Clinical utility of DNA methylation profiling for choroid plexus tumors.

Background: Choroid plexus tumors (CPTs) are rare, potentially aggressive CNS tumors with defined histologic criteria for grading. In recent years, several patients within our practice have demonstrated discordance between the histologic diagnosis and clinical behavior. DNA methylation profiling has emerged as a potential diagnostic adjunct for aiding the clinical approach. Methods: We reviewed the clinical and pathologic data of all CPTs diagnosed at Boston Children's Hospital from 1995 to 2023. All cases with available material (38/48) underwent DNA methylation profiling at NIH/NCI, and the classifier results were correlated with the WHO histologic grade and patient outcomes. Survival information was analyzed using Kaplan-Meier curves. Results: There was good correlation (11/12, 92%) between methylation class and WHO histologic grade for choroid plexus carcinomas (CPC); one histologic CPC grouped with choroid plexus papilloma (CPP) group pediatric (P). Five CPPs grouped with methylation class CPC (5/17, 29%). In the group of atypical CPPs (n = 9), there were two that grouped with methylation class CPC. Survival analysis showed utility of methylation classes in the prediction of biologic behavior. Conclusions: Results indicated that methylation profiling may serve as a valuable tool in the clinical decision-making process for patients with CPTs, providing additional prognostic information compared to WHO histologic grade alone. The value of methylation array analysis is particularly important given the lack of consensus on treatment regimens for CPTs.

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.

Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences.

Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.

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.

Positioning Transclival Tumor-Treating Fields for the Treatment of Diffuse Intrinsic Pontine Gliomas.

Diffuse intrinsic pontine glioma (DIPG) carries an extremely poor prognosis, with 2-year survival rates of <10% despite the maximal radiation therapy. DIPG cells have previously been shown to be sensitive to low-intensity electric fields in vitro. Accordingly, we sought to determine if the endoscopic endonasal (EE) implantation of an electrode array in the clivus would be feasible for the application of tumor-treating fields (TTF) in DIPG. Anatomic constraints are the main limitation in pediatric EE approaches. In our Boston Children's Hospital's DIPG cohort, we measured the average intercarotid distance (1.68 ± 0.36 cm), clival width (1.62 ± 0.19 cm), and clival length from the base of the sella (1.43 ± 0.69 cm). Using a linear regression model, we found that only clival length and sphenoid pneumatization were significantly associated with age (R2 = 0.568, p = 0.005 *; R2 = 0.605, p = 0.0002 *). Critically, neither of these parameters represent limitations to the implantation of a device within the dimensions of those currently available. Our findings confirm that the anatomy present within this age group is amenable to the placement of a 2 × 1 cm electrode array in 94% of patients examined. Our work serves to demonstrate the feasibility of implantable transclival devices for the provision of TTFs as a novel adjunctive therapy for DIPG.

Machine Learning in the Classification of Pediatric Posterior Fossa Tumors: A Systematic Review.

Background: Posterior fossa tumors (PFTs) are a morbid group of central nervous system tumors that most often present in childhood. While early diagnosis is critical to drive appropriate treatment, definitive diagnosis is currently only achievable through invasive tissue collection and histopathological analyses. Machine learning has been investigated as an alternative means of diagnosis. In this systematic review and meta-analysis, we evaluated the primary literature to identify all machine learning algorithms developed to classify and diagnose pediatric PFTs using imaging or molecular data. Methods: Of the 433 primary papers identified in PubMed, EMBASE, and Web of Science, 25 ultimately met the inclusion criteria. The included papers were extracted for algorithm architecture, study parameters, performance, strengths, and limitations. Results: The algorithms exhibited variable performance based on sample size, classifier(s) used, and individual tumor types being investigated. Ependymoma, medulloblastoma, and pilocytic astrocytoma were the most studied tumors with algorithm accuracies ranging from 37.5% to 94.5%. A minority of studies compared the developed algorithm to a trained neuroradiologist, with three imaging-based algorithms yielding superior performance. Common algorithm and study limitations included small sample sizes, uneven representation of individual tumor types, inconsistent performance reporting, and a lack of application in the clinical environment. Conclusions: Artificial intelligence has the potential to improve the speed and accuracy of diagnosis in this field if the right algorithm is applied to the right scenario. Work is needed to standardize outcome reporting and facilitate additional trials to allow for clinical uptake.

Immunotherapy approaches for the treatment of diffuse midline gliomas.

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.

Pediatric Cranial Dog Bite Injuries: More than Meets the Eye.

CASE PRESENTATION: A six-month-old female presented to a community hospital with small lacerations to the scalp, face, and left eyelid from a dog bite injury. Computed tomography imaging revealed an impacted right frontal bone fracture and left superior orbital fracture, prompting transfer, neurosurgical repair, and infectious disease management of the injury. DISCUSSION: This report highlights the importance of having a high level of suspicion for deeper injury in pediatric and especially infant craniofacial dog bites, obtaining radiographic imaging, and initiating appropriate multidisciplinary triage to prevent life-threatening infection and complications.

Optic nerve compression in craniopharyngioma by taut anterior cerebral arteries visualized in frontal and transsphenoidal exposures: illustrative cases.

BACKGROUND: During initial exposure and removal of craniopharyngioma in pediatric patients with severe visual field deficits, the authors have encountered severe deformation of the optic apparatus by taut anterior cerebral arteries as seen during both frontal craniotomy and transsphenoidal exposures. OBSERVATIONS: The authors report two pediatric patients with craniopharyngioma whose severe preoperative visual deficits were associated not only with large suprasellar masses but also with severe optic nerve and chiasm compression by taut anterior cerebral arteries. In each patient, the optic nerves were partially cleft by these vessels' indenting them. LESSONS: The role of a taut anterior cerebral artery complex in compression of the optic apparatus in patients with suprasellar tumors has been reported previously, but the intraoperative images in these two cases dramatically reveal this phenomenon.

Variables Associated With Shunt Failure in Children With Cerebrospinal Fluid Diverting Shunts.

OBJECTIVES: We sought to identify clinical characteristics that would negatively predict shunt failure, thus potentially obviating the need for further diagnostic workup or extended periods of observation. We hypothesized that viral symptoms and a patient history of epilepsy or chronic headaches would be negative predictors of shunt failure. METHODS: Data were retrospectively collected for children 19 years or younger with a cerebrospinal fluid diverting shunt in their medical history or problem list who underwent neuroimaging during an ED visit from March 2008 to September 2016. Patients were defined as having shunt failure if they required surgical exploration for shunt revision within 7 days of the ED visit. Descriptive statistics were used for patient demographics, current symptoms, and historical features. We conducted a logistic regression analysis to determine which characteristics were associated with the odds of shunt failure and used binary recursive partitioning to determine if there were features or a combination of features that were able to accurately classify patients without shunt failure. RESULTS: There were 606 visits by 277 patients during this interval, 34% of whom were experiencing shunt failure. Variables found to be significantly predictive of shunt failure were revision within the prior 6 months, vomiting, personality changes, family opinion of shunt failure, and cranial nerve palsies. Viral symptoms and a history of epilepsy or chronic headaches were not predictive of shunt failure. Binary recursive partitioning identified family opinion and personality changes as predictive of shunt failure, with a sensitivity of 72.2% (95% confidence interval, 65.5%-78.2%) and specificity of 46.6% (95% confidence interval, 41.7%-51.7%). CONCLUSIONS: Although certain clinical and historical features have modest predictive value in children with shunted hydrocephalus, these factors are insufficiently sensitive to exclude shunt failure, arguing for liberal neuroimaging and extended observation.

Extradural decompression versus duraplasty in Chiari malformation type I with syrinx: outcomes on scoliosis from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: Scoliosis is common in patients with Chiari malformation type I (CM-I)-associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression. METHODS: A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty. RESULTS: In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion. CONCLUSIONS: In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD.

Management strategies for recurrent pediatric craniopharyngioma: new recommendations.

OBJECTIVE: The goal of this study was to identify the independent risk factors for recurrence or progression of pediatric craniopharyngioma and to establish predictors of the appropriate timing of intervention and best management strategy in the setting of recurrence/progression, with the aim of optimizing tumor control. METHODS: This is a retrospective cohort study of all pediatric patients with craniopharyngioma who were diagnosed and treated at Boston Children's Hospital between 1990 and 2017. This study was approved by the institutional review board at Boston Children's Hospital. All statistical analyses were performed using Stata software. RESULTS: Eighty patients (43 males and 37 females) fulfilled the inclusion criteria. The mean age at the time of diagnosis was 8.6 ± 4.4 years (range 1.2-19.7 years). The mean follow-up was 10.9 ± 6.5 years (range 1.3-24.6 years). Overall, 30/80 (37.5%) patients developed recurrence/progression. The median latency to recurrence/progression was 12.75 months (range 3-108 months). Subtotal resection with no adjuvant radiotherapy (p < 0.001) and fine calcifications (p = 0.008) are independent risk factors for recurrence/progression. An increase (%) in the maximum dimension of the tumor at the time of recurrence/progression was considered a statistically significant predictor of the appropriate timing of intervention. CONCLUSIONS: Based on the identified independent risk factors for tumor recurrence/progression and the predictors of appropriate timing of intervention in the setting of recurrence/progression, the authors propose an algorithm for optimal management of recurrent pediatric craniopharyngioma to increase the likelihood of tumor control.

Occipital-Cervical Fusion and Ventral Decompression in the Surgical Management of Chiari-1 Malformation and Syringomyelia: Analysis of Data From the Park-Reeves Syringomyelia Research Consortium.

BACKGROUND: Occipital-cervical fusion (OCF) and ventral decompression (VD) may be used in the treatment of pediatric Chiari-1 malformation (CM-1) with syringomyelia (SM) as adjuncts to posterior fossa decompression (PFD) for complex craniovertebral junction pathology. OBJECTIVE: To examine factors influencing the use of OCF and OCF/VD in a multicenter cohort of pediatric CM-1 and SM subjects treated with PFD. METHODS: The Park-Reeves Syringomyelia Research Consortium registry was used to examine 637 subjects with cerebellar tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and at least 1 yr of follow-up after their index PFD. Comparisons were made between subjects who received PFD alone and those with PFD + OCF or PFD + OCF/VD. RESULTS: All 637 patients underwent PFD, 505 (79.2%) with and 132 (20.8%) without duraplasty. A total of 12 subjects went on to have OCF at some point in their management (PFD + OCF), whereas 4 had OCF and VD (PFD + OCF/VD). Of those with complete data, a history of platybasia (3/10, P = .011), Klippel-Feil (2/10, P = .015), and basilar invagination (3/12, P < .001) were increased within the OCF group, whereas only basilar invagination (1/4, P < .001) was increased in the OCF/VD group. Clivo-axial angle (CXA) was significantly lower for both OCF (128.8 ± 15.3°, P = .008) and OCF/VD (115.0 ± 11.6°, P = .025) groups when compared to PFD-only group (145.3 ± 12.7°). pB-C2 did not differ among groups. CONCLUSION: Although PFD alone is adequate for treating the vast majority of CM-1/SM patients, OCF or OCF/VD may be occasionally utilized. Cranial base and spine pathologies and CXA may provide insight into the need for OCF and/or OCF/VD.

Postoperative MR imaging surveillance of pediatric craniopharyngioma: new institutional guidelines.

PURPOSE: To develop postoperative surveillance protocols that yield efficient detection rates of tumor recurrence or progression using fewer imaging studies and less cost. METHOD: This is a retrospective cohort study of all pediatric craniopharyngioma patients who have been diagnosed and treated at Boston Children's Hospital (BCH) between 1990 and 2017. All statistical analyses were performed using Stata. RESULTS: Eighty patients (43 males and 37 females) fulfilled the inclusion criteria. The mean age at time of diagnosis was 8.6 ± 4.4 years. The mean follow-up period was 10.9 ± 6.5 years. Overall 30/80 (37.5%) patients experienced tumor recurrence/progression. The median latency to recurrence/progression was 12.75 months (range 3 to 108 months), with 76.6% of the recurrences/progressions taking place within the first 2 years postoperatively. Given the lack of any clinical symptoms/signs associated with the vast majority of the recurrent/progressed cases, we propose postoperative MR imaging surveillance protocols that are substantially less intensive than the current practice. Therefore, we recommend the following postoperative MR imaging surveillance protocols, stratified by management strategies; 0, 9, 15, 36, 48, and 60 months for patients who underwent GTR, 0, 3, 6,12, 18, and 24 months for patients who underwent STR alone and 0, 3, 12, 72, 96, and 120 months for patients who underwent STR followed by subsequent XRT. CONCLUSION: The proposed postoperative MR imaging surveillance protocols would provide a potential 50% decrement of healthcare costs. It may also minify the psychological burden of frequent MR scanning for these patients and their families.

Measure Twice: Promise of Liquid Biopsy in Pediatric High-Grade Gliomas.

PURPOSE: To review and critique the current state of liquid biopsy in pHGG. MATERIALS AND METHODS: Published literature was reviewed for articles related to liquid biopsy in pediatric glioma and adult glioma with a focus on high-grade gliomas. RESULTS: This review discusses the current state of liquid biomarkers of pHGG and their potential applications for liquid biopsy development. CONCLUSIONS: While nascent, the progress toward identifying circulating analytes of pHGG primes the field of neuro-oncoogy for liquid biopsy development.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Treatment of Pediatric Hydrocephalus: Update of the 2014 Guidelines.

BACKGROUND: The Congress of Neurological Surgeons reviews its guidelines according to the Institute of Medicine's recommended best practice of reviewing guidelines every 5 yrs. The authors performed a planned 5-yr review of the medical literature used to develop the "Pediatric hydrocephalus: systematic literature review and evidence-based guidelines" and determined the need for an update to the original guideline based on new available evidence. OBJECTIVE: To perform an update to include the current medical literature for the "Pediatric hydrocephalus: systematic literature review and evidence-based guidelines", originally published in 2014. METHODS: The Guidelines Task Force used the search terms and strategies consistent with the original guidelines to search PubMed and Cochrane Central for relevant literature published between March 2012 and November 2019. The same inclusion/exclusion criteria were also used to screen abstracts and to perform the full-text review. Full text articles were then reviewed and when appropriate, included as evidence and recommendations were added or changed accordingly. RESULTS: A total of 41 studies yielded by the updated search met inclusion criteria and were included in this update. CONCLUSION: New literature resulting from the update yielded a new recommendation in Part 2, which states that neuro-endoscopic lavage is a feasible and safe option for the removal of intraventricular clots and may lower the rate of shunt placement (Level III). Additionally a recommendation in part 7 of the guideline now states that antibiotic-impregnated shunt tubing reduces the risk of shunt infection compared with conventional silicone hardware and should be used for children who require placement of a shunt (Level I). .

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Pediatric Myelomeningocele: Executive Summary.

BACKGROUND: The incidence of spina bifida (SB) in the developing world is higher than in the United States because of malnutrition and folic acid deficiency during pregnancy. Advances in technology have made prenatal repair of myelomeningocele (MM) possible. OBJECTIVE: The objective of the guidelines are, (1) To create clinical recommendations for best practices, based on a systematic review and analysis of available literature, (2) to obtain multi-disciplinary endorsement of these guidelines from relevant organizations, and (3) to disseminate the educational content to physicians to improve the care of infants with MM. METHODS: The Guidelines Task Force developed search terms and strategies used to search PubMed and Embase for literature published between 1966 and September 2016. Strict inclusion/exclusion criteria were used to screen abstracts and to develop a list of relevant articles for full-text review. RESULTS: Guidelines authors aimed to systematically review the literature and make evidence based recommendations about the timing of closure after birth, hydrocephalus, the impact of prenatal closure, and the effect of prenatal closure on ambulation ability and tethered spinal cord. Evidence concerning persistent ventriculomegaly and cognitive impairment was also evaluated. Hundreds of abstracts were identified and reviewed for each of the 5 topics. A total of 14 studies met stringent inclusion criteria. CONCLUSION: Based on a comprehensive systematic review, a total of 5 clinical practice recommendations were developed, with 1 Level I, 2 Level II and 2 Level III recommendations.The full guideline can be found at https://www.cns.org/guidelines/guidelines-spina-bifida-chapter-1.