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IntroductionThe histopathological basis of “unidentified bright objects” (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1.Methods3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO–cNAWM pairs.ResultsNo significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered.ConclusionOur results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in ‘extracellular-like’, intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo.

Combining information from DKI, DSC-MRI, and CSI increases diagnostic accuracy to differentiate low- from high-grade gliomas, possibly providing diagnosis for the individual patient.

Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one.This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used.

SUMMARYObjective: Since 2008, we have changed our presurgical diagnostic imaging evaluation for medically refractory focal epilepsy to include high-resolution epilepsy protocol on 3 T magnetic resonance imaging (MRI), and combined magnetoencephalography and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) in selected patients with normal or subtle changes on MRI or discordant diagnostic tests. The aim of this study was to evaluate the effectiveness of the change in imaging practice on epilepsy surgery outcome in a tertiary pediatric epilepsy surgery center. Methods: The change in practice occurred in early 2008, and patients were classified based on old or new practice. The patient characteristics, surgical variables, and seizure-free surgical outcome were compared, and the trend in seizure-free outcome over time was assessed. Results: There was a trend for increased abnormal MRI (92% vs. 86%, respectively, p = 0.062), and increased utilization of FDG-PET (34% vs. 3% respectively, p < 0.001) with new relative to old practice. There were no statistically significant differences in invasive monitoring, location, and type of surgery and histology between the two periods (all p > 0.05). During the old practice, there was no statistically significant change in yearly trend of seizure-free outcome (odds ratio [OR] 0.960, 95% confidence interval [CI] 0.875-1.053, p = 0.386). The change in practice in 2008 was associated with a significant improvement in seizure-free outcome (OR 1.535, 95% CI 1.100-2.142, p = 0.012). During the new practice, there was a significant positive trend in yearly seizure-free outcome (OR 1.219, 95% CI 1.053-1.411, p = 0.008), after adjusting for age at seizure onset, invasive monitoring, location and type of surgery, histology, MRI, magnetoencephalography, and FDG-PET. Significance: We have found an improvement in seizure-free surgical outcome following the change in imaging practice. This study highlights the importance of optimizing and improving presurgical diagnostic imaging evaluation to improve surgical outcome. KEY WORDS: Seizure-free outcome, Magnetic resonance imaging, 18-Fluorodeoxyglucose-positron emission tomography, Magnetoencephalography.In children with medically refractory focal epilepsy, surgery has the potential to render these patients seizure-free. Meta-analysis of pediatric epilepsy surgery outcome has shown that for combined temporal and extratemporal lobe epilepsy surgery, seizure-free outcome was 59% and for temporal lobe epilepsy surgery, seizure-free outcome was 62%. 1 We have previously shown that pediatric epilepsy surgery is a cost-effective treatment in the management of children with intractable epilepsy relative to medical therapy.2 As part of the presurgical diagnostic evaluation, the

To date, mutations in 15 actin-or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.Microtubules (MTs) and filamentous actin form key structural components of the cytoskeleton, a dynamic intracellular structure that is essential for several basic cell functions, including migration, the formation of cellular processes (including axons and dendrites), axonal guidance, and vesicular trafficking. Mammalian genomes contain two spectraplakins-MACF1 (also known as ACF7) and DST (also known as BPAG1)-that function as actin-MT cross-linkers and essential integrators and modulators of cytoskeletal processes. [1][2][3] MACF1 is a large gene that expresses many isoforms, several of which are brain specific, through alternative splicing. The N terminus of the major isoforms contains two calponin-homology (CH) domains that bind actin, a plakin domain, and a long spectrin-repeat rod domain that confers flexibility. The C terminus of all isoforms functions as a MT binding domain and contains two calcium-binding EF-hand domains, a zinc-binding GAR (growth-arrest specific 2 or Gas2-related) domain, a positively charged Gly-Ser-Arg (GSR) region, and an EB1-binding SxIP domain. 1-3

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

Summary Febrile infection‐related epilepsy syndrome (FIRES) is a rare severe epileptic syndrome occurring in previously healthy children and characterized by refractory status epilepticus (SE) following a febrile illness. Brain imaging findings in affected patients have been reported in few case series and some case reports. This article is a comprehensive review of the magnetic resonance imaging (MRI) characteristics in all reported patients with a diagnosis of FIRES, describing the findings in the acute and chronic phases of the disease, and discussing possible pathogenesis and radiologic differential diagnoses. Most of the patients had normal brain scans in the acute phase (61%) and about 25% of the patients reported in literature had abnormalities in the temporal lobes. Changes in the basal ganglia and rarely in thalami or brainstem have also been described, as well as diffuse cerebral edema in a minority of patients during the acute phase. The chronic phase of the disease was characterized by atrophic changes and evidence of mesiotemporal sclerosis. An understanding of these MRI abnormalities is necessary to support the diagnosis of FIRES and exclude mimics.