Faculty Bibliography

Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders.

BACKGROUND:New-onset hydrocephalus following foramen magnum decompression (FMD) for Chiari I malformation (CM-I) is rare; its natural history and pathophysiology are poorly understood. OBJECTIVE:To describe a series of patients who developed hydrocephalus following FMD for CM-I, provide possible explanations of this phenomenon, and outline treatment options. METHODS:Out of patients undergoing FMD for CM-I from 6 different tertiary centers, we evaluated patients presenting with new-onset hydrocephalus following FMD. The retrospectively collected data included demographics, clinical, and radiological findings of the CM-I and hydrocephalus patients. Time from FMD and hydrocephalus onset, treatment, and surgical techniques were assessed. RESULTS:Of 549 patients who underwent FMD for CM-I, 28 (5.1%) subsequently developed hydrocephalus (18 females, 10 males), with a mean age of 11.7 ± 11.9 yr (range 6 mo to 52 yr). Hydrocephalus occurred on average 2.2 ± 2.6 mo after FMD (range 1 wk to 8 mo). Four patients did not have a violation of the arachnoid during the FMD surgery. Main presenting symptoms of hydrocephalus were headaches (17, 41%), vomiting (10, 24.4%), and cerebrospinal fluid (CSF) leak or pseudomeningocele (7, 17%).Overall, 23 patients (82.1%) underwent CSF shunting, 1 patient (3.5%) had an endoscopic third ventriculostomy, 3 patients (10.7%) temporary CSF diversion only, and 1 patient (3.5%) was treated with acetazolamide. CONCLUSION/CONCLUSIONS:Hydrocephalus following FMD for CM-I is uncommon, but important. Based on our series and literature review, its incidence is about 5% to 7% and most likely will require further surgery. Shunting appears to be the favored treatment option.

PURPOSE/OBJECTIVE:All treatments for childhood craniopharyngioma are associated with complications that potentially affect quality of life. This study was designed to investigate the impact of gross total resection on long-term quality of life and sexual functioning in adulthood. METHODS:Adults treated with primary gross total resection for childhood craniopharyngioma and ≥ 10 years of follow-up were included in this retrospective cohort study. The Short Form 36 Health Survey Questionnaire Version 2 (SF-36v2), Medical Outcomes Study (MOS) sexual functioning survey, and a sociodemographic/health questionnaire were administered. RESULTS:). Preoperative hypothalamic involvement correlated with a significantly higher BMI, although the proportion of participants with class 3 obesity (BMI ≥ 40) did not differ significantly from that of the general population (9% and 7%, respectively). CONCLUSIONS:Young adults with gross total resection of childhood craniopharyngioma report similar quality of life and sexual functioning compared to the general population, but appear to be less sexually active. Hypothalamic involvement on preoperative imaging was associated with a higher BMI in long-term follow-up.

PURPOSE/OBJECTIVE:Molecular subgroups of pediatric brain tumors associated with divergent biological, clinical, and prognostic features have been identified. However, data regarding the impact of subgroup affiliation on the outcome of children with malignant brain tumors treated with radiation-sparing protocol is limited. We report long-term clinical outcomes and the molecular subgroups of malignant brain tumors in young children whose first-line treatment was high-dose chemotherapy without irradiation. METHODS:Tumor subclassification was performed using the Illumina HumanMethylation450 BeadChip (450k) genome-wide methylation array profiling platform. Clinical information was obtained from chart review. RESULTS:Methylation array profiling yielded information on molecular subgroups in 22 children. Median age at surgery was 26 months (range 1-119 months). Among medulloblastomas (MB), all 6 children in the infant sonic hedgehog (SHH) subgroup were long-term survivors, whereas all 4 children in subgroup 3 MB died. There was one long-term survivor in subgroup 4 MB. One out of five children with ependymoma was a long-term survivor (RELPOS). Both children with primitive neuroectodermal tumors died. One child with ATRT TYR and one child with choroid plexus carcinoma were long-term survivors. CONCLUSIONS:The efficacy of high-dose chemotherapy radiation-sparing treatment appears to be confined to favorable molecular subgroups of pediatric brain tumors, such as infant SHH MB. Identification of molecular subgroups that benefit from radiation-sparing therapy will aid in the design of prospective, "precision medicine"-driven clinical trials.

BACKGROUND:Ventriculoatrial shunts can be afflicted with distal malfunctions due to thrombus formation at the distal tip. Distal tip thrombus formation may occur more commonly in oncologic patients who are predisposed to hypercoagulability. CASE DESCRIPTION/METHODS:A patient who had a ventriculo-atrial shunt placed for leptomeningeal carcinomatosis presented with headaches and confusion and was found to have a partial distal shunt obstruction. Intra-reservoir administration of alteplase resulted in resolution of her symptoms. Nuclear medicine shunt patency test demonstrated restoration of distal flow. CONCLUSIONS:Intra-reservoir administration of alteplase can be a useful non-operative treatment strategy for ventriculo-atrial shunt malfunction. This strategy may be particularly useful in cases with higher peri-operative risk, such as patients with advanced metastatic cancer.

OBJECTIVEThe choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs.METHODSA retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed.RESULTSThe 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children.CONCLUSIONSApproximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.

OBJECTIVE:Incomplete resection of neocortical epileptogenic foci correlates with failed epilepsy surgery in children. We often treat patients with neocortical epilepsy with a staged approach using invasive monitoring to localize the focus, resect the seizure onset zone, and, in select cases, post-resection invasive monitoring (PRM). We report the technique and the outcomes of children treated with staged surgery including PRM. METHODS:We retrospectively reviewed the charts of pediatric patients with neocortical epilepsy who underwent resective surgery with PRM. RESULTS:We identified 71 patients, 5 patients with MRI-negative epilepsy and 66 patients with MRI-identified neocortical lesions; 64/66 (97%) patients had complete lesionectomy. In 61/71 (86%) patients PRM was associated with positive outcomes. Those findings were: 1) clinical seizures with electrographic involvement at resection margins (47%); 2) subclinical seizures and interictal discharges at resection margins (29%); and 3) clinical and subclinical seizures revealing a new epileptogenic focus (20%). In 55/71 (77%) patients, PRM data led to additional resection (re-resection; RR). Six additional patients had no further resection due to overlap with eloquent cortex. Histopathology showed tuberous sclerosis complex (TSC; n = 46), focal cortical dysplasia (FCD; n = 16)), gliosis (n = 4), tumors (n = 4), and Sturge-Weber syndrome (n = 1). There were no major complications. Seizure-free outcome in children with TSC was 63% at 1-year follow-up and 56% at 2-year follow-up. In FCD, seizure freedom after 1 and 2 years was 85%. SIGNIFICANCE/CONCLUSIONS:Post-resection monitoring may provide additional information about the extent of the epileptogenic zone, such as residual epileptogenic activity at the margins of the resection cavity, and may unmask additional seizure foci. This method may be especially useful in achieving long-term stable seizure-free outcome.

OBJECTIVE:The majority of the 65 million people worldwide with epilepsy live in low- and middle-income countries. Many of these countries have inadequate resources to serve the large patient population affected by epilepsy. Panama is a middle-income country that currently has only 2 facilities that can provide basic epilepsy services and no epilepsy surgery services. To address this need, a group of Panamanian physicians partnered with U.S. epilepsy health care providers to test a hybrid epilepsy surgery program, combining resources and expertise. METHODS:From 2011 to 2017, a multidisciplinary team of neurologists, neurosurgeons, and an electroencephalography (EEG) technician from the United States traveled to Panama 6 times and, in collaboration with the local team, performed surgical procedures for intractable epilepsy at the national children's hospital. Resective surgeries were performed with intraoperative electrocorticography and/or implantation of subdural and depth electrodes and extra-operative monitoring. Cost was calculated using Panama government data. RESULTS:Twenty-seven children with intractable epilepsy were surgically treated. Fifteen children are seizure-free (Engle class I), 11 children are Engel II, and one child is Engel III. No major morbidity or mortality occurred, with only one postoperative infection. The average cost of treatment was calculated at $9850 per patient. SIGNIFICANCE/CONCLUSIONS:This program is a model for creating a multinational and multi-institutional collaboration to provide surgical epilepsy treatment in a middle-income country without an adequate infrastructure. To be successful, this collaboration needed to address medical, technical, and cultural challenges. This partnership helps to alleviate some of the present need for surgical epilepsy services while laying the groundwork for the development of a future local independent epilepsy surgery program.

OBJECTIVE: New onset hydrocephalus following foramen magnum decompression (FMD) for Chiari I malformation (CMI) is rare, and its natural history and pathophysiology is poorly understood. We describe a series of patients who presented with hydrocephalus following FMD for CMI, provide possible explanations of this condition, and outline treatment options. MATERIAL-METHODS: Of patients undergoing FMD for CMI from 6 different tertiary centres in North America, Europe and Middle East, we evaluated patients presenting with new onset hydrocephalus following the FMD. Retrospectively collected data included demographics, clinical and radiological findings of both the CMI and hydrocephalus, time from FMD and hydrocephalus onset, and treatment as well as surgical techniques. RESULTS: None of the patients had obvious symptoms related to idiopathic intracranial hypertension nor hydrocephalus prior to FMD. Of 367 patients who underwent FMD for CMI, 28 (7.6%) subsequently developed symptoms related to hydrocephalus (18 females-64.2%, and 10 males - 35.8%), (7 Le Bonheur Children's Hospital, 6 Tel Aviv Medical Center and Dana Children's Hospital, 6 Cincinnati Children's Hospital Medical Center, 5 Children's National Medical Center, 3 NYU Langone Medical Center, 1 Charite Universitatsmedizin) with a mean age of 11.7 +/- 11.9 years old (range 6 months to 52 years old). Hydrocephalus occurred on average 2.2 +/- 2.6 months after FMD (ranging from 1 week to 8 months). Presenting symptoms of hydrocephalus were headaches (41%), vomiting (24.4%), CSF leak/pseudomeningocele (17%), decreased level of consciousness (7.3%), cranial nerves signs (7.3%) and papilledema (2.4%). 23 patients (82.1%) underwent CSF shunting, 1 patient had an endoscopic third ventriculostomy (3.5%), 3 patients (10.7%) temporary CSF diversion only, and 1 patient (3.5%) acetazolamide. CONCLUSION: Hydrocephalus following FMD for CMI is uncommon. Based on our series and literature review, its incidence is ~7% and most likely will require further surgery. Considering different treatment options, shunting appears to be the favoured option