Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease

Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordThere is another record in ORE for this publication: http://hdl.handle.net/10871/33419The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.We thank D.R. Alessi (Dundee) and R.P. Lifton (Rockefeller) for their support. K.T.K. is supported by the March of Dimes Basil O'Connor Award, a Simons Foundation SFARI Grant, the Hydrocephalus Association Innovator Award, and the NIH (4K12NS080223-05). J.M.S. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808) and the US Department of Veterans Affairs (1BX002889); R.M. is supported by the Howard Hughes Medical Institute

Surgery for Petroclival Meningiomas: A Comprehensive Review of Outcomes in the Skull Base Surgery Era

Skull base surgery has evolved to a point that its focus is now shifting to outcome analysis. To do so for petroclival meningiomas is difficult. The rarity of the tumor, different treatment philosophies, and variations in reporting complicate the outcome analysis. With this limitation in mind, we analyzed the literature on this disease and report the combined outcomes in a unified fashion in hopes that it will serve as a starting point for further prospective analysis. Data was extracted from all available reports on MEDLINE/PubMed published in English. All studies were retrospective and uncontrolled. The majority of studies represent the experience of a single surgeon at a single institution. Of the 19 studies with detailed demographic and outcome data, no data met criteria for meta-analysis. A total of 1000 patients were reported. The mean age of the patients was 50 years. The male to female ratio is 1:3. GTR (gross total resection) was reported in 49% of patients. Thirty-four percent of patients experienced some neurological deficit in the early postoperative period (<3 months). The most common morbidities reported were cranial nerve deficits (34.4% [range: 20 to 79%]) with facial nerve injury accounting for 19%, followed by motor deficits (14%), infection rates (1.6%), CSF leaks (5%), hemorrhage (1.2%), and hydrocephalus (1%). Death within 1 year of surgery was reported for 1.4% of patients. Once considered untreatable, petroclival meningiomas can now be approached relatively safely. There, however, still remains an ∼34% morbidity with the most common being cranial nerve. Despite this, >75% of patients return to independence at 1 year, many of which will resume employment. The nature of this study limits the conclusions that can be drawn; however, it provides some generalizations that may help guide patient questions regarding treatment outcomes

Tatiana Riabouchinska (centre on floor), Anton Dolin (?) (centre rear), and artists of the company, in Les sylphides, Covent Garden Russian Ballet, Australian tour, His Majesty's Theatre, Melbourne,1938 [picture] /

Condition: Poor, silvering.; From: Les sylphides : a romantic reverie in one act / by Michel Fokine ; music by Frédéric Chopin, orchestrated by Vittorio Rieti.; Inscription: "Y3".; Part of the collection: Hugh P. Hall collection of photographs, 1938-1940.; Performed Sept-Nov 1938 and April 1939.; Choreography by Michel Fokine ; scenery by Prince A. Schervachidze, after Jean Corot ; costumes executed by O. Larose.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4180334. One of a collection of photographs taken by Hugh P. Hall of 28 ballet productions performed by the Covent Garden Russian Ballet (toured Australia 1938-1939) and the Original Ballet Russe (toured Australia 1939-1940). These are the second and third of the three Ballets Russes companies which toured Australasia between 1936 and 1940. The photographs were taken from the auditorium during a live performance in His Majesty's Theatre, Melbourne and mounted on cardboard for display purposes. For conservation and storage, the photographs have been demounted. The original arrangement of the photographs has been recorded, and details are available from the Pictures Branch of the National Library

Malignant Cerebellar Edema Subsequent to Accidental Prescription Opioid Intoxication in Children

We present two recent cases of toddlers who developed malignant cerebellar edema subsequent to accidental ingestion of prescription opioids. Both children presented acute neurological decline, hydrocephalus, and tonsillar herniation requiring emergent ventricular drain placement, suboccipital craniectomy, and partial cerebellectomy. Together with several other reports, these cases suggest the existence of an uncommon yet severe syndrome of acute opioid-induced malignant cerebellar edema. We hypothesize that the condition results from a combination of primary opioid receptor-mediated changes in neuronal metabolism that are exacerbated by secondary hypoxic insult. If recognized promptly, this syndrome can be treated with emergent neurosurgical intervention with good clinical outcomes. These cases also illustrate the unintended consequences and innocent victims of the spiraling prescription opioid epidemic, which will likely increase in prevalence. Recognition of this syndrome by clinicians is thus critical