The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis.

Arachnoid cysts (ACs) are the most common space-occupying lesions in the human brain and present significant challenges for clinical management. While most cases of ACs are sporadic, nearly 40 familial forms have been reported. Moreover, ACs are seen with increased frequency in multiple Mendelian syndromes, including Chudley-McCullough syndrome, acrocallosal syndrome, and autosomal recessive primary ciliary dyskinesia. These findings suggest that genetic factors contribute to AC pathogenesis. However, traditional linkage and segregation approaches have been limited in their ability to identify causative genes for ACs because the disease is genetically heterogeneous and often presents asymptomatically and sporadically. Here, we comprehensively review theories of AC pathogenesis, the genetic evidence for AC formation, and discuss a different approach to AC genomics that could help elucidate this perplexing lesion and shed light on the associated neurodevelopmental phenotypes seen in a significant subset of these patients.

A neural stem cell paradigm of pediatric hydrocephalus.

Pediatric hydrocephalus, the leading reason for brain surgery in children, is characterized by enlargement of the cerebral ventricles classically attributed to cerebrospinal fluid (CSF) overaccumulation. Neurosurgical shunting to reduce CSF volume is the default treatment that intends to reinstate normal CSF homeostasis, yet neurodevelopmental disability often persists in hydrocephalic children despite optimal surgical management. Here, we discuss recent human genetic and animal model studies that are shifting the view of pediatric hydrocephalus from an impaired fluid plumbing model to a new paradigm of dysregulated neural stem cell (NSC) fate. NSCs are neuroprogenitor cells that comprise the germinal neuroepithelium lining the prenatal brain ventricles. We propose that heterogenous defects in the development of these cells converge to disrupt cerebrocortical morphogenesis, leading to abnormal brain-CSF biomechanical interactions that facilitate passive pooling of CSF and secondary ventricular distention. A significant subset of pediatric hydrocephalus may thus in fact be due to a developmental brain malformation leading to secondary enlargement of the ventricles rather than a primary defect of CSF circulation. If hydrocephalus is indeed a neuroradiographic presentation of an inborn brain defect, it suggests the need to focus on optimizing neurodevelopment, rather than CSF diversion, as the primary treatment strategy for these children.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior.

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy.SIGNIFICANCE STATEMENT The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. For the first time, we developed two behavioral tasks and demonstrate that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) decreased cortical slow wave activity and improved task performance in the postictal period. Because preclinical task performance studies are crucial to explore the effectiveness and safety of DBS treatment, our work is clinically relevant as it could support and help set the foundations for a human neurostimulation trial to improve postictal responsiveness in patients with medically and surgically refractory epilepsy.

Pre-operative headaches and obstructive hydrocephalus predict an extended length of stay following suboccipital decompression for pediatric Chiari I malformation.

PURPOSE: For young children and adolescents with Chiari malformation type I (CM-I), the determinants of extended length of hospital stay (LOS) after neurosurgical suboccipital decompression are obscure. Here, we investigate the impact of patient- and hospital-level risk factors on extended LOS following surgical decompression for CM-I in young children to adolescents. METHODS: The Kids' Inpatient Database year 2012 was queried. Pediatric CM-I patients (6-18 years) undergoing surgical decompression were identified. Weighted patient demographics, comorbidities, complications, LOS, disposition, and total cost were recorded. A multivariate logistic regression was used to determine the odds ratio for risk-adjusted LOS. The primary outcome was the degree patient comorbidities or post-operative complications correlated with extended LOS. RESULTS: A total of 1592 pediatric CM-I patients were identified for which 328 (20.6%) patients had extended LOS (normal LOS, 1264; extended LOS, 328). Age, gender, race, median household income quartile, and healthcare coverage distributions were similar between the two cohorts. Patients with extended LOS had significantly greater admission comorbidities including headache symptoms, nausea and vomiting, obstructive hydrocephalus, lack of coordination, deficiency anemias, and fluid and electrolyte disorders. On multivariate logistic regression, several risk factors were associated with extended LOS, including headache symptoms, obstructive hydrocephalus, and fluid and electrolyte disorders. CONCLUSIONS: Our study using the Kids' Inpatient Database demonstrates that presenting symptoms and signs, including headaches and obstructive hydrocephalus, respectively, are significantly associated with extended LOS following decompression for pediatric CM-I.

Genomics of human congenital hydrocephalus.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of pathological cerebrospinal fluid (CSF) accumulation and, therefore, treated largely by neurosurgical CSF diversion. The persistence of ventriculomegaly and poor neurodevelopmental outcomes in some post-surgical patients highlights our limited knowledge of disease mechanisms. Recent whole-exome sequencing (WES) studies have shown that rare, damaging de novo and inherited mutations with large effect contribute to ~ 25% of sporadic CH. Interestingly, multiple CH genes are key regulators of neural stem cell growth and differentiation and converge in human transcriptional networks and cell types pertinent to fetal neurogliogenesis. These data implicate genetic disruption of early brain development as the primary pathomechanism in a substantial minority of patients with sporadic CH, shedding new light on human brain development and the pathogenesis of hydrocephalus. These data further suggest WES as a clinical tool with potential to re-classify CH according to a molecular nomenclature of increased precision and utility for genetic counseling, outcome prognostication, and treatment stratification.

Laser interstitial thermal therapy for treatment of cerebral radiation necrosis.

Radiation necrosis is a well described complication after radiosurgical treatment of intracranial pathologies - best recognized after the treatment of patients with arteriovenous malformations and brain metastases but possibly also affecting patients treated with radiosurgery for meningioma. The pathophysiology of radiation necrosis is still not well understood but is most likely a secondary local tissue inflammatory response to brain tissue injured by radiation. Radiation necrosis in brain metastases patients may present radiographically and behave clinically like recurrent tumor. Differentiation between radiation necrosis and recurrent tumor has been difficult based on radiographic changes alone. Biopsy or craniotomy therefore remains the gold standard method of diagnosis. For symptomatic patients, corticosteroids are first-line therapy, but patients may fail medical management due to intolerance of chronic steroids or persistence of symptoms. In these cases, open surgical resection has been shown to be successful in management of surgically amenable lesions but may be suboptimal in patients with deep-seated lesions or extensive prior cranial surgical history, both carrying high risk for peri-operative morbidity. Laser interstitial thermal therapy has emerged as a viable, alternative surgical option. In addition to allowing access to tissue for diagnosis, thermal treatment of the lesion can also be delivered precisely and accurately under real-time imaging guidance. This review highlights the pertinent studies that have shaped the impetus for use of laser interstitial thermal therapy in the treatment of radiation necrosis, reviewing indications, outcomes, and nuances toward successful application of this technology in patients with suspected radiation necrosis.

Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain Stimulation.

Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy and are refractory to all current medical and surgical therapies in about one-sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the central lateral nucleus of the intralaminar thalamus (CL) and the pontine nucleus oralis (PnO) bilaterally during focal limbic seizures restored normal-appearing cortical electrophysiology and markedly improved behavioral arousal. In contrast, single-site bilateral stimulation of CL or PnO alone was insufficient to achieve the same result. These findings support the "network inhibition hypothesis" that focal limbic seizures impair consciousness through widespread inhibition of subcortical arousal. Driving subcortical arousal function would be a novel therapeutic approach to some forms of refractory epilepsy and may be compatible with devices already in use for responsive neurostimulation. Multisite deep brain stimulation of subcortical arousal structures may benefit not only patients with epilepsy but also those with other disorders of consciousness.

Venous Thromboembolism during Interventional MRI-Guided Stereotactic Surgery.

BACKGROUND/AIMS: Interventional MRI (iMRI) allows real-time confirmation of electrode and microcatheter location in anesthetized patients; however, MRI-compatible pneumatic compression devices (PCD) to reduce the periprocedural venous thromboembolism (VTE) risk are not commercially available. Given the paucity of literature on VTE following iMRI surgery, better characterizing patients suffering this complication and the incidence of this event following iMRI procedures is pivotal for defining best surgical practices. We aim to investigate the incidence of postoperative VTE in iMRI procedures without the use of PCD. METHODS: Medical records and operative times of patients were retrospectively reviewed. Patient demographics and mean surgical durations were reported with statistical comparisons via ANOVA and the 2-tailed Student t test, an α of 0.05, and the Bonferroni correction. Patients experiencing postoperative VTE underwent an in-depth chart review. RESULTS: Two out of two hundred ten (0.95%) iMRI procedures resulted in postoperative VTE events. There were statistically significant differences in procedure times between unilateral electrode (157.5 ± 5.7 min), bilateral electrode (193.6 ± 2.9 min), and bilateral gene therapy procedures (467.3 ± 26.5 min). Both patients had longer-than-average operative times for their respective procedures. CONCLUSIONS: The incidence of postoperative VTE is low following iMRI procedures, even without the use of PCD during surgery.

Neurostimulation to improve level of consciousness in patients with epilepsy.

When drug-resistant epilepsy is poorly localized or surgical resection is contraindicated, current neurostimulation strategies such as deep brain stimulation and vagal nerve stimulation can palliate the frequency or severity of seizures. However, despite medical and neuromodulatory therapy, a significant proportion of patients continue to experience disabling seizures that impair awareness, causing disability and risking injury or sudden unexplained death. We propose a novel strategy in which neuromodulation is used not only to reduce seizures but also to ameliorate impaired consciousness when the patient is in the ictal and postictal states. Improving or preventing alterations in level of consciousness may have an effect on morbidity (e.g., accidents, drownings, falls), risk for death, and quality of life. Recent studies may have elucidated underlying networks and mechanisms of impaired consciousness and yield potential novel targets for neuromodulation. The feasibility, benefits, and pitfalls of potential deep brain stimulation targets are illustrated in human and animal studies involving minimally conscious/vegetative states, movement disorders, depth of anesthesia, sleep-wake regulation, and epilepsy. We review evidence that viable therapeutic targets for impaired consciousness associated with seizures may be provided by key nodes of the consciousness system in the brainstem reticular activating system, hypothalamus, basal ganglia, thalamus, and basal forebrain.

Isolated unilateral alar ligamentous injury: illustrative cases.

BACKGROUND: Isolated unilateral alar ligament injury (IUALI) is a rare and likely underreported occurrence after upper cervical trauma, with only 16 cases documented in the literature to date. Patients generally present with neck pain, and definitive diagnosis is typically made by magnetic resonance imaging (MRI). Unfortunately, likely due in part to its rarity, there are no formal guidelines for the treatment of an IUALI. Furthermore, there is a limited understanding of the long-term consequences associated with its inadequate treatment. OBSERVATIONS: Here, the authors report on three pediatric patients, each found to have an IUALI after significant trauma. All patients presented with neck tenderness, and two of the three had associated pain-limited range of neck motion. Imaging revealed either a laterally deviated odontoid process on cervical radiographs and/or MRI evidence of ligamentous strain or discontinuity. Each patient was placed in a hard cervical collar for 1 to 2 months with excellent resolution of symptoms. A comprehensive review of the literature showed that all patients with IUALI who had undergone external immobilization with either rigid cervical collar or halo fixation had favorable outcomes at follow-up. LESSONS: For patients with IUALI, a moderate course of nonsurgical management with rigid external immobilization appears to be an adequate first-line treatment.

Primary intraosseous xanthoma of the frontal bone in a child: illustrative case.

BACKGROUND: Skull lesions are a common finding in children, with dermoid cysts and eosinophilic granulomas observed most frequently. However, primary intraosseous xanthomas of the calvaria, which are lytic, expansile lesions that develop without underlying hyperlipidemic disease, are rare in children, with only one prior case reported. OBSERVATIONS: The authors describe the case of a healthy 6-year-old male who presented with a 2-month history of an enlarging midline skull mass that developed after a recent minor trauma. Imaging showed a full-thickness, lytic frontal bone lesion with an aggressive appearance and heterogeneous contrast enhancement. The patient underwent gross-total resection of the lesion with placement of a mesh cranioplasty. Histopathology revealed a primary intraosseous xanthoma. The patient was discharged on postoperative day 2 and required no further treatment at the 1-month follow-up. LESSONS: This is the first reported case of a primary intraosseous xanthoma in the frontal bone of a pediatric patient. It emphasizes the need to include primary xanthomas in the differential diagnosis for pediatric skull lesions, particularly when the lesion has an aggressive radiographic appearance or the patient has a history of focal trauma. Furthermore, our findings indicate that resection, together with subsequent monitoring for lesion reccurrence, is an adequate first-line treatment.

Management of dynamic cervical kyphosis with dorsal epidural lipomatosis: a Hirayama disease variant? Illustrative case.

BACKGROUND: Hirayama disease, a cervical myelopathy characterized most commonly by a self-limiting atrophic weakness of the upper extremities, is a rare entity, scarcely reported in the literature. Diagnosis is made by spinal magnetic resonance imaging (MRI), which typically shows loss of normal cervical lordosis, anterior displacement of the cord during flexion, and a large epidural cervical fat pad. Treatment options include observation or cervical immobilization by collar or surgical decompression and fusion. OBSERVATIONS: Here, the authors report an unusual case of a Hirayama-like disease in a young White male athlete who presented with rapidly progressive paresthesia in all 4 extremities and no weakness. Imaging showed characteristic findings of Hirayama disease as well as worsened cervical kyphosis and spinal cord compression in cervical neck extension, which has not previously been reported. Two-level anterior cervical discectomy and fusion and posterior spinal fusion improved both cervical kyphosis on extension and symptoms. LESSONS: Given the disease's self-limiting nature, and a lack of current reporting, there remains no consensus on how to manage these patients. Such findings presented here demonstrate the potentially heterogeneous MRI findings that can be observed in Hirayama disease and emphasize the utility of aggressive surgical management in young, active patients whereby a cervical collar may not be tolerated.

Human genetics and molecular genomics of Chiari malformation type 1.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

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.

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10 -5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

Child Neurology: Functional Reorganization Mediating Supplementary Motor Area Syndrome Recovery in Agenesis of the Corpus Callosum.

Supplementary motor area (SMA) syndrome is a typically transient condition resulting from damage to the medial premotor cortex. The exact mechanism of recovery remains unknown but is traditionally described as a process involving functional compensation by the contralateral SMA through corpus callosal fibers. The purpose of this case study is to highlight a distinct extra-callosal mechanism of functional recovery from SMA syndrome in a patient with agenesis of the corpus callosum (ACC). We present the clinical presentation and perioperative functional neuroimaging features of a 16-year-old patient with complete ACC who exhibited recovery from an SMA syndrome resulting from surgical resection of a right-sided low-grade glioma. Preoperative functional MRI (fMRI) revealed anatomically concordant activation areas during finger and toe tapping tasks bilaterally. Three months following surgery, the patient had fully recovered, and a repeat fMRI revealed shift of the majority of the left toe tapping area from the expected contralateral hemisphere to the ipsilateral left paracentral lobule and SMA. The fMRI signal remodeling observed in this acallosal patient suggests that within-hemisphere plasticity of the healthy hemisphere may constitute an alternative critical process in SMA syndrome resolution and challenges the traditional view that transcallosal fibers are necessary for functional recovery.