temporal lobe of the brain causing debilitating problems in memory, especially verbal memory. It is postulated that immunomodulation with the corticosteroid, dexamethasone, could improve outcomes by reducing brain swelling. However, there are concerns (so far not observed) that such immunosuppression might facilitate increased viral replication with resultant worsening of disease. A previous trail closed early because of slow recruitment. METHOD:DexEnceph is a pragmatic multicentre, randomised, controlled, open-label, observer-blind trial to determine whether adults with HSV encephalitis who receive dexamethasone alongside standard antiviral treatment with aciclovir for have improved clinical outcomes compared with those who receive standard treatment alone. Overall, 90 patients with HSV encephalitis are being recruited from a target of 45 recruiting sites; patients are randomised 1:1 to the dexamethasone or control arms of the study. The primary outcome measured is verbal memory as assessed by the Weschler Memory Scale fourth edition Auditory Memory Index at 26 weeks after randomisation. Secondary outcomes are measured up to 72 weeks include additional neuropsychological, clinical and functional outcomes as well as comparison of neuroimaging findings. Patient safety monitoring occurs throughout and includes the detection of HSV DNA in cerebrospinal fluid 2 weeks after randomisation, which is indicative of ongoing viral replication. Innovative methods are being used to ensure recrutiment targets are met for this rare disease. DISCUSSION:DexEnceph aims to be the first completed randomised controlled trial of corticosteroid therapy in HSV encephalitis. The results will provide evidence for future practice in managing adults with the condition and has the potential to improve outcomes . ETHICS AND DISSEMINATION:The trial has ethical approval from the UK National Research Ethics Committee (Liverpool Central, REF: 15/NW/0545, 10 August 2015). Protocol V.2.1, July 2019. The results will be published and presented as soon as possible on completion. TRIAL REGISTRATION NUMBERS:ISRCTN11774734, EUDRACT 2015-001609-16.

BACKGROUND: Contrast enhancement in a brain tumor on magnetic resonance imaging is typically indicative of a high-grade glioma. However, a significant proportion of nonenhancing gliomas can be either grade II or III. While gross total resection remains the primary goal, imaging biomarkers may guide management when surgery is not possible, especially for nonenhancing gliomas. The utility of diffusion tensor imaging and dynamic susceptibility contrast magnetic resonance imaging was evaluated in differentiating nonenhancing gliomas. METHODS: Retrospective analysis was performed on imaging data from 72 nonenhancing gliomas, including grade II (n = 49) and III (n = 23) gliomas. Diffusion tensor imaging and dynamic susceptibility contrast data were used to generate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity as well as cerebral blood volume, cerebral blood flow, and mean transit time maps. Univariate and multivariate logistic regression and area under the curve analyses were used to measure sensitivity and specificity of imaging parameters. A sub-analysis was performed to evaluate the utility of imaging parameters in differentiating between different histologic groups. RESULTS: Logistic regression analysis indicated that tumor volume and relative mean transit time could differentiate between grade II and III nonenhancing gliomas. At a cutoff value of 0.33, this combination provided an area under the curve of 0.71, 70.6% sensitivity, and 64.3% specificity. Logistic regression analyses demonstrated much higher sensitivity and specificity in the differentiation of astrocytomas from oligodendrogliomas or identification of grades within these histologic subtypes. CONCLUSIONS: Diffusion tensor imaging and dynamic susceptibility contrast imaging can aid in differentiation of nonenhancing grade II and III gliomas and between histologic subtypes.