Retrospective Analysis of Presymptomatic Treatment In Sturge-Weber Syndrome.

Background: Ninety percent of infants with Sturge-Weber syndrome (SWS) brain involvement have seizure onset before 2 years of age; this is associated with worse neurologic outcome. Presymptomatic treatment before seizure onset may delay seizure onset and improve outcome, as has been shown in other conditions with a high-risk of developing epilepsy such as tuberous sclerosis complex. Electroencephalogram (EEG) may be a biomarker to predict seizure onset. This retrospective clinical data analysis aims to assess impact of presymptomatic treatment in SWS. Methods: This two-centered, IRB-approved, retrospective study analyzed records from patients with SWS brain involvement. Clinical data recorded included demographics, age of seizure onset (if present), brain involvement extent (unilateral versus bilateral), port-wine birthmark (PWB) extent, family history of seizure, presymptomatic treatment if received, neuroscore, and anti-seizure medication. EEG reports prior to seizure onset were analyzed. Results: Ninety-two patients were included (48 females), and 32 received presymptomatic treatment outside of a formal protocol (5 aspirin, 16 aspirin and levetiracetam; 9 aspirin and oxcarbazepine, 2 valproic acid). Presymptomatically-treated patients were more likely to be seizure-free at 2 years (15 of 32; 47% versus 7 of 60; 12%; p<.001). A greater percentage of presymptomatically-treated patients had bilateral brain involvement (38% treated versus 17% untreated; p=.026). Median hemiparesis neuroscore at 2 years was better in presymptomatically-treated patients. In EEG reports prior to seizure onset, the presence of slowing, epileptiform discharges, or EEG-identified seizures was associated with seizure onset by 2 (p=.001). Conclusion: Presymptomatic treatment is a promising approach to children diagnosed with SWS prior to seizure onset. Further study is needed, including prospective drug trials, long-term neuropsychological outcome, and prospective EEG analysis to assess this approach and determine biomarkers for presymptomatic treatment.

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.

The spectrum of movement disorders in young children with ARX-related epilepsy-dyskinesia syndrome.

Children with developmental and epileptic encephalopathies often present with co-occurring dyskinesias. Pathogenic variants in ARX cause a pleomorphic syndrome that includes infantile epilepsy with a variety of movement disorders ranging from focal hand dystonia to generalized dystonia with frequent status dystonicus. In this report, we present three patients with severe movement disorders as part of ARX-associated epilepsy-dyskinesia syndrome, including a patient with a novel pathogenic missense variant (p.R371G). These cases illustrate diagnostic and management challenges of ARX-related disorder and shed light on broader challenges concerning epilepsy-dyskinesia syndromes.

Camera trap surveys of Atlantic Forest mammals: A data set for analyses considering imperfect detection (2004-2020).

Camera traps became the main observational method of a myriad of species over large areas. Data sets from camera traps can be used to describe the patterns and monitor the occupancy, abundance, and richness of wildlife, essential information for conservation in times of rapid climate and land-cover changes. Habitat loss and poaching are responsible for historical population losses of mammals in the Atlantic Forest biodiversity hotspot, especially for medium to large-sized species. Here we present a data set from camera trap surveys of medium to large-sized native mammals (>1 kg) across the Atlantic Forest. We compiled data from 5380 ground-level camera trap deployments in 3046 locations, from 2004 to 2020, resulting in 43,068 records of 58 species. These data add to existing data sets of mammals in the Atlantic Forest by including dates of camera operation needed for analyses dealing with imperfect detection. We also included, when available, information on important predictors of detection, namely the camera brand and model, use of bait, and obstruction of camera viewshed that can be measured from example pictures at each camera location. Besides its application in studies on the patterns and mechanisms behind occupancy, relative abundance, richness, and detection, the data set presented here can be used to study species' daily activity patterns, activity levels, and spatiotemporal interactions between species. Moreover, data can be used combined with other data sources in the multiple and expanding uses of integrated population modeling. An R script is available to view summaries of the data set. We expect that this data set will be used to advance the knowledge of mammal assemblages and to inform evidence-based solutions for the conservation of the Atlantic Forest. The data are not copyright restricted; please cite this paper when using the data.

As armadilhas fotográficas tornaram­se o principal método de observação de muitas espécies em grandes áreas. Os dados obtidos com armadilhas fotográficas podem ser usados para descrever os padrões e monitorar a ocupação, abundância e riqueza da vida selvagem, informação essencial para a conservação em tempos de rápidas mudanças climáticas e de cobertura do solo. A perda de habitat e a caça furtiva são responsáveis pelas perdas populacionais históricas de mamíferos no hotspot de biodiversidade da Mata Atlântica, especialmente para espécies de médio e grande porte. Aqui apresentamos um conjunto de dados de levantamentos com armadilhas fotográficas de mamíferos de médio e grande porte (>1 kg) em toda a Mata Atlântica. Compilamos dados de 5.380 armadilhas fotográficas instaladas no nível do chão em 3.046 locais, de 2004 a 2020, resultando em 43.068 registros de 58 espécies. Esses dados acrescentam aos conjuntos de dados existentes de mamíferos na Mata Atlântica por incluir as datas de operação das câmeras, que são necessárias para análises que lidam com detecção imperfeita. Também incluímos, quando disponíveis, informações sobre importantes preditores de detecção, como marca e modelo da câmera, uso de isca e obstrução do visor da câmera que pode ser medido a partir de imagens de exemplo em cada local da câmera. Além de estudos sobre os padrões e mecanismos por trás da ocupação, abundância relativa, riqueza e detecção, o conjunto de dados aqui apresentado pode ser usado para estudar os padrões de atividade diária das espécies, nível de atividade e interações espaço­temporais entre as espécies. Além disso, os dados podem ser usados em combinação com outras fontes de dados em diversas análises com modelagem populacional integrada. Um script R está disponível para visualizar um resumo do conjunto de dados. Esperamos que este conjunto de dados seja usado para aumentar o conhecimento sobre as assembleias de mamíferos e usado para informar soluções baseadas em evidências para a conservação da Mata Atlântica. Os dados não são restritos por direitos autorais e, por favor, cite este documento ao usar os dados.

MRC1 and LYVE1 expressing macrophages in vascular beds of GNAQ p.R183Q driven capillary malformations in Sturge Weber syndrome.

Sturge-Weber syndrome (SWS), a neurocutaneous disorder, is characterized by capillary malformations (CM) in the skin, brain, and eyes. Patients may suffer from seizures, strokes, and glaucoma, and only symptomatic treatment is available. CM are comprised of enlarged vessels with endothelial cells (ECs) and disorganized mural cells. Our recent finding indicated that the R183Q mutation in ECs leads to heightened signaling through phospholipase Cß3 and protein kinase C, leading to increased angiopoietin-2 (ANGPT2). Furthermore, knockdown of ANGPT2, a crucial mediator of pro-angiogenic signaling, inflammation, and vascular remodeling, in EC-R183Q rescued the enlarged vessel phenotype in vivo. This prompted us to look closer at the microenvironment in CM-affected vascular beds. We analyzed multiple brain histological sections from patients with GNAQ-R183Q CM and found enlarged vessels devoid of mural cells along with increased macrophage-like cells co-expressing MRC1 (CD206, a mannose receptor), CD163 (a scavenger receptor and marker of the monocyte/macrophage lineage), CD68 (a pan macrophage marker), and LYVE1 (a lymphatic marker expressed by some macrophages). These macrophages were not found in non-SWS control brain sections. To investigate the mechanism of increased macrophages in the perivascular environment, we examined THP1 (monocytic/macrophage cell line) cell adhesion to EC-R183Q versus EC-WT under static and laminar flow conditions. First, we observed increased THP1 cell adhesion to EC-R183Q compared to EC-WT under static conditions. Next, using live cell imaging, we found THP1 cell adhesion to EC-R183Q was dramatically increased under laminar flow conditions and could be inhibited by anti-ICAM1. ICAM1, an endothelial cell adhesion molecule required for leukocyte adhesion, was strongly expressed in the endothelium in SWS brain histological sections, suggesting a mechanism for recruitment of macrophages. In conclusion, our findings demonstrate that macrophages are an important component of the perivascular environment in CM suggesting they may contribute to the CM formation and SWS disease progression.

FOXG1 variants can be associated with milder phenotypes than congenital Rett syndrome with unassisted walking and language development.

Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next-generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 variants presenting a mild phenotype, defined as able to speak and walk independently. We also reviewed data from three previously reported patients meeting our criteria. We identified five new patients with pathogenic FOXG1 missense variants, primarily in the forkhead domain, showing varying nonspecific intellectual disability and developmental delay. These features are not typical of congenital Rett syndrome and were rarely associated with microcephaly and epilepsy. Our findings are consistent with a previous genotype-phenotype analysis by Mitter et al. suggesting the delineation of five different FOXG1 genotype groups. Milder phenotypes were associated with missense variants in the forkhead domain. This information may facilitate prognostic assessments in children carrying a FOXG1 variant and improve the interpretation of new variants identified with genomic sequencing.

Case report: PIK3CA somatic mutation leading to Klippel Trenaunay Syndrome and multiple tumors.

We report a case of Klippel Trenaunay Syndrome that was monitored both clinically and molecularly over a period of 9 years. A somatic mosaic mutation of PIK3CA (p(E545G)) was identified using both cfDNA NGS liquid biopsy and tissue biopsy. At the age of 56, due to intervening clonal mutations in PIK3CA background, she developed a squamous cell carcinoma in the right affected leg which was treated surgically. Nine years later, lung bilateral adenocarcinoma arose on PIK3CA mutated tissues supported by different clonal mutations. One year later, the patient died from metastases led by a new FGFR3 clone unresponsive to standard-of-care, immunotherapy-based. Our results highlight the presence of a molecular hallmark underlying neoplastic transformation that occurs upon an angiodysplastic process and support the view that PIK3CA mutated tissues must be treated as precancerous lesions. Importantly, they remark the effectiveness of combining cfDNA NGS liquid and tissue biopsies to monitor disease evolution as well as to identify aggressive clones targetable by tailored therapy, which is more efficient than conventional protocols.

Menstrual cycle alterations in reproductive age women after anti COVID-19 vaccination. A survey in 419 Italian women and quality of life and sexual function evaluation.

BACKGROUND: Pharmacovigilance agencies did not collect data regarding menstrual changes after COVID-19 vaccination even if many women experienced it. Our aim was to evaluate whether COVID-19 vaccination is associated with secondary changes in menstrual cycle and to assess both quality of life (QoL) and sexual function (SF). METHODS: This study is a retrospective analysis referred to our Department from January 2021 to December 2021. The study cohort responded to same questionnaires before the second dose of vaccination (referring to previous 3 months) and 3 months after that (referring to three menstrual cycles after full-dose vaccination). The surveys administered were FSFI, FSDS, SF-36, MEDI-Q and the VAS-scale for dysmenorrhea. RESULTS: Four-hundred-nineteen vaccinated women were included in the study. The survey did not show a significant change in menstrual cycle length before and after COVID-19 vaccine (5.88±3.67 vs. 4.97±2.89, P=0.21); the interval between periods was significantly higher after a full-cycle vaccination (28.32±7.34 vs. 32.38±7.45, P<0.02); 32 patients (7.6%) developed amenorrhea after the second dose; VAS Scale did not change significantly (median range 3 (3-5) vs. 4 (3-6), P=0.20). MEDI-Q did not show significant variations before and after the vaccination (43.21±11.65 vs. 40.28±9.88, P=0.35). QoL and SF did not change significantly (FSFI median 27 [24-29] vs. 28 [25-30], P=0.12, FSDS median 9 [5-11] vs. 8 [4-12], P=0.22), SF-36 median 81 [70-85] vs. 82 [72-86], P=0.43). CONCLUSIONS: COVID-19 vaccination is associated with a significant change in intervals between menstrual cycles without other alterations in menstrual characteristics, in QoL or SF.

Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.

Development of a Training Strategy Aimed at Increasing Veterinarians' Awareness of the Proper Use of Antibiotics on Rabbit Farms.

The rabbit sector faces significant challenges with antimicrobial usage (AMU) and antimicrobial resistance (AMR). A focus group involving nine rabbit sector stakeholders identified key issues contributing to high AMU and the need for veterinarians' training. Participants emphasized the lack of clear legislation, biosecurity standards, and the importance of training on best practices to reduce AMU. To address these concerns, a blended learning course for rabbit veterinarians was organized, focusing on responsible drug use to lower AMU. The course design promoted participant interaction using group exercises and online discussions. The output was an operational tool, encompassing crucial elements to reduce drug dependence, covering housing, environmental conditions, feed, reproduction, disease prevention, diagnosis, and treatments. Validated in veterinarians' daily practices, the tool proved valuable. The tool, presented as a checklist, assists veterinarians in supporting field activities regarding proper drug use and AMR issues. It also helps farmers address knowledge gaps in breeding management and adopt biosecurity practices for disease prevention. Participants were encouraged to use the tool during farm visits and collaborate with farmers. The project presented in the manuscript is a crucial step towards the development of effective strategies for responsible AMU and AMR mitigation in the rabbit sector and beyond.

Focal drug-resistant temporal lobe epilepsy associated with an ipsilateral anterior choroidal artery aneurysm: illustrative case.

BACKGROUND: The occurrence of both an intracranial aneurysm and epilepsy, especially drug-resistant epilepsy (DRE), is rare. Although the overall incidence of aneurysms associated with DRE is unclear, it is thought to be particularly infrequent in the pediatric population. Surgical ligation of the offending aneurysm has been reported in conjunction with resolving seizure activity, although few cases have cited a combined approach of aneurysm ligation and resection of an epileptogenic focus. OBSERVATIONS: We present the case of a 14-year-old female patient with drug-resistant temporal lobe epilepsy and an ipsilateral supraclinoid internal carotid artery aneurysm. Seizure semiology, electroencephalography monitoring, and magnetic resonance imaging all indicated a left temporal epileptogenic focus, in addition to an incidental aneurysm. The authors recommended a combined surgery involving resection of the temporal lesion and surgical clip ligation of the aneurysm. Near-total resection and successful ligation were achieved, and the patient has remained seizure free since surgery at 1 year postoperatively. LESSONS: In patients with focal DRE and an adjacent intracranial aneurysm, a combined surgical approach involving both resection and surgical ligation can be used. Several surgical timing and neuroanesthetic considerations should be made to ensure the overall safety and efficacy of this procedure.

Pearls & Oy-sters: Paroxysmal Exercise-Induced Dyskinesias Due to Pyruvate Dehydrogenase Deficiency.

Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency, or mitochondrial respiratory chain disorders. A 4-year-old boy with a history of febrile seizures presented with paroxysmal dystonia, triggered by exercise, or occurring at rest. Additional investigations demonstrated pallidal hyperintensities on brain MRI and low CSF glucose. Pyruvate and lactate were elevated. The clinical presentation combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurologic presentations.

Small mammals from the Caatinga: A dataset for the Brazilian semiarid biome.

The Caatinga is an exclusively Brazilian biome, and is the largest and most biodiverse Seasonal Tropical Dry Forest in the world. Despite that, the mammalian fauna, especially small mammals, is the least studied of all Brazilian biomes. In order to fill gaps and provide detailed information on small mammals (Didelphimorphia, Rodentia) in the Caatinga biome, we compiled reliable records focusing on richness, composition and some biometric data. These records came from mammal collections, papers, theses, books, and unpublished data, prioritizing records with vouchers housed in scientific collections. We compiled a total of 3133 records from 816 locations, resulting in a richness of 47 native species (12 marsupials and 35 rodents, plus three exotic rodents, Rattus rattus, Rattus norvegicus, and Mus musculus). This dataset includes records of three new species for the biome and its transition zone: the rodents Calomys mattevii, Holochilus oxe, and Nectomys squamipes. Of the total number of records, 1808 (57.71%) are from consulting activities, 95 (3.03%) are from zoonoses studies and 104 (3.32%) are from the National Plague Service (SNP). All nine Brazilian states with territory in the Caatinga have sampling data for small mammals, but the number of records and localities are unevenly distributed, with the state of Rio Grande do Norte having the lowest number of records and locations sampled. Our dataset is the first of its kind for the Caatinga biome and has considerable potential value for studies of habitat use, landscape ecology, macroecology, biogeography, and conservation. There are no copyright restrictions on the data. Please cite this data paper when the data are used in publications. We also request that researchers and teachers inform us of how they are using the data.

Sexual function analysis and clitoral vascularization in postmenopausal women with genitourinary syndrome treated with ospemifene.

BACKGROUND: The aim of this study was to evaluate the efficacy of ospemifene in the Vaginal Health Index (VHI), in the vulvovaginal vascular perfusion, and to assess its impact on quality of life and sexual function. METHODS: Among 52 eligible patients, 43 consecutive postmenopausal patients affected by vulvo-vaginal atrophy (VVA), or genitourinary syndrome (GSM) were evaluated. VVA evaluation and ultrasound of the vulvo-vaginal vascularization by sampling the Pulsatility Index (PI) of clitoris dorsal artery were performed before and after 3 months-treatment with ospemifene. The 36-Item Short Form Survey (SF-36) for the quality-of-life assessment before and after 3 months were available for all women; instead, Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) questionnaires for the sexual function evaluation were performed for sexually active women in the study. The Patient Impression of Global Improvement (PGI-I) after 3 months of treatment was also calculated. RESULTS: The number of sexually active women significantly increased after 3 months (26 [60.46%] vs. 35 [81.39%]; P=0.01). The mean number of intercourses during the treatment increased (12.87±3.43 vs. 15.79±3.12, P=0.03). The PI of clitoris dorsal artery has significantly changed before and after treatment respectively (PI [1.69±0.42 vs. 1.28±0.45, P=0.001] RI [0.74±0.11 vs. 0.54±0.15, P=0.001]). The FSFI, FSDS and SF-36 Questionnaires scores showed a significant improvement after 3 months. VHI and PI were the independent factors of a lower FSFI after 3 months of treatment at multivariate analysis. CONCLUSIONS: Ospemifene improve the VHI and vulvovaginal vascular perfusion demonstrating a positive impact on sexual function and quality of life.