Variation in neuroimaging and outcomes in patients with Sturge Weber syndrome Type III.

OBJECTIVES: Sturge Weber syndrome (SWS) is a neurovascular condition with an estimated incidence of 1 in 20,000 to 50,000 live births. SWS Types I and II involve cutaneous and ophthalmological findings, with neurological involvement in Type I. SWS Type III is exclusive to brain stigmata. Our study aims to describe the characteristics of brain MRI findings and report neuroradiological features with seizure and cognitive outcomes in patients with SWS Type III. METHODS: This is a retrospective case series examining the clinical, radiological, and cognitive characteristics of patients with SWS Type III referred to the SWS Clinic at Boston Children's Hospital. We analyzed brain MRI findings based on vascular and parenchymal features. Clinical and cognitive outcomes were based on a validated assessment tool in this population (Neuroscore). RESULTS: This dedicated case series of patients with Type III SWS from a single center identified ten patients. All patients had classic stigmata indicative of SWS. Two distinct radiological phenotypes were found, one characterized by more pronounced deep venous enlargement, and the other, with more pronounced parenchymal abnormalities. There was heterogeneity in seizure presentation and outcome. Earlier age of onset and seizures predict more severe outcomes, as seen in classic SWS. CONCLUSION: We could not find significant divergence in outcomes between patients with differing neuroimaging phenotypes. These results raise the question of whether the two distinct radiological phenotypes found in SWS Type III are reflective of different disease entities, with underlying genetic heterogeneity. These results suggest the need for larger, multi-center natural history studies.

Noninvasive Molecular Subtyping of Pediatric Low-Grade Glioma with Self-Supervised Transfer Learning.

Purpose To develop and externally test a scan-to-prediction deep learning pipeline for noninvasive, MRI-based BRAF mutational status classification for pediatric low-grade glioma. Materials and Methods This retrospective study included two pediatric low-grade glioma datasets with linked genomic and diagnostic T2-weighted MRI data of patients: Dana-Farber/Boston Children's Hospital (development dataset, n = 214 [113 (52.8%) male; 104 (48.6%) BRAF wild type, 60 (28.0%) BRAF fusion, and 50 (23.4%) BRAF V600E]) and the Children's Brain Tumor Network (external testing, n = 112 [55 (49.1%) male; 35 (31.2%) BRAF wild type, 60 (53.6%) BRAF fusion, and 17 (15.2%) BRAF V600E]). A deep learning pipeline was developed to classify BRAF mutational status (BRAF wild type vs BRAF fusion vs BRAF V600E) via a two-stage process: (a) three-dimensional tumor segmentation and extraction of axial tumor images and (b) section-wise, deep learning-based classification of mutational status. Knowledge-transfer and self-supervised approaches were investigated to prevent model overfitting, with a primary end point of the area under the receiver operating characteristic curve (AUC). To enhance model interpretability, a novel metric, center of mass distance, was developed to quantify the model attention around the tumor. Results A combination of transfer learning from a pretrained medical imaging-specific network and self-supervised label cross-training (TransferX) coupled with consensus logic yielded the highest classification performance with an AUC of 0.82 (95% CI: 0.72, 0.91), 0.87 (95% CI: 0.61, 0.97), and 0.85 (95% CI: 0.66, 0.95) for BRAF wild type, BRAF fusion, and BRAF V600E, respectively, on internal testing. On external testing, the pipeline yielded an AUC of 0.72 (95% CI: 0.64, 0.86), 0.78 (95% CI: 0.61, 0.89), and 0.72 (95% CI: 0.64, 0.88) for BRAF wild type, BRAF fusion, and BRAF V600E, respectively. Conclusion Transfer learning and self-supervised cross-training improved classification performance and generalizability for noninvasive pediatric low-grade glioma mutational status prediction in a limited data scenario. Keywords: Pediatrics, MRI, CNS, Brain/Brain Stem, Oncology, Feature Detection, Diagnosis, Supervised Learning, Transfer Learning, Convolutional Neural Network (CNN) Supplemental material is available for this article. © RSNA, 2024.

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Pediatric nasal chondromesenchymal hamartomas: a case series.

PURPOSE: Nasal chondromesenchymal hamartomas (NCMH) are rare, predominantly benign tumors of the sinonasal tract. The distinction from higher grade malignancy may be challenging based on imaging features alone. To increase the awareness of this entity among radiologists, we present a multi-institutional case series of pediatric NCMH patients showing the varied imaging presentation. METHODS: Descriptive assessment of imaging appearances of the lesions on computed tomography (CT) and magnetic resonance imaging (MRI) was performed. In addition, we reviewed demographic information, clinical data, results of genetic testing, management, and follow-up data. RESULTS: Our case series consisted of 10 patients, with a median age of 0.5 months. Intraorbital and intracranial extensions were both observed in two cases. Common CT findings included bony remodeling, calcifications, and bony erosions. MRI showed heterogeneous expansile lesion with predominantly hyperintense T2 signal and heterogenous post-contrast enhancement in the majority of cases. Most lesions exhibited increased diffusivity on diffusion weighted imaging and showed signal drop-out on susceptibility weighted images in the areas of calcifications. Genetic testing was conducted in 4 patients, revealing the presence of DICER1 pathogenic variant in three cases. Surgery was performed in all cases, with one recurrence in two cases and two recurrences in one case on follow-up. CONCLUSION: NCMHs are predominantly benign tumors of the sinonasal tract, typically associated with DICER1 pathogenic variants and most commonly affecting pediatric population. They may mimic aggressive behavior on imaging; therefore, awareness of this pathology is important. MRI and CT have complementary roles in the diagnosis of this entity.

The Brain Tumor Segmentation (BraTS) Challenge 2023: Focus on Pediatrics (CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs).

Pediatric tumors of the central nervous system are the most common cause of cancer-related death in children. The five-year survival rate for high-grade gliomas in children is less than 20%. Due to their rarity, the diagnosis of these entities is often delayed, their treatment is mainly based on historic treatment concepts, and clinical trials require multi-institutional collaborations. The MICCAI Brain Tumor Segmentation (BraTS) Challenge is a landmark community benchmark event with a successful history of 12 years of resource creation for the segmentation and analysis of adult glioma. Here we present the CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge, which represents the first BraTS challenge focused on pediatric brain tumors with data acquired across multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. The BraTS-PEDs 2023 challenge focuses on benchmarking the development of volumentric segmentation algorithms for pediatric brain glioma through standardized quantitative performance evaluation metrics utilized across the BraTS 2023 cluster of challenges. Models gaining knowledge from the BraTS-PEDs multi-parametric structural MRI (mpMRI) training data will be evaluated on separate validation and unseen test mpMRI dataof high-grade pediatric glioma. The CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge brings together clinicians and AI/imaging scientists to lead to faster development of automated segmentation techniques that could benefit clinical trials, and ultimately the care of children with brain tumors.

Somatic Mosaicism in PIK3CA Variant Correlates With Stereoelectroencephalography-Derived Electrophysiology.

Objectives: Brain-limited pathogenic somatic variants are associated with focal pediatric epilepsy, but reliance on resected brain tissue samples has limited our ability to correlate epileptiform activity with abnormal molecular pathology. We aimed to identify the pathogenic variant and map variant allele fractions (VAFs) across an abnormal region of epileptogenic brain in a patient who underwent stereoelectroencephalography (sEEG) and subsequent motor-sparing left frontal disconnection. Methods: We extracted genomic DNA from peripheral blood, brain tissue resected from peri-sEEG electrode regions, and microbulk brain tissue adherent to sEEG electrodes. Samples were mapped based on an anatomic relationship with the presumed seizure onset zone (SOZ). We performed deep panel sequencing of amplified and unamplified DNA to identify pathogenic variants with subsequent orthogonal validation. Results: We detect a pathogenic somatic PIK3CA variant, c.1624G>A (p.E542K), in the brain tissue samples, with VAF inversely correlated with distance from the SOZ. In addition, we identify this variant in amplified electrode-derived samples, albeit with lower VAFs. Discussion: We demonstrate regional mosaicism across epileptogenic tissue, suggesting a correlation between variant burden and SOZ. We also validate a pathogenic variant from individual amplified sEEG electrode-derived brain specimens, although further optimization of techniques is required.

Orbital and Eyelid Characteristics, Strabismus, and Intracranial Pressure Control in Apert Children Treated by Endoscopic Strip Craniectomy versus Fronto-Orbital Advancement.

Apert syndrome is characterized by eyelid dysmorphology, V-pattern strabismus, extraocular muscle excyclorotation, and elevated intracranial pressure (ICP). We compare eyelid characteristics, severity of V-pattern strabismus, rectus muscle excyclorotation, and ICP control in Apert syndrome patients initially treated by endoscopic strip craniectomy (ESC) at about 4 months of age versus fronto-orbital advancement (FOA) performed about 1 year of age. Methods: Twenty-five patients treated at Boston Children's Hospital met inclusion criteria for this retrospective cohort study. Primary outcomes were magnitude of palpebral fissure downslanting at 1, 3, and 5 years of age, severity of V-pattern strabismus, rectus muscle excyclorotation, and interventions to control ICP. Results: Before craniofacial repair and through 1 year of age, none of the studied parameters differed for FOA versus ESC treated patients. Palpebral fissure downslanting became statistically greater for those treated by FOA by 3 (P < 0.001) and 5 years of age (P = 0.001). Likewise, severity of palpebral fissure downslanting correlated with severity of V-pattern strabismus at 3 (P = 0.004) and 5 (P = 0.002) years of age. Palpebral fissure downslanting and rectus muscle excyclorotation were typically coexistent (P = 0.053). Secondary interventions to control ICP were required in four of 14 patients treated by ESC (primarily FOA) and in two of 11 patients initially treated by FOA (primarily third ventriculostomy) (P = 0.661). Conclusions: Apert patients initially treated by ESC had less severe palpebral fissure downslanting and V-pattern strabismus, normalizing their appearance. Thirty percent initially treated by ESC required secondary FOA to control ICP.

Stereoelectroencephalography followed by combined electrode removal and MRI-guided laser interstitial thermal therapy or open resection: a single-center series in pediatric patients with medically refractory epilepsy.

OBJECTIVE: Stereoelectroencephalography (SEEG) and MRI-guided laser interstitial thermal therapy (MRgLITT) have emerged as safe, effective, and less invasive alternatives to subdural grid placement and open resection, respectively, for the localization and treatment of medically refractory epilepsy (MRE) in children. Reported pediatric experience combining these complementary techniques is limited, with traditional workflows separating electrode removal and ablation/resection. The authors describe the largest reported series of pediatric epilepsy patients who underwent MRgLITT following SEEG contrasted with a cohort that underwent craniotomy following SEEG, combining ablation/resection with electrode explantation as standard practice. METHODS: The medical records of all patients with MRE who had undergone SEEG followed by MRgLITT or open resection/disconnection at Boston Children's Hospital between November 2015 and December 2020 were retrospectively reviewed. Primary outcome variables included surgical complication rates, length of hospital stay following treatment, and Engel classification at the last follow-up. RESULTS: Of 74 SEEG patients, 27 (median age 12.1 years, 63% female) underwent MRgLITT and 47 (median age 12.1 years, 49% female) underwent craniotomy. Seventy patients (95%) underwent SEEG followed by combined electrode removal and treatment. Eight MRgLITT cases (30%) and no open cases targeted the insula (p < 0.001). Complication rates did not differ, although trends toward more subdural/epidural hematomas, infarcts, and permanent unanticipated neurological deficits were evident following craniotomy, whereas a trend toward more temporary unanticipated neurological deficits was seen following MRgLITT. The median duration of hospitalization after treatment was 3 and 5 days for MRgLITT and open cases, respectively (p = 0.078). Seizure outcomes were similar between the cohorts, with 74% of MRgLITT and craniotomy patients attaining Engel class I or II outcomes (p = 0.386) at the last follow-up (median 1.1 and 1.9 years, respectively). CONCLUSIONS: MRgLITT and open resection following SEEG can both effectively treat MRE in pediatric patients and generally can be performed in a two-surgery workflow during a single hospitalization. In appropriately selected patients, MRgLITT tended to be associated with shorter hospitalizations and fewer complications following treatment and may be best suited for focal deep-seated targets associated with relatively challenging open surgical approaches.

Mimics of Pediatric Small Vessel Primary Angiitis of the Central Nervous System.

OBJECTIVE: Small vessel primary angiitis of the central nervous system is a rare and often severe disease characterized by central nervous system-restricted inflammatory vasculitis on histopathology. Diagnosis requires brain biopsy for confirmation and is suggested prior to starting immunotherapy when feasible. However, emerging evidence suggests that other neuroinflammatory conditions may have a clinical and radiographic phenotype that mimics small vessel primary angiitis, at times with overlapping pathologic features as well. Such diagnoses, including myelin oligodendrocyte glycoprotein antibody-associated disease and central nervous system-restricted hemophagocytic lymphohistiocytosis, can be non-invasively diagnosed with serum antibody or genetic testing that would prompt different monitoring and treatment paradigms. To determine the ultimate diagnosis of patients who were suspected prior to biopsy to have small vessel primary angiitis, we reviewed the clinical, radiographic, and pathological features of a cohort of patients at a single center undergoing brain biopsy for non-oncologic indications. METHODS: Clinical data were retrospectively extracted from the medical record. Pathology and neuroimaging review was conducted. RESULTS: We identified 21 patients over a 19-year time-period, of whom 14 (66.7%) were ultimately diagnosed with entities other than small vessel primary angiitis that would have obviated the need for brain biopsy. Diagnoses included anti-myelin oligodendrocyte glycoprotein antibody associated disease (n = 9), central nervous system-restricted hemophagocytic lymphohistiocytosis (n = 3), anti-GABAA receptor encephalitis (n = 1), and Aicardi-Goutières syndrome (n = 1). INTERPRETATION: This study highlights the importance of pursuing now readily available non-invasive testing for mimicking diagnoses before performing a brain biopsy for suspected small vessel primary angiitis of the central nervous system. ANN NEUROL 2023;93:109-119.

Limited utility of structural MRI to identify the epileptogenic zone in young children with tuberous sclerosis.

BACKGROUND AND PURPOSE: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC. METHODS: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG). RESULTS: None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (κ = .60), and fair (κ = .24) for all other features. CONCLUSIONS: In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

BACKGROUND: The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

Presurgical accuracy of dipole clustering in MRI-negative pediatric patients with epilepsy: Validation against intracranial EEG and resection.

OBJECTIVE: To assess the utility of interictal magnetic and electric source imaging (MSI and ESI) using dipole clustering in magnetic resonance imaging (MRI)-negative patients with drug resistant epilepsy (DRE). METHODS: We localized spikes in low-density (LD-EEG) and high-density (HD-EEG) electroencephalography as well as magnetoencephalography (MEG) recordings using dipoles from 11 pediatric patients. We computed each dipole's level of clustering and used it to discriminate between clustered and scattered dipoles. For each dipole, we computed the distance from seizure onset zone (SOZ) and irritative zone (IZ) defined by intracranial EEG. Finally, we assessed whether dipoles proximity to resection was predictive of outcome. RESULTS: LD-EEG had lower clusterness compared to HD-EEG and MEG (p < 0.05). For all modalities, clustered dipoles showed higher proximity to SOZ and IZ than scattered (p < 0.001). Resection percentage was higher in optimal vs. suboptimal outcome patients (p < 0.001); their proximity to resection was correlated to outcome (p < 0.001). No difference in resection percentage was seen for scattered dipoles between groups. CONCLUSION: MSI and ESI dipole clustering helps to localize the SOZ and IZ and facilitate the prognostic assessment of MRI-negative patients with DRE. SIGNIFICANCE: Assessing the MSI and ESI clustering allows recognizing epileptogenic areas whose removal is associated with optimal outcome.

3D Modeling and Advanced Visualization of the Pediatric Brain, Neck, and Spine.

The ready availability of advanced visualization tools on picture archiving and communication systems workstations or even standard laptops through server-based or cloud-based solutions has enabled greater adoption of these techniques. We describe how radiologists can tailor imaging techniques for optimal 3D reconstructions provide a brief overview of the standard and newer "on-screen" techniques. We describe the process of creating 3D printed models for surgical simulation and education, with examples from the authors' institution and the existing literature. Finally, the review highlights current uses and potential future use cases for virtual reality and augmented reality applications in a pediatric neuroimaging setting.

Artificial Intelligence Algorithm Improves Radiologist Performance in Skeletal Age Assessment: A Prospective Multicenter Randomized Controlled Trial.

Background Previous studies suggest that use of artificial intelligence (AI) algorithms as diagnostic aids may improve the quality of skeletal age assessment, though these studies lack evidence from clinical practice. Purpose To compare the accuracy and interpretation time of skeletal age assessment on hand radiograph examinations with and without the use of an AI algorithm as a diagnostic aid. Materials and Methods In this prospective randomized controlled trial, the accuracy of skeletal age assessment on hand radiograph examinations was performed with (n = 792) and without (n = 739) the AI algorithm as a diagnostic aid. For examinations with the AI algorithm, the radiologist was shown the AI interpretation as part of their routine clinical work and was permitted to accept or modify it. Hand radiographs were interpreted by 93 radiologists from six centers. The primary efficacy outcome was the mean absolute difference between the skeletal age dictated into the radiologists' signed report and the average interpretation of a panel of four radiologists not using a diagnostic aid. The secondary outcome was the interpretation time. A linear mixed-effects regression model with random center- and radiologist-level effects was used to compare the two experimental groups. Results Overall mean absolute difference was lower when radiologists used the AI algorithm compared with when they did not (5.36 months vs 5.95 months; P = .04). The proportions at which the absolute difference exceeded 12 months (9.3% vs 13.0%, P = .02) and 24 months (0.5% vs 1.8%, P = .02) were lower with the AI algorithm than without it. Median radiologist interpretation time was lower with the AI algorithm than without it (102 seconds vs 142 seconds, P = .001). Conclusion Use of an artificial intelligence algorithm improved skeletal age assessment accuracy and reduced interpretation times for radiologists, although differences were observed between centers. Clinical trial registration no. NCT03530098 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Rubin in this issue.

Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.

BACKGROUND AND OBJECTIVES: AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations. METHODS: We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity. RESULTS: We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age. DISCUSSION: Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.

Hippocampal Involvement With Vigabatrin-Related MRI Signal Abnormalities in Patients With Infantile Spasms: A Novel Finding.

BACKGROUND: In a subset of infants exhibiting typical vigabatrin-related magnetic resonance imaging (MRI) changes, the authors observed additional hippocampal signal abnormalities. The authors investigated occurrence and significance of additional signal abnormalities. METHODS: A retrospective review of infantile spasms patients with typical vigabatrin-related MRI abnormalities was performed. Atypical features included signal changes unilaterally or at previously unreported sites. Comparisons were made between patients with and without atypical features. RESULTS: In all, 26/55 (47%) exhibited typical vigabatrin-related MRI changes, with additional signal abnormalities in the hippocampi in 6 of 26. On follow-up, evolution of hippocampal signal changes paralleled changes at typical locations in 4 patients. Two patients, clinically well, without follow-up MRI. Patients with and without additional hippocampal signal changes did not differ with respect to clinical factors, including seizure status. One patient had unilateral thalamic/cerebral peduncle signal abnormality along with typical vigabatrin changes. CONCLUSIONS: Hippocampal changes seen in subset of patients with typical vigabatrin-related changes may be attributable to vigabatrin exposure in the appropriate circumstance.

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

Visual outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children.

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.