Management of Choroid Plexus Tumors and the Benefit of Preoperative Embolization in Pediatric Patients: Report of 46 Cases from a Single Institution.

OBJECTIVE: Optimal choroid plexus tumor (CPT) treatment involves gross total resection; however, intraoperative hemorrhage risk remains significant given tumor vascularity. This study describes pediatric CPT management and identifies patients most likely to benefit from preoperative embolization. METHODS: CPTs resected from 1997 to 2021 were included. The characteristics of embolized patients were compared to nonembolized patients; nonembolized patients were further stratified based on open vascular control-pedicle feeder ligation versus no pedicle ligation prior to tumor debulking. Statistical analyses identified factors associated with estimated blood loss (EBL), transfusion, length of stay, and complications. RESULTS: Among the 46 CPT cases identified, 98% achieved gross total resection, and 15% received embolization. Embolized patients were younger, smaller, and had larger tumors compared to nonembolized patients (median: 0.8 vs. 2.1 years; 9.3 vs. 14.4 kg; 91.08 vs. 5.5 cm3). Transfused patients were similarly younger and smaller (P < 0.05) than nontransfused patients. Among nonembolized patients, open vascular control was achieved in smaller tumors (<13 cm3) with significantly lower EBL (P = 0.002). Higher EBL was observed in patients with larger tumors, hydrocephalus, transependymal edema, vomiting, lethargy, and developmental regression (all P < 0.05). Patients with lethargy had longer hospital stays and a higher likelihood of postoperative complications (P < 0.05). There were no significant differences in complication rates between the embolization and nonembolization groups. CONCLUSIONS: Despite higher surgical risk profiles, embolized patients had similar complication rates and postoperative hydrocephalus management as nonembolized patients. Embolization was particularly beneficial in patients at high risk for surgical morbidity, such as those <2 years, weighing <10 kg, and with a tumor volume >15 cm3.

Single-institution Series of Hirayama Disease in North America.

STUDY DESIGN: A retrospective chart review. OBJECTIVE: The aims of this study were to review pathophysiology, workup, and treatment for Hirayama disease (HD); and to assess outcomes from a single institution. SUMMARY OF BACKGROUND DATA: HD is a rare, painless, cervical myelopathy with distal upper extremity weakness, muscle wasting, and spinal cord atrophy. Disease progression-a consequence of repeat flexion injury-occurs up to 5 years from the initial diagnosis. METHODS: Single-institution review of pediatric HD patients from 2010 to 2020. RESULTS: Patients (n=10 male, n=2 female) presented in the second decade (14-20 y) with painless progressive distal upper extremity weakness and atrophy without sensory loss. Electromyography (n=12) demonstrated denervation in C7-T1 myotomes and flexion/extension magnetic resonance imaging showed focal cord atrophy and anterior displacement of the posterior dura with epidural enhancement in flexion. Treatment included observation and external orthoses (n=9) and anterior cervical discectomy with fusion (n=3). One of the 9 patients managed conservatively experienced further deterioration; no patient who underwent anterior cervical discectomy with fusion progressed. CONCLUSIONS: Patients with HD require a multidisciplinary approach to diagnosis and treatment to preserve function. Treatment is preventive and aims to minimize flexion injury by inhibiting motion across involved joints. First-line management is avoidance of neck flexion and use of rigid orthosis; in cases of failed conservative management and/or rapid clinical deterioration, surgical fixation can be offered.

Benefits and limitations of a dual faculty neurosurgeon approach to resection of pediatric craniopharyngioma.

PURPOSE: The utility and safety of including two neurosurgeons for tumor resections is unknown. This study compares outcomes among pediatric patients with craniopharyngiomas operated on with a dual or single surgeon approach (DSA, SSA). METHODS: A single-center review identified all craniopharyngioma transsphenoidal or craniotomy resections from 2000 to 2020. Surgical years of experience (YOE) and rates of 5-year reoperations, complications, recurrence, and postoperative radiotherapy were analyzed. RESULTS: Twenty-six transsphenoidal and 68 craniotomies were identified among 62 patients. Eleven transsphenoidal (42.3%) utilized DSA and 15 utilized (57.7%) SSA. Eight craniotomies (11.8%) were DSA and 60 (88.2%) were SSA. The surgeon for SSA transsphenoidal procedures had a median of 10.7 YOE (IQR: 9.9-13.7) versus 6.6 (IQR: 2.7-16; p = 0.058) for the lead surgeon in DSAs. The co-surgeon in transsphenoidal DSAs had a median of 27 YOE (IQR: 11.8-35.7). The surgeon for SSA craniotomies had a median of 19.3 YOE (IQR: 12.1-26.4) versus 4.5 years (IQR: 1.3-15.3; p = 0.017) for the lead surgeon in DSA cases. The co-surgeon in DSA craniotomies had a median of 23.2 YOE (IQR: 12.6-31.4). Case complexity was similar across transsphenoidal groups. DSA transsphenoidal resections had fewer complications (18% DSA vs. 33% SSA), reoperations (45% vs. 53%), and radiation therapy (9.1% DSA vs. 33% SSA) than SSA. CONCLUSION: Lead surgeons in DSAs are frequently junior surgeons while SSAs typically employ senior surgeons. Outcomes did not significantly differ between DSA and SSA. Mentorship through DSAs does not negatively affect patient care.

H3K27-altered diffuse midline gliomas with MAPK pathway alterations: Prognostic and therapeutic implications.

Large-scale sequencing led to the identification of driver molecular alterations such as FGFR1 and BRAF in occasional diffuse midline gliomas (DMGs) H3K27-mutant but their significance has not been completely explored. We evaluated these associations in our institutional cohorts. We searched our archives for H3K2M7-mutant gliomas and analyzed the co-occurring genetic alterations. The demographics, clinical information, and pathology were reviewed. Oncoplots and Kaplan-Meier survival curves were generated with the maftools R package. We identified 81 patients (age range 2-68, median 26), of which 79 (97%) were DMGs, and 2 were glioneuronal tumors. The 2 glioneuronal tumors (1 with BRAF fusion and 1 BRAF-V600E-mutant) were removed from the outcome analysis. Four cases had BRAF V600E mutation, 12 had FGFR1 hotspot mutations, and one each had KRAS and NRAS pathogenic mutations. The most common correlating anatomic location was the brainstem for the BRAF group and thalamus for the FGFR1group. Follow-up ranged from 0 to 78 months, average 20.4 months. The overall survival in FGFR1- and BRAF V600E-mutant DMGs was not statistically improved when compared with those that were wildtype. However, the possibility of targeted therapy argues for comprehensive sequencing of H3K27-altered gliomas.

Discovery and Characterization of Ephrin B2 and EphB4 Dysregulation and Novel Mutations in Cerebral Cavernous Malformations: In Vitro and Patient-Derived Evidence of Ephrin-Mediated Endothelial Cell Pathophysiology.

Intracranial vascular malformations manifest on a continuum ranging from predominantly arterial to predominantly venous in pathology. Cerebral cavernous malformations (CCMs) are capillary malformations that exist at the midpoint of this continuum. The axon guidance factor Ephrin B2 and its receptor EphB4 are critical regulators of vasculogenesis in the developing central nervous system. Ephrin B2/EphB4 dysregulation has been implicated in the pathogenesis of arterial-derived arteriovenous malformations and vein-based vein of Galen malformations. Increasing evidence supports the hypothesis that aberrant Ephrin B2/EphB4 signaling may contribute to developing vascular malformations, but their role in CCMs remains largely uncharacterized. Evidence of Ephrin dysregulation in CCMs would be important to establish a common link in the pathogenic spectrum of EphrinB2/Ephb4 dysregulation. By studying patient-derived primary CCM endothelial cells (CCMECs), we established that CCMECs are functionally distinct from healthy endothelial cell controls; CCMECs demonstrated altered patterns of migration, motility, and impaired tube formation. In addition to the altered phenotype, the CCMECs also displayed an increased ratio of EphrinB2/EphB4 compared to the healthy endothelial control cells. Furthermore, whole exome sequencing identified mutations in both EphrinB2 and EphB4 in the CCMECs. These findings identify functional alterations in the EphrinB2/EphB4 ratio as a feature linking pathophysiology across the spectrum of arterial, capillary, and venous structural malformations in the central nervous system while revealing a putative therapeutic target.

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.

Disease specific urinary biomarkers in the central nervous system.

Urinary biomarkers can diagnose and monitor pathophysiologic conditions in the central nervous system (CNS). However, focus is often on single diseases, with limited data on discriminatory capability of this approach in a general setting. Here, we demonstrate that different classes of CNS disease exhibit distinct biomarker patterns, evidence of disease-specific "fingerprinting." Urine from 218 patients with pathology-confirmed tumors or cerebrovascular disease, controls (n = 33) were collected. ELISA and/or bead-based multiplexing quantified levels of 21 putative urinary biomarkers. Analysis identified biomarkers capable of distinguishing each disease from controls and other diseases. Mann-Whitney U tests identified biomarkers with differential expression between disease types and controls (P ≤ 0.001). Subsequent receiver-operating characteristic (ROC) analyses revealed distinguishing biomarkers with high sensitivity and specificity. Areas under the curve (AUCs) ranged 0.8563-1.000 (P values ≤ 0.0003), sensitivities ranged 80.00-100.00%, and specificities ranged 80.95-100.00%. These data demonstrate proof-of-principle evidence that disease-specific urinary biomarker signatures exist. In contrast to non-specific responses to ischemia or injury, these results suggest that urinary biomarkers accurately reflect unique biological processes distinct to different diseases. This work can be used to generate disease-specific panels for enhancing diagnosis, assisting less-invasive follow-up and herald utility by revealing putative disease-specific therapeutic targets.

Use of intraoperative bone scintigraphy for resection of spinal osteoid osteoma.

BACKGROUND: The location and proximity to the spinal cord in spinal osteoid osteoma can increase the likelihood of an incomplete resection. Intraoperative bone scintigraphy (IOBS) can be used to verify location and complete surgical resection. OBJECTIVE: To review our experience using IOBS for resection of intraspinal osteoid osteoma. METHODS: IRB approved, retrospective review of IOBS-guided resection over 10 years. Patients underwent injection of 200 uCi/kg (1-20 mCi) 99mTc-MDP 3-4 h prior surgery. Portable single-headed gamma camera equipped with a pinhole collimator (3- or 4-mm aperture) was used. Images were obtained pre-operatively, at the start of the procedure, and intraoperatively. Operative notes were reviewed. Evaluation of recurrence and clinical follow-up was performed. RESULTS: Twenty IOBS-guided resections were performed in 18 patients (median age 13.5 years, 6-22 years, 12 males). Size ranged 5-16 mm, with 38.9% (7/18) cervical, 22.2% (4/18) thoracic, 22.2% (4/18) lumbar, and 16.7% (3/18) sacral. In all cases, IOBS was able to localize the lesion. After suspected total excision, IOBS altered the surgical plan in 75% of cases (15/20), showing residual activity prompting further resection. Median length of follow-up was 6 months (range 1-156 months) with 90% (18/20) showing complete resection without recurrence. Two patients had osteoid osteoma recurrence at 7 and 10 months following the original resection, requiring re-intervention. CONCLUSIONS: IOBS is a useful tool for real-time localization and assessment of spinal osteoid osteoma resection. In all cases, IOBS was able to localize the lesion and changed surgical planning in 75% of cases. Ninety percent of patients achieved complete resection and remain recurrence free.

The evolution of spinal cord surgery: history, people, instruments, and results.

INTRODUCTION: Spinal cord surgery has and always will be a challenging operation with satisfying results, but also with potentially devastating results. Over the last century, there has been an evolution in the way we perceive and conduct spinal cord surgery. The phenomenal evolution in technology from the very first x-ray pictures helps to localize the spinal pathology through the use of high-resolution MRI and ultrasonography that allows for high precision surgery with relatively minimal exposure. METHODS: The advancements in the surgical technique and the utilization of neuromonitoring allow for maximal safe resection of these delicate and intricate tumors. We also are beginning to understand the biology of spinal cord tumors and vascular lesions, as in the recent 2021 WHO classification which identifies specific entities such as spinal ependymomas, MYCN-amplified, as separate entity from the other subtypes of ependymomas. Surgeons have also accepted the importance of maximal safe resection for most of the spinal cord pathologies rather than just performing biopsy and adjuvant treatment. CONCLUSION: There have been significant advances since the first resection of an intramedullary tumor including diagnosis, imaging, and surgical technique for children. These advances have improved the prognosis and outcome in these children.

Endoscopic third ventriculostomy with choroid plexus cauterization: predictors of long-term success and comparison with shunt placement for primary treatment of infant hydrocephalus.

OBJECTIVE: Endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) can avoid ventriculoperitoneal shunt (VPS) dependence in very young hydrocephalic children, although long-term success as a primary treatment in North America has not been previously reported. Moreover, optimal age at surgery, impact of preoperative ventriculomegaly, and relationship to prior cerebrospinal fluid (CSF) diversion remain poorly defined. The authors compared ETV/CPC and VPS placement for averting reoperation, and they evaluated preoperative predictors for reoperation and shunt placement after ETV/CPC. METHODS: All patients under 12 months of age who underwent initial hydrocephalus treatment via ETV/CPC or VPS placement at Boston Children's Hospital between December 2008 and August 2021 were reviewed. Analyses included Cox regression for independent outcome predictors, and both Kaplan-Meier and log-rank rank tests for time-to-event outcomes. Cutoff values for age and preoperative frontal and occipital horn ratio (FOHR) were determined with receiver operating characteristic curve analysis and Youden's J index. RESULTS: In total, 348 children (150 females) were included with principal etiologies of posthemorrhagic hydrocephalus (26.7%), myelomeningocele (20.1%), and aqueduct stenosis (17.0%). Of these, 266 (76.4%) underwent ETV/CPC and 82 (23.6%) underwent VPS placement. Treatment choice largely reflected surgeon preferences before practice shifted toward endoscopy, with endoscopy not considered for > 70% of initial VPS cases. ETV/CPC patients trended toward fewer reoperations, and Kaplan-Meier analysis estimated that 59% of patients would achieve long-term shunt freedom through 11 years (median 42 months of actual follow-up). Among all patients, corrected age < 2.5 months (p < 0.001), prior temporizing CSF diversion (p = 0.003), and excess intraoperative bleeding (p < 0.001) independently predicted reoperation. Among ETV/CPC patients, corrected age < 2.5 months (p = 0.031), prior CSF diversion (p = 0.001), preoperative FOHR > 0.613 (p = 0.011), and excessive intraoperative bleeding (p = 0.001) independently predicted ultimate conversion to VPS. The actual VPS insertion rates remained low in patients who were ≥ 2.5 months old at ETV/CPC either with prior CSF diversion (2/10 [20.0%]) or without prior CSF diversion (24/123 [19.5%]); however, the actual VPS insertion rates increased in patients who were < 2.5 months old at ETV/CPC with prior CSF diversion (19/26 [73.1%]) or without prior CSF diversion (44/107 [41.1%]). CONCLUSIONS: ETV/CPC successfully treated hydrocephalus in most patients younger than 1 year irrespective of etiology, averting observed shunt dependence in 80% of patients ≥ 2.5 months of age regardless of prior CSF diversion and in 59% of those < 2.5 months of age without prior CSF diversion. For infants aged < 2.5 months with prior CSF diversion, particularly those with severe ventriculomegaly, ETV/CPC was unlikely to succeed unless safely delayed.

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.

ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma.

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.

Intracranial venous malformation masquerading as a meningioma in PI3KCA-related overgrowth spectrum disorder.

Gain of function PIK3CA pathogenic variants have been identified in overgrowth syndromes collectively termed "PIK3CA-related overgrowth spectrum" (PROS). There are no previously reported cases of cerebrovascular venous malformations in PROS syndromes, though somatic activating PIK3CA variants have been identified in extracranial venous malformation. This study was approved by the Institutional Review Boar at Boston Children's Hospital. A 14-year-old female mosaic for the de novo p.R108H pathogenic variant in the PIK3CA gene was found to have a large tumor involving the superior sagittal sinus with mass effect on the motor cortex most consistent with a parafalcine meningioma. She underwent surgical resection with pathology demonstrating a venous malformation. PIK3CA pathogenic variants have been identified in nonsyndromic extracranial venous and lymphatic malformations as well in brain tumors, including glioma and meningioma. However, PIK3CA variants have not previously been identified in purely intracranial venous malformations. This distinction is relevant to treatment decisions, given that mTOR inhibitors may provide an alternative option for noninvasive therapy in cases of suspected venous malformation.

Predictors of progression in radiation-induced versus nonradiation-induced pediatric meningiomas: a large single-institution surgical experience.

OBJECTIVE: The goal in this study was to outline unique differences between radiation-induced and nonradiation-induced pediatric meningiomas and to identify independent risk factors of tumor recurrence/progression. METHODS: This is a retrospective cohort study of all pediatric meningiomas diagnosed and surgically treated at the authors' institution between 1993 and 2017. Multivariable Cox regression was applied to identify independent risk factors for tumor recurrence/progression. RESULTS: Thirty-five patients were identified. The primary etiology was nonradiation-induced (n = 24: n = 3 with neurofibromatosis type 2) or radiation-induced (n = 11: acute lymphoblastic leukemia [n = 5], medulloblastoma [n = 4], germ cell tumor [n = 1], and primitive neuroectodermal tumor [n = 1]) meningioma. The mean age at time of diagnosis was 10.7 ± 5.7 years for nonradiation-induced and 17.3 ± 3.5 years for radiation-induced meningiomas. Overall, 8/24 patients with nonradiation-induced meningioma experienced either recurrence or progression of the tumor. Of the 8 patients with tumor recurrence or progression, the pathological diagnosis was clear cell meningioma (n = 3: 2 recurrent and 1 progressive); grade I (n = 2 progressive); grade I with atypical features (n = 2: 1 recurrent and 1 progressive); or atypical meningioma (n = 1 recurrent). None of the patients with radiation-induced meningioma experienced recurrence or progression. Predictors of tumor recurrence/progression by univariate analysis included age at time of diagnosis ≤ 10 years (p = 0.002), histological subtype clear cell meningioma (p = 0.003), and primary etiology nonradiation-induced meningioma (p = 0.04), and there was a notable trend with elevated MIB-1 staining index (SI) (p = 0.09). There was no significant difference between nonradiation-induced and radiation-induced meningiomas (p = 0.258), although there was a trend between recurrent and nonrecurrent meningiomas (p = 0.09). Multivariate Cox regression, adjusted for length of follow-up, identified younger age at diagnosis (p = 0.004) and a higher MIB-1 SI (p = 0.044) as independent risk factors for recurrence. Elevated MIB-1 SI statistically correlated with atypia (p < 0.001). However, there was no significant statistical correlation between tumor recurrence/progression and atypia (p = 0.2). CONCLUSIONS: Younger patient age and higher MIB-1 SI are independent risk factors for recurrence. Atypia was not a predictor of recurrence.

Low threshold for intracranial imaging in fever of unknown origin associated with cyanotic heart disease in the pediatric population.

Intracranial abscess in the pediatric population is an overall rare occurrence-4 in a million. The most common predisposing factor is underlying cyanotic congenital heart disease (CCHD), which is associated with ~ 30% of all cases. We present an unusual case of cerebral abscess in a 17-month-old female with partially treated Tetralogy of Fallot and fever of unknown origin without associated neurologic symptoms. We propose a low threshold for intracranial imaging as part of the fever of unknown origin work-up in children with underlying cyanotic congenital heart disease.

Single-institution case series of pituitary biopsy for suspected germinoma in the pediatric population: diagnostic utility, operative risks, and biopsy approaches.

Little has been reported on the safety and efficacy of pituitary biopsy in the pediatric population for suspected germinoma. An updated review is needed. Patients who underwent biopsy (endoscopic endonasal vs. open craniotomy) for isolated pituitary stalk thickening were identified. Age, pre- and post-operative endocrine status, surgical approach, length of surgery, estimated blood loss, surgical morbidity, length of ICU stay, total length of stay, and pathology reports were reviewed. Nine patients met inclusion criteria. Germinoma diagnosis was rendered in 7 of 9 patients; 1 patient required two biopsy attempts. Two-patients had histology consistent with inflammation and a subsequently self-limited disease course. Average operative time, blood loss, ICU stay and overall length of stay was just over 2 h, 28 mL, 1.6 days and 3.7 days respectively. There were no intraoperative complications and all patients were discharged home. One patient developed new diabetes insipidus post-operatively. Patients who underwent endoscopic biopsy had decreased operative times and shorter hospitalizations. Biopsy for isolated pituitary stalk thickening for suspected germinoma is generally safe with high diagnostic utility. Importantly, 22% of presumed germinomas on imaging yielded alternative diagnoses on biopsy, adding support for pathology-proven data to guide treatment in relevant cases.

Complex Management of Hydrocephalus Secondary To Choroid Plexus Hyperplasia.

BACKGROUND: Hyperplasia of the choroid plexus represents a rare cause of communicating hydrocephalus in children. Recent work has associated such disease with genetic abnormalities (such as perturbations in chromosome 9). Given such extensive cerebrospinal fluid (CSF) overproduction, patients with choroid plexus hyperplasia often fail CSF diversion and therefore require adjuvant interventions. CASE DESCRIPTION: We present the case of a male infant with a ventriculoperitoneal shunt and radiographic choroid hyperplasia who presented to our institution with a massive abdominal hydrocele caused by an inability to absorb the significant amount of CSF drainage into the abdomen. CONCLUSION: The child was treated with an endoscopic third ventriculostomy and choroid plexus coagulation; however, he still required CSF diversion via a ventriculoatrial shunt. A genetic workup showed tetraploidy of chromosome 9. We discuss criteria for selection of treatment strategies, including endoscopic third ventriculostomy with choroid plexus coagulation and/or CSF diversion, that may prevent the need for re-operation in select patients with hydrocephalus due to choroid plexus hyperplasia.

Dysregulation of the EphrinB2-EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients.

We investigated (1) EphrinB2 and EphB4 receptor expression in cerebral AVMs, (2) the impact of an altered EphrinB2:EphB4 ratio on brain endothelial cell function and (3) potential translational applications of these data. The following parameters were compared between AVM endothelial cells (AVMECs) and human brain microvascular endothelial cells (HBMVECs): quantified EphrinB2 and EphB4 expression, angiogenic potential, and responses to manipulation of the EphrinB2:EphB4 ratio via pharmacologic stimulation/inhibition. To investigate the clinical relevance of these in vitro data, Ephrin expression was assessed in AVM tissue (by immunohistochemistry) and urine (by ELISA) from pediatric patients with AVM (n = 30), other cerebrovascular disease (n = 14) and control patients (n = 29), and the data were subjected to univariate and multivariate statistical analyses. Compared to HBMVECs, AVMECs demonstrated increased invasion (p = 0.04) and migration (p = 0.08), impaired tube formation (p = 0.06) and increased EphrinB2:EphB4 ratios. Altering the EphrinB2:EphB4 ratio (by increasing EphrinB2 or blocking EphB4) in HBMVECs increased invasion (p = 0.03 and p < 0.05, respectively). EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients. Using the optimal urinary cutoff value (EphrinB2 > 25.7 pg/µg), AVMs were detected with high accuracy (80% vs. controls) and were distinguished from other cerebrovascular disease (75% accuracy). Post-treatment urinary EphrinB2 levels normalized in an index patient. In summary, AVMECs have an EphrinB2:EphB4 ratio that is increased compared to that of normal HBMVECs. Changing this ratio in HBMVECs induces AVMEC-like behavior. EphrinB2 is clinically relevant, and its levels are increased in AVM tissue and patient urine. This work suggests that dysregulation of the EphrinB2:EphB4 signaling cascade and increases in EphrinB2 may play a role in AVM development, with potential utility as a diagnostic and therapeutic target.