The purpose of this review is to highlight some of the pertinent concepts and controversies surrounding the diagnosis and treatment of pediatric supratentorial high-grade gliomas. Unlike the adult counterparts, pediatric high-grade gliomas are likely derived from distinct cytogenetic and molecular alterations. Surgery has been shown to play a role in extending patient survival. Some success is associated with the provision of chemotherapy. Radiotherapy remains an important adjunct in children older than age 3 years. The challenges involved in improving the poor prognosis of children in whom these very aggressive tumors have been diagnosed will be discussed, as well as some of the novel approaches being investigated to improve patient survival and quality of life.
Mandeep S. Tamber and James T. Rutka
Ann Marie Flannery, Ann-Christine Duhaime, Mandeep S. Tamber and Joanna Kemp
This systematic review was undertaken to answer the following question: Do technical adjuvants such as ventricular endoscopic placement, computer-assisted electromagnetic guidance, or ultrasound guidance improve ventricular shunt function and survival?
The US National Library of Medicine PubMed/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words specifically chosen to identify published articles detailing the use of cerebrospinal fluid shunts for the treatment of pediatric hydrocephalus. Articles meeting specific criteria that had been delineated a priori were then examined, and data were abstracted and compiled in evidentiary tables. These data were then analyzed by the Pediatric Hydrocephalus Systematic Review and Evidence-Based Guidelines Task Force to consider evidence-based treatment recommendations.
The search yielded 163 abstracts, which were screened for potential relevance to the application of technical adjuvants in shunt placement. Fourteen articles were selected for full-text review. One additional article was selected during a review of literature citations. Eight of these articles were included in the final recommendations concerning the use of endoscopy, ultrasonography, and electromagnetic image guidance during shunt placement, whereas the remaining articles were excluded due to poor evidence or lack of relevance.
The evidence included 1 Class I, 1 Class II, and 6 Class III papers. An evidentiary table of relevant articles was created.
Recommendation: There is insufficient evidence to recommend the use of endoscopic guidance for routine ventricular catheter placement. Strength of Recommendation: Level I, high degree of clinical certainty.
Recommendation: The routine use of ultrasound-assisted catheter placement is an option. Strength of Recommendation: Level III, unclear clinical certainty.
Recommendation: The routine use of computer-assisted electromagnetic (EM) navigation is an option. Strength of Recommendation: Level III, unclear clinical certainty.
Joanna Kemp, Ann Marie Flannery, Mandeep S. Tamber and Ann-Christine Duhaime
The objective of this guideline was to answer the following question: Do the entry point and position of the ventricular catheter have an effect on shunt function and survival?
Both the US National Library of Medicine/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words specifically chosen to identify published articles detailing the use of CSF shunts for the treatment of pediatric hydrocephalus. Articles meeting specific criteria that had been delineated a priori were then examined, and data were abstracted and compiled in evidentiary tables.
The search yielded 184 abstracts, which were screened for potential relevance to the clinical question of the effect of ventricular catheter entry site on shunt survival. An initial review of the abstracts identified 14 papers that met the inclusion criteria, and these were recalled for full-text review. After review of these articles, only 4 were noted to be relevant for an analysis of the impact of entry point on shunt survival; an additional paper was retrieved during the review of full-text articles and was included as evidence to support the recommendation. The evidence included 1 Class II paper and 4 Class III papers. An evidentiary table was created including the relevant articles.
Recommendation: There is insufficient evidence to recommend the occipital versus frontal point of entry for the ventricular catheter; therefore, both entry points are options for the treatment of pediatric hydrocephalus. Strength of Recommendation: Level III, unclear degree of clinical certainty.
Xiao Zhu, Michael M. McDowell, William C. Newman, Gary E. Mason, Stephanie Greene and Mandeep S. Tamber
Nivolumab is an immune checkpoint inhibitor (ICI) currently undergoing Phase III clinical trials for the treatment of glioblastoma. The authors present the case of a 10-year-old girl with glioblastoma treated with nivolumab under compassionate-use guidelines. After the first dose of nivolumab the patient developed hemiparesis, cerebral edema, and significant midline shift due to severe tumor necrosis. She was managed using intravenous dexamethasone and discharged on a dexamethasone taper. The patient's condition rapidly deteriorated after the second dose of nivolumab, demonstrating hemiplegia, seizures, and eventually unresponsiveness with a fixed and dilated left pupil. Computed tomography of her brain revealed malignant cerebral edema requiring emergency decompressive hemicraniectomy. Repeat imaging demonstrated increased size of the lesion, reflecting immune-mediated inflammation and tumor necrosis. The patient remained densely hemiplegic, but became progressively more interactive and was ultimately extubated. She resumed nivolumab several weeks later, but again her condition deteriorated with headache, vomiting, swelling at the craniectomy site, and limited right-sided facial movement following the sixth dose. MRI demonstrated severe midline shift and uncal herniation despite her craniectomy. Her condition gradually declined, and she died several days later under “do not resuscitate/do not intubate” orders. To the authors' knowledge, this represents the first case of malignant cerebral edema requiring operative intervention following nivolumab treatment for glioblastoma in a pediatric patient.
Mandeep S. Tamber, Paul Klimo Jr., Catherine A. Mazzola and Ann Marie Flannery
The objective of this systematic review was to answer the following question: What is the optimal treatment strategy for CSF shunt infection in pediatric patients with hydrocephalus?
The US National Library of Medicine and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I–III). Evidentiary tables were constructed that summarized pertinent study results, and based on the quality of the literature, recommendations were made (Levels I–III).
A review and critical appraisal of 27 studies that met the inclusion criteria allowed for a recommendation for supplementation of antibiotic treatment using partial (externalization) or complete shunt hardware removal, with a moderate degree of clinical certainty. However, a recommendation regarding whether complete shunt removal is favored over partial shunt removal (that is, externalization) could not be made owing to severe methodological deficiencies in the existing literature. There is insufficient evidence to recommend the use of intrathecal antibiotic therapy as an adjunct to systemic antibiotic therapy in the management of routine CSF shunt infections. This also holds true for other clinical scenarios such as when an infected CSF shunt cannot be completely removed, when a shunt must be removed and immediately replaced in the face of ongoing CSF infection, or when the setting is ventricular shunt infection caused by specific organisms (for example, gram-negative bacteria).
Supplementation of antibiotic treatment with partial (externalization) or complete shunt hardware removal are options in the management of CSF shunt infection. There is insufficient evidence to recommend either shunt externalization or complete shunt removal as the preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. In addition, there is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection when the infected shunt hardware cannot be fully removed, when the shunt must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use.
Recommendation: Supplementation of antibiotic treatment with partial (externalization) or with complete shunt hardware removal is an option in the management of CSF shunt infection. Strength of Recommendation: Level II, moderate degree of clinical certainty.
Recommendation: There is insufficient evidence to recommend either shunt externalization or complete shunt removal as a preferred surgical strategy for the management of CSF shunt infection. Therefore, clinical judgment is required. Strength of Recommendation: Level III, unclear degree of clinical certainty.
Recommendation: There is insufficient evidence to recommend the combination of intrathecal and systemic antibiotics for patients with CSF shunt infection in whom the infected shunt hardware cannot be fully removed or must be removed and immediately replaced, or when the CSF shunt infection is caused by specific organisms. The potential neurotoxicity of intrathecal antibiotic therapy may limit its routine use. Strength of Recommendation: Level III, unclear degree of clinical certainty.
James M. Drake, Jay Riva-Cambrin, Andrew Jea, Kurtis Auguste, Mandeep Tamber and Maria Lamberti-Pasculli
Complications of specific pediatric neurosurgical procedures are well recognized. However, focused surveillance on a specific neurosurgical unit, for all procedures, may lead to better understanding of the most important complications, and allow targeted strategies for quality improvement.
The authors prospectively recorded the morbidity and mortality events at a large pediatric neurosurgical unit over a 2-year period. Morbidity was defined as any significant adverse outcome or death (for obstructive shunt failure, within 30 days). Multiple and unrelated complications in the same patient were recorded as separate events.
There were 1082 surgical procedures performed during the evaluation period. One hundred seventy-seven complications (16.4%) occurred in 147 patients. By procedure, the most common complications occurred in vascular surgery (41.7%) and brain tumor surgery (27.9%). The most common complications were CSF leakage (31 cases), a new neurological deficit (27 cases), early shunt or endoscopic third ventriculostomy obstruction (27 cases), and shunt infection (24 cases). Meningitis occurred in 19 cases: in 58% of shunt infections, 13% of CSF leaks, and 10% of wound infections. Sixty-four percent of adverse events required a second procedure, most commonly an external ventricular drain placement or shunt revision.
Complications in pediatric neurosurgical procedures are common, result in significant morbidity, and more than half the time require a repeat surgical procedure. Targeted strategies to prevent common complications, such as shunt infections or CSF leaks, might significantly reduce this burden.
Abhaya V. Kulkarni, Jay Riva-Cambrin, Richard Holubkov, Samuel R. Browd, D. Douglas Cochrane, James M. Drake, David D. Limbrick, Curtis J. Rozzelle, Tamara D. Simon, Mandeep S. Tamber, John C. Wellons III, William E. Whitehead, John R. W. Kestle and for the Hydrocephalus Clinical Research Network
Endoscopic third ventriculostomy (ETV) is now established as a viable treatment option for a subgroup of children with hydrocephalus. Here, the authors report prospective, multicenter results from the Hydrocephalus Clinical Research Network (HCRN) to provide the most accurate determination of morbidity, complication incidence, and efficacy of ETV in children and to determine if intraoperative predictors of ETV success add substantially to preoperative predictors.
All children undergoing a first ETV (without choroid plexus cauterization) at 1 of 7 HCRN centers up to June 2013 were included in the study and followed up for a minimum of 18 months. Data, including detailed intraoperative data, were prospectively collected as part of the HCRN's Core Data Project and included details of patient characteristics, ETV failure (need for repeat hydrocephalus surgery), and, in a subset of patients, postoperative complications up to the time of discharge.
Three hundred thirty-six eligible children underwent initial ETV, 18.8% of whom had undergone shunt placement prior to the ETV. The median age at ETV was 6.9 years (IQR 1.7–12.6), with 15.2% of the study cohort younger than 12 months of age. The most common etiologies were aqueductal stenosis (24.8%) and midbrain or tectal lesions (21.2%). Visible forniceal injury (16.6%) was more common than previously reported, whereas severe bleeding (1.8%), thalamic contusion (1.8%), venous injury (1.5%), hypothalamic contusion (1.5%), and major arterial injury (0.3%) were rare. The most common postoperative complications were CSF leak (4.4%), hyponatremia (3.9%), and pseudomeningocele (3.9%). New neurological deficit occurred in 1.5% cases, with 0.5% being permanent.
One hundred forty-one patients had documented failure of their ETV requiring repeat hydrocephalus surgery during follow-up, 117 of them during the first 6 months postprocedure. Kaplan-Meier rates of 30-day, 90-day, 6-month, 1-year, and 2-year failure-free survival were 73.7%, 66.7%, 64.8%, 61.7%, and 57.8%, respectively. According to multivariate modeling, the preoperative ETV Success Score (ETVSS) was associated with ETV success (p < 0.001), as was the intraoperative ability to visualize a “naked” basilar artery (p = 0.023).
The authors' documented experience represents the most detailed account of ETV results in North America and provides the most accurate picture to date of ETV success and complications, based on contemporaneously collected prospective data. Serious complications with ETV are low. In addition to the ETVSS, visualization of a naked basilar artery is predictive of ETV success.
Abhaya V. Kulkarni, Jay Riva-Cambrin, Jerry Butler, Samuel R. Browd, James M. Drake, Richard Holubkov, John R. W. Kestle, David D. Limbrick, Tamara D. Simon, Mandeep S. Tamber, John C. Wellons III, William E. Whitehead and for the Hydrocephalus Clinical Research Network
The Hydrocephalus Clinical Research Network (HCRN), which comprises 7 pediatric neurosurgical centers in North America, provides a unique multicenter assessment of the current outcomes of CSF shunting in nonselected patients. The authors present the initial results for this cohort and compare them with results from prospective multicenter trials performed in the 1990s.
Analysis was restricted to patients with newly diagnosed hydrocephalus undergoing shunting for the first time. Detailed perioperative data from 2008 through 2012 for all HCRN centers were prospectively collected and centrally stored by trained research coordinators. Historical control data were obtained from the Shunt Design Trial (1993–1995) and the Endoscopic Shunt Insertion Trial (1996–1999). The primary outcome was time to first shunt failure, which was determined by using Cox regression survival analysis.
Mean age of the 1184 patients in the HCRN cohort was older than mean age of the 720 patients in the historical cohort (2.51 years vs 1.60 years, p < 0.0001). The distribution of etiologies differed (p < 0.0001, chi-square test); more tumors and fewer myelomeningoceles caused the hydrocephalus in the HCRN cohort patients. The hazard ratio for first shunt failure significantly favored the HCRN cohort, even after the model was adjusted for the prognostic effects of age and etiology (adjusted HR 0.82, 95% CI 0.69–0.96).
Current outcomes of shunting in general pediatric neurosurgery practice have improved over those from the 1990s, although the reasons remain unclear.
Abhaya V. Kulkarni, Jay Riva-Cambrin, Samuel R. Browd, James M. Drake, Richard Holubkov, John R. W. Kestle, David D. Limbrick, Curtis J. Rozzelle, Tamara D. Simon, Mandeep S. Tamber, John C. Wellons III and William E. Whitehead
The use of endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) has been advocated as an alternative to CSF shunting in infants with hydrocephalus. There are limited reports of this procedure in the North American population, however. The authors provide a retrospective review of the experience with combined ETV + CPC within the North American Hydrocephalus Clinical Research Network (HCRN).
All children (< 2 years old) who underwent an ETV + CPC at one of 7 HCRN centers before November 2012 were included. Data were collected retrospectively through review of hospital records and the HCRN registry. Comparisons were made to a contemporaneous cohort of 758 children who received their first shunt at < 2 years of age within the HCRN.
Thirty-six patients with ETV + CPC were included (13 with previous shunt). The etiologies of hydrocephalus were as follows: intraventricular hemorrhage of prematurity (9 patients), aqueductal stenosis (8), myelomeningocele (4), and other (15). There were no major intraoperative or early postoperative complications. There were 2 postoperative CSF infections. There were 2 deaths unrelated to hydrocephalus and 1 death from seizure. In 18 patients ETV + CPC failed at a median time of 30 days after surgery (range 4–484 days). The actuarial 3-, 6-, and 12-month success for ETV + CPC was 58%, 52%, and 52%. Time to treatment failure was slightly worse for the 36 patients with ETV + CPC compared with the 758 infants treated with shunts (p = 0.012). Near-complete CPC (≥ 90%) was achieved in 11 cases (31%) overall, but in 50% (10 of 20 cases) in 2012 versus 6% (1 of 16 cases) before 2012 (p = 0.009). Failure was higher in children with < 90% CPC (HR 4.39, 95% CI 0.999–19.2, p = 0.0501).
The early North American multicenter experience with ETV + CPC in infants demonstrates that the procedure has reasonable safety in selected cases. The degree of CPC achieved might be associated with a surgeon's learning curve and appears to affect success, suggesting that surgeon training might improve results.
Jay Riva-Cambrin, John R. W. Kestle, Curtis J. Rozzelle, Robert P. Naftel, Jessica S. Alvey, Ron W. Reeder, Richard Holubkov, Samuel R. Browd, D. Douglas Cochrane, David D. Limbrick Jr., Chevis N. Shannon, Tamara D. Simon, Mandeep S. Tamber, John C. Wellons III, William E. Whitehead, Abhaya V. Kulkarni and for the Hydrocephalus Clinical Research Network
Endoscopic third ventriculostomy combined with choroid plexus cauterization (ETV+CPC) has been adopted by many pediatric neurosurgeons as an alternative to placing shunts in infants with hydrocephalus. However, reported success rates have been highly variable, which may be secondary to patient selection, operative technique, and/or surgeon training. The objective of this prospective multicenter cohort study was to identify independent patient selection, operative technique, or surgical training predictors of ETV+CPC success in infants.
This was a prospective cohort study nested within the Hydrocephalus Clinical Research Network’s (HCRN) Core Data Project (registry). All infants under the age of 2 years who underwent a first ETV+CPC between June 2006 and March 2015 from 8 HCRN centers were included. Each patient had a minimum of 6 months of follow-up unless censored by an ETV+CPC failure. Patient and operative risk factors of failure were examined, as well as formal ETV+CPC training, which was defined as traveling to and working with the experienced surgeons at CURE Children’s Hospital of Uganda. ETV+CPC failure was defined as the need for repeat ETV, shunting, or death.
The study contained 191 patients with a primary ETV+CPC conducted by 17 pediatric neurosurgeons within the HCRN. Infants under 6 months corrected age at the time of ETV+CPC represented 79% of the cohort. Myelomeningocele (26%), intraventricular hemorrhage associated with prematurity (24%), and aqueductal stenosis (17%) were the most common etiologies. A total of 115 (60%) of the ETV+CPCs were conducted by surgeons after formal training. Overall, ETV+CPC was successful in 48%, 46%, and 45% of infants at 6 months, 1 year, and 18 months, respectively. Young age (< 1 month) (adjusted hazard ratio [aHR] 1.9, 95% CI 1.0–3.6) and an etiology of post–intraventricular hemorrhage secondary to prematurity (aHR 2.0, 95% CI 1.1–3.6) were the only two independent predictors of ETV+CPC failure. Specific subgroups of ages within etiology categories were identified as having higher ETV+CPC success rates. Although training led to more frequent use of the flexible scope (p < 0.001) and higher rates of complete (> 90%) CPC (p < 0.001), training itself was not independently associated (aHR 1.1, 95% CI 0.7–1.8; p = 0.63) with ETV+CPC success.
This is the largest prospective multicenter North American study to date examining ETV+CPC. Formal ETV+CPC training was not found to be associated with improved procedure outcomes. Specific subgroups of ages within specific hydrocephalus etiologies were identified that may preferentially benefit from ETV+CPC.