Reduction cranioplasty for hydrocephalic macrocephaly: a systematic review of surgical outcomes.

OBJECTIVE: Hydrocephalic macrocephaly can result in poor psychosocial development, positioning difficulties, skin breakdown, and poor cosmesis. Although reduction cranioplasty can address these sequelae, the postoperative outcomes, complications, and mortality risk of reduction cranioplasty are not well understood given the rarity of hydrocephalic macrocephaly. Therefore, the primary objective of this systematic review was to evaluate the surgical outcomes of reduction cranioplasty for the treatment of hydrocephalic macrocephaly. METHODS: A systematic review was performed using the PubMed, Scopus, and Web of Science databases while following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened 350 studies; 27 studies reporting surgical outcomes on reduction cranioplasty for hydrocephalic macrocephaly met inclusion criteria. Data on study design, patient demographics, operative details, and surgical outcomes were collected. RESULTS: There were 65 reduction cranioplasties among the 27 included studies. Eighteen (66.7%) studies presented level V evidence, 7 (25.9%) presented level IV evidence, and 2 (7.4%) presented level III evidence. Following reduction cranioplasty, there was improvement in postoperative head positioning in 23 (85.2%) studies, improvement in postoperative cosmesis in 22 (81.5%) studies, and improvement in global postoperative neurological functioning in 20 (74.1%) studies. The median estimated blood loss was 633 mL (range 20-2600 mL). Shunt revisions were the most common complication, reported in 9 (47.4%) of the 19 studies assessing complications. Of the 65 patients, there was a mortality rate of 6.2% (n = 4). CONCLUSIONS: The majority of the included studies reported improvement in head size, head positioning, cranial cosmesis, and global neurological functioning following reduction cranioplasty for hydrocephalic macrocephaly. However, the prevalence of lower-level evidence, risk of blood loss, complications, and mortality indicates the need for a serious discussion of surgical indication, an experienced team, and thorough perioperative planning to perform these complex surgeries.

Prospects of CSF shunt independence among chronically shunted patients.

BACKGROUND AND OBJECTIVES: CSF shunt placement for hydrocephalus and other etiologies has arguably been the most life-saving intervention in pediatric neurosurgery in the past 6 decades. Yet, chronic shunting remains a source of morbidity for patients of all ages. Neuroendoscopic surgery has made shunt independence possible for newly diagnosed hydrocephalic patients. In this study, we examine the prospects of shunt independence with or without endoscopic third ventriculostomy (ETV) in chronically shunted patients. METHODS: After IRB approval, a retrospective analysis was completed on patients whose shunt was ligated or removed to achieve shunt independence, with or without ETV. Clinical and imaging data were collected. RESULTS: Eighty-eight patients with CSF shunts had their shunt either ligated or removed, 57 of whom had a concomitant ETV. Original reasons for shunting included: congenital hydrocephalus 20 (23%), post-hemorrhagic hydrocephalus (PHH) of prematurity 14 (16%), aqueductal stenosis 10 (11%), intracranial cyst 8 (9%), tumor 8 (9%), infantile subdural hematomas 8 (9%), myelomeningocele 7 (8%), post-traumatic hydrocephalus 7 (8%) and post-infectious hydrocephalus 6 (7%). The decision to perform a simultaneous ETV was made based on etiology. Forty-nine (56%) patients became shunt independent. The success rate was 46% in the ETV group and 73% in the no ETV group. Using multivariate analysis and Cox Proportional Hazards models, age > 4 months at shunt placement (p = 0.032), no shunt revisions (p = 0.01), select etiologies (p = 0.043), and ETVSS > 70 (in the ETV group) (p = 0.017), were protective factors for shunt independence. CONCLUSION: Considering the long-term complications of shunting, achieving shunt independence may provide hope for improved quality of life. While this study is underpowered, it provides pilot data identifying factors that predict shunt independence in chronically shunted patients, namely age, absence of prior shunt revision, etiology, and in the ETV group, the ETVSS.

RosetteArray® Platform for Quantitative High-Throughput Screening of Human Neurodevelopmental Risk.

Neural organoids have revolutionized how human neurodevelopmental disorders (NDDs) are studied. Yet, their utility for screening complex NDD etiologies and in drug discovery is limited by a lack of scalable and quantifiable derivation formats. Here, we describe the RosetteArray® platform's ability to be used as an off-the-shelf, 96-well plate assay that standardizes incipient forebrain and spinal cord organoid morphogenesis as micropatterned, 3-D, singularly polarized neural rosette tissues (>9000 per plate). RosetteArrays are seeded from cryopreserved human pluripotent stem cells, cultured over 6-8 days, and immunostained images can be quantified using artificial intelligence-based software. We demonstrate the platform's suitability for screening developmental neurotoxicity and genetic and environmental factors known to cause neural tube defect risk. Given the presence of rosette morphogenesis perturbation in neural organoid models of NDDs and neurodegenerative disorders, the RosetteArray platform could enable quantitative high-throughput screening (qHTS) of human neurodevelopmental risk across regulatory and precision medicine applications.

The role of occipital condyle and atlas anomalies on occipital cervical fusion outcomes in Chiari malformation type I with syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF). METHODS: The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio. RESULTS: Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle-C2 sagittal vertical alignment (C-C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95). CONCLUSIONS: The authors' results indicate that the occipital condyle-atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

Mother-Daughter Ventricular Endoscopy: A Technical Note and 2-Dimensional Video.

BACKGROUND AND IMPORTANCE: While navigating the ventricles with a rigid endoscope provides excellent visualization and the ability to use endoscopic instruments for complex surgery, these endoscopes are often too large to navigate tight areas. We present a surgical video showing the technique of mother-daughter endoscopy, which consists of the introduction of a flexible 1-mm fiberoptic endoscope through the channel of a large rigid endoscope to allow visualization across small spaces or channels, in this case, the cerebral aqueduct. This combination of superior visualization and handling of rigid endoscopes and flexibility and small size of fiberoptic endoscopes enhances safety and broadens possibilities in ventricular surgery. CLINICAL PRESENTATION: A 64-year-old woman with prior endoscopic aqueductoplasty for triventricular hydrocephalus and a failed endoscopic third ventriculostomy presented with focal restenosis of the aqueduct. A repeat endoscopic aqueductoplasty with stent placement were performed. Mother-daughter endoscopy was used to explore the occluded aqueduct for improved safety before fenestration and to ensure proper stent placement after fenestration. CONCLUSION: Mother-daughter endoscopy can add safety to complex or high-risk endoscopic procedures, particularly those with tight spaces that the large mother endoscope cannot visualize.

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.

Intraoperative neural monitoring during head and neck surgery in patients with concern for cervical spine instability.

Cervical and craniocervical instability are associated with catastrophic procedural outcomes. We discuss three individuals who required otolaryngologic surgical intervention: two with symptomatic spinal instability and one in whom spinal stability was unable to be assessed. Two cases were managed with procedural positioning precautions and evoked potential monitoring, and the other with procedural positioning precautions alone. Methods of monitoring and triggers for repositioning are discussed. This series is intended to discuss the approach and potential added value of evoked potential monitoring for risk mitigation in pediatric patients with concern for cervical spine instability.

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.

Transgenerational epigenetic inheritance of axonal regeneration after spinal cord injury.

Human epidemiological studies reveal that dietary and environmental alterations influence the health of the offspring and that the effect is not limited to the F1 or F2 generations. Non-Mendelian transgenerational inheritance of traits in response to environmental stimuli has been confirmed in non-mammalian organisms including plants and worms and are shown to be epigenetically mediated. However, transgenerational inheritance beyond the F2 generation remains controversial in mammals. Our lab previously discovered that the treatment of rodents (rats and mice) with folic acid significantly enhances the regeneration of injured axons following spinal cord injury in vivo and in vitro, and the effect is mediated by DNA methylation. The potential heritability of DNA methylation prompted us to investigate the following question: Is the enhanced axonal regeneration phenotype inherited transgenerationally without exposure to folic acid supplementation in the intervening generations? In the present review, we condense our findings showing that a beneficial trait (i.e., enhanced axonal regeneration after spinal cord injury) and accompanying molecular alterations (i.e., DNA methylation), triggered by an environmental exposure (i.e., folic acid supplementation) to F0 animals only, are inherited transgenerationally and beyond the F3 generation.

Purified regenerating retinal neurons reveal regulatory role of DNA methylation-mediated Na+/K+-ATPase in murine axon regeneration.

While embryonic mammalian central nervous system (CNS) axons readily grow and differentiate, only a minority of fully differentiated mature CNS neurons are able to regenerate injured axons, leading to stunted functional recovery after injury and disease. To delineate DNA methylation changes specifically associated with axon regeneration, we used a Fluorescent-Activated Cell Sorting (FACS)-based methodology in a rat optic nerve transection model to segregate the injured retinal ganglion cells (RGCs) into regenerating and non-regenerating cell populations. Whole-genome DNA methylation profiling of these purified neurons revealed genes and pathways linked to mammalian RGC regeneration. Moreover, whole-methylome sequencing of purified uninjured adult and embryonic RGCs identified embryonic molecular profiles reactivated after injury in mature neurons, and others that correlate specifically with embryonic or adult axon growth, but not both. The results highlight the contribution to both embryonic growth and adult axon regeneration of subunits encoding the Na+/K+-ATPase. In turn, both biochemical and genetic inhibition of the Na+/K+-ATPase pump significantly reduced RGC axon regeneration. These data provide critical molecular insights into mammalian CNS axon regeneration, pinpoint the Na+/K+-ATPase as a key regulator of regeneration of injured mature CNS axons, and suggest that successful regeneration requires, in part, reactivation of embryonic signals.

Hemangioblastoma and mosaic von Hippel Lindau disease: rare presentation and review of the literature.

Hemangioblastomas are benign vascular tumors that can occur throughout the central nervous system (CNS) sporadically or in association with von Hippel-Lindau (VHL) disease. We present a case of an 11-year-old girl with a hemangioblastoma that tested negative for germline mutation of VHL disease at the time of diagnosis. Our patient went on to have multiple recurrences and further areas of concern for disease within the CNS. Repeat VHL testing was pursued many years later and remained negative for germline mutations. However, next-generation sequencing (NGS) testing on prior tumor tissue returned positive for VHL somatic mutations. The diagnosis of VHL mosaicism has important implications on management and risk of recurrence of hemangioblastoma, along with the need for close follow-up with surveillance imaging.

The Nomenclature of Chiari Malformations.

The current nomenclature of Chiari malformations includes the standard designations, Chiari 1-4, which were described by Hans Chiari in the late nineteenth century, and more recent additions, Chiari 0, 0.5, and 1.5, which emerged when the standard nomenclature failed to include important anatomical variations. The authors describe these entities and propose that to best optimize clinical care and research, it would be wise to place less focus on the eponyms and more effort on developing a descriptive or pathophysiological nomenclature.

Wide Arterial Sparing Encephalo-Duro-Synangiosis for Moyamoya: Surgical Technique and Outcomes.

BACKGROUND: Moyamoya is managed by surgical revascularization, but no standardized method has yet been universally adopted. OBJECTIVE: To describe a new indirect bypass technique for pediatric moyamoya, wide arterial sparing encephalo-duro-synangiosis (WASEDS), which provides a much wider area of revascularization with minimal compromise to the middle meningeal arterial tree compared with traditional procedures. Initially used as a salvage technique after failed encephalo-duro-arterio-synangiosis, its success later motivated its use as a first-line procedure. METHODS: Clinical and radiographic records of patients who underwent WASEDS for moyamoya from 2009 to 2020 were reviewed. Brain perfusion relative cerebral blood volume on the side of the WASEDS procedure was calculated. Two-tailed paired t tests were performed to identify the statistically significant differences ( P ≤ .05). RESULTS: WASEDS was successfully performed on 8 patients for a total of 14 cerebral hemispheres. Age ranged from 2 to 25 years. There were no mortalities. The average clinical and radiographic follow-up was 49.79 months (range 2-126 months), demonstrating improvement in neurological condition and no postoperative stroke and significant diminution or cessation of transient ischemic attacks in all patients. Relative cerebral blood volume increased 9.24% after the WASEDS procedure ( P = .012). There were no neurological complications. There were 2 pseudomeningoceles related to the extensive dural openings. CONCLUSION: WASEDS is a safe and effective indirect revascularization technique for both primary and salvage techniques. It provides an extensive area of cortical revascularization with no compromise of the middle meningeal vasculature and subjective reports of early improvement in cognition and behavior. The main disadvantage is elevated risk of pseudomeningocele secondary to the large craniotomy.

Complications and outcomes of posterior fossa decompression with duraplasty versus without duraplasty for pediatric patients with Chiari malformation type I and syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: The aim of this study was to determine differences in complications and outcomes between posterior fossa decompression with duraplasty (PFDD) and without duraplasty (PFD) for the treatment of pediatric Chiari malformation type I (CM1) and syringomyelia (SM). METHODS: The authors used retrospective and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM1-SM who received PFD or PFDD and had at least 1 year of follow-up data. Preoperative, treatment, and postoperative characteristics were recorded and compared between groups. RESULTS: A total of 692 patients met the inclusion criteria for this database study. PFD was performed in 117 (16.9%) and PFDD in 575 (83.1%) patients. The mean age at surgery was 9.86 years, and the mean follow-up time was 2.73 years. There were no significant differences in presenting signs or symptoms between groups, although the preoperative syrinx size was smaller in the PFD group. The PFD group had a shorter mean operating room time (p < 0.0001), fewer patients with > 50 mL of blood loss (p = 0.04), and shorter hospital stays (p = 0.0001). There were 4 intraoperative complications, all within the PFDD group (0.7%, p > 0.99). Patients undergoing PFDD had a 6-month complication rate of 24.3%, compared with 13.7% in the PFD group (p = 0.01). There were no differences between groups for postoperative complications beyond 6 months (p = 0.33). PFD patients were more likely to require revision surgery (17.9% vs 8.3%, p = 0.002). PFDD was associated with greater improvements in headaches (89.6% vs 80.8%, p = 0.04) and back pain (86.5% vs 59.1%, p = 0.01). There were no differences between groups for improvement in neurological examination findings. PFDD was associated with greater reduction in anteroposterior syrinx size (43.7% vs 26.9%, p = 0.0001) and syrinx length (18.9% vs 5.6%, p = 0.04) compared with PFD. CONCLUSIONS: PFD was associated with reduced operative time and blood loss, shorter hospital stays, and fewer postoperative complications within 6 months. However, PFDD was associated with better symptom improvement and reduction in syrinx size and lower rates of revision decompression. The two surgeries have low intraoperative complication rates and comparable complication rates beyond 6 months.

Intralesional glucocorticoid treatment of an isolated intracranial juvenile xanthogranuloma: a case report.

Juvenile xanthogranuloma is a type of non-Langerhans cell histiocytic process that appears primarily in children and is described as a benign lesion. Although they typically present as a cutaneous lesion, it can also present in other areas including within the central nervous system. We report a 6-month-old infant who presented with seizure-like activity who was found to have a single intracranial mass within the right temporal area on magnetic resonance imaging of the head. The mass was biopsied and pathologically identified as a juvenile xanthogranuloma. In order to avoid the morbidity associated with a gross total resection, an intralesional steroid injection was utilized for treatment which our patient tolerated well. Intralesional steroid injection for the treatment of a symptomatic isolated intracranial juvenile xanthogranuloma has not been described but was successful for our patient.

Socioeconomic and demographic factors in the diagnosis and treatment of Chiari malformation type I and syringomyelia.

OBJECTIVE: The goal of this study was to assess the social determinants that influence access and outcomes for pediatric neurosurgical care for patients with Chiari malformation type I (CM-I) and syringomyelia (SM). METHODS: The authors used retro- and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM-I and SM who received surgical treatment and had at least 1 year of follow-up data. Race, ethnicity, and insurance status were used as comparators for preoperative, treatment, and postoperative characteristics and outcomes. RESULTS: A total of 637 patients met inclusion criteria, and race or ethnicity data were available for 603 (94.7%) patients. A total of 463 (76.8%) were non-Hispanic White (NHW) and 140 (23.2%) were non-White. The non-White patients were older at diagnosis (p = 0.002) and were more likely to have an individualized education plan (p < 0.01). More non-White than NHW patients presented with cerebellar and cranial nerve deficits (i.e., gait ataxia [p = 0.028], nystagmus [p = 0.002], dysconjugate gaze [p = 0.03], hearing loss [p = 0.003], gait instability [p = 0.003], tremor [p = 0.021], or dysmetria [p < 0.001]). Non-White patients had higher rates of skull malformation (p = 0.004), platybasia (p = 0.002), and basilar invagination (p = 0.036). Non-White patients were more likely to be treated at low-volume centers than at high-volume centers (38.7% vs 15.2%; p < 0.01). Non-White patients were older at the time of surgery (p = 0.001) and had longer operative times (p < 0.001), higher estimated blood loss (p < 0.001), and a longer hospital stay (p = 0.04). There were no major group differences in terms of treatments performed or complications. The majority of subjects used private insurance (440, 71.5%), whereas 175 (28.5%) were using Medicaid or self-pay. Private insurance was used in 42.2% of non-White patients compared to 79.8% of NHW patients (p < 0.01). There were no major differences in presentation, treatment, or outcome between insurance groups. In multivariate modeling, non-White patients were more likely to present at an older age after controlling for sex and insurance status (p < 0.01). Non-White and male patients had a longer duration of symptoms before reaching diagnosis (p = 0.033 and 0.004, respectively). CONCLUSIONS: Socioeconomic and demographic factors appear to influence the presentation and management of patients with CM-I and SM. Race is associated with age and timing of diagnosis as well as operating room time, estimated blood loss, and length of hospital stay. This exploration of socioeconomic and demographic barriers to care will be useful in understanding how to improve access to pediatric neurosurgical care for patients with CM-I and SM.

Ventriculoperitoneal Shunt Drainage Increases With Gravity and Cerebrospinal Fluid Pressure Pulsations: Benchtop Model.

BACKGROUND: There have been few improvements in cerebrospinal fluid (CSF) shunt technology since John Holter introduced the silicon valve, with overdrainage remaining a major source of complications. OBJECTIVE: To better understand why valves are afflicted by supra-normal CSF flow rates. We present in Vitro benchtop analyses of flow through a differential pressure valve under simulated physiological conditions. METHODS: The pseudo-ventricle benchtop valve testing platform that comprises a rigid pseudo-ventricle, compliance chamber, pulsation generator, and pressure sensors was used to measure flow rates through a differential pressure shunt valve under the following simulated physiological conditions: orientation (horizontal/vertical), compliance (low/medium/high), and pulsation generator force (low/medium/high). RESULTS: Our data show that pulse pressures are faithfully transmitted from the ventricle to the valve, that lower compliance and higher pulse generator forces lead to higher pulse pressures in the pseudo-ventricle, and that both gravity and higher pulse pressure lead to higher flow rates. The presence of a valve mitigates but does not eliminate these higher flow rates. CONCLUSION: Shunt valves are prone to gravity-dependent overdrainage, which has motivated the development of gravitational valves and antisiphon devices. This study shows that overdrainage is not limited to the vertical position but that pulse pressures that simulate rhythmic (eg, cardiac) and provoked (eg, Valsalva) physiological CSF pulsations increase outflow in both the horizontal and vertical positions and are dependent on compliance. A deeper understanding of the physiological parameters that affect intracranial pressure and flow through shunt systems is prerequisite to the development of novel valves.