Robot-assisted stereoelectroencephalography in young children: technical challenges and considerations.

Robot-assisted stereoelectroencephalography (sEEG) is frequently employed to localize epileptogenic zones in patients with medically refractory epilepsy (MRE). Its methodology is well described in adults, but less so in children. Given the limited information available on pediatric applications, the objective is to describe the unique technical challenges and considerations of sEEG in the pediatric population. In this report, we describe our institutional experience with the technical aspects of robot-assisted sEEG in an exclusively pediatric epilepsy surgery unit, focusing on pre-, intra-, and post-operative nuances that are particular to the pediatric population. The pediatric population presents several unique challenges in sEEG, including reduced skull thickness relative to adults, incomplete neurologic development, and often special behavioral considerations. Pre-operative selection of putative epileptogenic zones requires careful multidisciplinary decision-making. Intraoperative attention to nuances in positioning, clamp selection, registration, and electrode placement are necessary. Activity considerations and electrode migration and removal are key post-operative considerations. Robot-assisted sEEG is a valuable tool in the armamentarium of techniques to characterize MRE. However, special considerations must be given to the pediatric population to optimize safety and efficacy.

Clinicopathologic characteristics of metastatic esophageal carcinoma isolated to the pineal region: A case report and review of the literature.

Metastasis to the pineal region is a rare event, and esophageal adenocarcinoma metastatic to the pineal region is exceptionally rare, with only two cases reported in the current literature. Here, we characterize a third case of metastatic esophageal adenocarcinoma to the pineal region, and compare clinicopathological characteristics among all three cases. The three patients were men, with ages at neurological presentation ranging from 48 to 65years. Time from initial esophageal adenocarcinoma diagnosis to development of neurologic symptoms ranged from 12 to 23months. Neuroimaging in all cases showed an isolated enhancing pineal region mass with sizes ranging from 1.8 to 2.2cm. All cases were believed to have local control of esophageal disease prior to metastatic sequela, with initial treatment including esophageal resection with or without chemoradiation therapy. No cases had evidence of primary site disease progression at time of metastatic presentation, nor were there signs of other sites of metastasis. All patients underwent tumor excision and were referred for subsequent radiotherapy. Overall, all three cases demonstrate similar demographics, histology, and clinical presentations. In the appropriate clinical setting it is important to keep esophageal metastasis in the differential diagnosis, particularly in the setting of isolated pineal lesions.

Natural History and Management of Blunt Traumatic Pseudoaneurysms of the Internal Carotid Artery: The Harborview Algorithm Based Off a 10-Year Experience.

OBJECTIVE: To define the natural history of, and treatment strategy for, blunt traumatic internal carotid artery (ICA) pseudoaneurysms. BACKGROUND: The natural history and management of traumatic ICA pseudoaneurysms is controversial. METHODS: We retrospectively identified all traumatic ICA pseudoaneurysms diagnosed on head/neck computed tomographic angiography at a high-volume trauma center over a 10-year period. Radiographic and clinical data were recorded, and a treatment algorithm was derived. RESULTS: Forty-three pseudoaneurysms were diagnosed in 39 patients. All patients were treated with daily aspirin unless contraindicated, and 82% underwent daily transcranial Doppler ultrasonography with embolic monitoring. A rate of 8 or more emboli per hour was predictive of embolic stroke (P = 0.0076). Acute ischemic or embolic stroke was seen in 7 patients (16%) with an overall mortality in this subpopulation of 42% (n = 3). Four patients (9%) underwent acute surgical treatment (parent vessel sacrifice and/or arterial bypass) for ongoing ischemia. Long-term radiographic and clinical follow-up was obtained for 36 surviving patients (mean = 8 months; range: 1 week-5 years), all of whom were maintained on daily aspirin. No delayed ischemic or embolic events were reported. For ICA pseudoaneurysms treated with aspirin and observation alone, 9 (28%) increased in size, 17 (53%) decreased or stabilized, and 6 (19%) resolved. Enlargement of 5 mm or more in maximal diameter underwent delayed endovascular treatment with a 100% obliteration rate and no complications. CONCLUSIONS: Traumatic ICA pseudoaneurysms are safely treated with daily aspirin, embolic monitoring, and radiographic surveillance. Acute stroke or hemorrhage, or delayed radiographic progression, are indications for endovascular or surgical treatment.

Embolization and Resection of Epidural Spinal Arteriovenous Malformations: Case Report.

BACKGROUND AND IMPORTANCE: Spinal vascular malformations (sVMs) are relatively uncommon, accounting for 5% to 10% of all spinal cord lesions. Spetzler and Kim developed a paradigm to classify sVMs based on a variety of characteristics into 1 of 6 types, including a subcategory for exclusively epidural sVMs. There is a paucity of literature focused on this category, specifically sources describing the clinical manifestation and management of these lesions. CLINICAL PRESENTATION: We report 2 cases of purely epidural spinal arteriovenous fistula, with an emphasis on the radiographic features and combined endovascular and microsurgical treatment. We report 2 patients known to have epidural spinal arteriovenous fistula who underwent both embolization and surgical resection between May 2019 and August 2020 at our institution. Data collected included demographic, clinical, and operative course, including age, sex, medical history, presenting symptoms, and preoperative and postoperative imaging. Both of these patients were managed with a combination of an endovascular approach for embolization of feeding arterial source and surgical exploration/resection. In both cases, no residual vascular malformation was identified, and the patients went on to be symptom free after 6 weeks. CONCLUSION: This report describes the use of a combination of endovascular and surgical approaches to achieve maximal benefit for 2 patients. These cases reinforce the value of a staged multimodal treatment approach in achieving good functional outcomes for patients with these rare and challenging entities.

Resolution of Primary or Recalcitrant Chiari-Associated Syringomyelia Requires Adequate Cerebrospinal Fluid Egress from the Fourth Ventricle.

Syringomyelia is often resistant to various treatment modalities.1 Chiari I malformations are associated with syringomyelia in approximately 69% of operative cases.2 Failure to resolve syringomyelia after Chiari decompression is common.3 The pathophysiology of Chiari-associated syringomyelia has been well studied, with Oldfield emphasizing the water-hammer mechanism, with treatment limited to bony decompression and duraplasty.4 On the other hand, capacious fourth ventricular drainage is thought to be essential for syrinx resolution. Persistence or progression of the syrinx after decompression is an indication for reoperation. Direct shunting of the syrinx is associated with high failure rates.1,5-7 The technique of shunting the fourth ventricle has been applied successfully in the pediatric population.3,8-10 We emphasize the need to ensure outflow from the fourth ventricle in Chiari decompressions associated with syringomyelia. In revisions to treat progressive syringomyelia after failed decompression, we undertake the following steps: 1) adequate lateral bony decompression,11-13 2) lysis of scar/adhesions around the cisterna magna, 3) opening the fourth ventricle outlet by releasing any web/adhesions, 4) insertion of a shunt from the fourth ventricle to the cervical subarachnoid space, and 5) bipolar coagulation of the lateral tonsillar pia to maintain patency of cerebrospinal fluid pathways.8 We favor autologous fascia or pericranium for expansile duraplasty, as the use of nonautologous materials may cause excessive scarring.14-16 In this video, we demonstrate these tenets in 3 cases of Chiari-associated syringomyelia, 2 revisions and 1 primary case, with excellent resolution of the syrinx (Video 1). The patients consented to surgery and publication of images.

Primary Intracranial Brainstem Malignant Melanoma: A Technical Case Report.

BACKGROUND AND IMPORTANCE: Primary intracranial malignant melanomas (PIMMs) are quite rare, comprising 1% of melanomas and 0.07% of intracranial tumors. PIMMs have been reported in a variety of intracranial locations, but there has only been 1 reported instance of PIMM occurring in the brainstem. In this study, we describe the second reported case of primary pontine malignant melanoma and its treatment. CLINICAL PRESENTATION: A 40-year-old man presented with right hemiparesis, diplopia, and dysarthria. MRI demonstrated a hemorrhagic, expansile, and heterogeneously enhancing lesion in the left pons with edema extending to the left thalamus and posterior limb of the internal capsule. Surgical resection was performed through a transpetrosal approach. Pathology resulted as malignant melanoma immunopositive for BRAF V600E mutation. Complete oncological workup revealed no other lesions; thus, he was diagnosed with PIMM of the brainstem. CONCLUSION: We report a rare case of primary pontine malignant melanoma in which microsurgical resection resulted in dramatic clinical improvement despite the challenging location. This is only the second reported case of brainstem PIMM. More patients with longer-term follow-up will be necessary to determine the best treatment approach.

A single-cell based precision medicine approach using glioblastoma patient-specific models.

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multi-omic single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multi-omic data with single-cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that modulate cell state transitions across subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches to an individual patient in a concurrent, adjuvant, or recurrent setting.

Somatic Mosaicism of a PDGFRB Activating Variant in Aneurysms of the Intracranial, Coronary, Aortic, and Radial Artery Vascular Beds.

Background Activating variants in platelet-derived growth factor receptor beta (PDGFRB), including a variant we have previously described (p.Tyr562Cys [g.149505130T>C [GRCh37/hg19]; c.1685A>G]), are associated with development of multiorgan pathology, including aneurysm formation. To investigate the association between the allele fraction genotype and histopathologic phenotype, we performed an expanded evaluation of post-mortem normal and aneurysmal tissue specimens from the previously published index patient. Methods and Results Following death due to diffuse subarachnoid hemorrhage in a patient with mosaic expression of the above PDGFRB variant, specimens from the intracranial, coronary, radial and aortic arteries were harvested. DNA was extracted and alternate allele fractions (AAF) of PDGFRB were determined using digital droplet PCR. Radiographic and histopathologic findings, together with genotype expression of PDGFRB were then correlated in aneurysmal tissue and compared to non-aneurysmal tissue. The PDGFRB variant was identified in the vertebral artery, basilar artery, and P1 segment aneurysms (AAF: 28.7%, 16.4%, and 17.8%, respectively). It was also identified in the coronary and radial artery aneurysms (AAF: 22.3% and 20.6%, respectively). In phenotypically normal intracranial and coronary artery tissues, the PDGFRB variant was not present. The PDGFRB variant was absent from lymphocyte DNA and normal tissue, confirming it to be a non-germline somatic variant. Primary cell cultures from a radial artery aneurysm localized the PDGFRB variant to CD31-, non-endothelial cells. Conclusions Constitutive expression of PDGFRB within the arterial wall is associated with the development of human fusiform aneurysms. The role of targeted therapy with tyrosine kinase inhibitors in fusiform aneurysms with PDGFRB mutations should be further studied.

WHO grade III meningioma: De novo tumors show improved progression free survival as compared to secondary progressive tumors.

Emerging evidence suggest WHO grade III meningiomas that arise de novo as opposed to dedifferentiating from a lower grade may harbor differing prognoses. To investigate this, a single institution retrospective analysis of prospectively acquired patients between 1999 and 2018 was performed. Clinical data and radiographic parameters were reviewed to calculate progression free survival and overall survival in patients undergoing microsurgical resection. Next generation targeted sequencing of meningioma associated genes was performed on 11 tumors. Eighteen patients were identified as undergoing surgical resection of WHO grade III meningioma. Nine patients (50%) had de novo arising tumors and nine patients had secondary progressive tumors. To compare outcomes, only those patients undergoing gross total resection (Simpson grade I) were included for survival analysis. There was an improvement in median progression free survival for de novo resected tumors as compared to secondary progressive tumors (p = 0.02). Median overall survival for patients with de novo tumors was not statistically improved compared to that of secondary progressive tumors (p = 0.22). Next generation sequencing of targeted genes (NF2, BAP1, TRAF7, KLF4, SMO and AKT) revealed 5/11 tumors containing mutations in the NF2 gene, 2/11 containing BAP1 mutations, and a single tumor containing mutations in both NF2 and TRAF7. More mutations in NF2 and BAP1 were seen in the secondary progressive tumors. In conclusion, patients undergoing gross total resection for de novo arising grade III meningiomas showed improved progression free survival, though similar overall survival, as compared to those patients with secondary progressive tumors. Further studies focused on tumor associated genes and other associated risk factors are needed to improve risk-stratification.

Computational modelling of perivascular-niche dynamics for the optimization of treatment schedules for glioblastoma.

Glioblastoma stem-like cells dynamically transition between a chemoradiation-resistant state and a chemoradiation-sensitive state. However, physical barriers in the tumour microenvironment restrict the delivery of chemotherapy to tumour compartments that are distant from blood vessels. Here, we show that a massively parallel computational model of the spatiotemporal dynamics of the perivascular niche that incorporates glioblastoma stem-like cells and differentiated tumour cells as well as relevant tissue-level phenomena can be used to optimize the administration schedules of concurrent radiation and temozolomide-the standard-of-care treatment for glioblastoma. In mice with platelet-derived growth factor (PDGF)-driven glioblastoma, the model-optimized treatment schedule increased the survival of the animals. For standard radiation fractionation in patients, the model predicts that chemotherapy may be optimally administered about one hour before radiation treatment. Computational models of the spatiotemporal dynamics of the tumour microenvironment could be used to predict tumour responses to a broader range of treatments and to optimize treatment regimens.

Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression.

Methods for quantifying gene expression1 and chromatin accessibility2 in single cells are well established, but single-cell analysis of chromatin regions with specific histone modifications has been technically challenging. In this study, we adapted the CUT&Tag method3 to scalable nanowell and droplet-based single-cell platforms to profile chromatin landscapes in single cells (scCUT&Tag) from complex tissues and during the differentiation of human embryonic stem cells. We focused on profiling polycomb group (PcG) silenced regions marked by histone H3 Lys27 trimethylation (H3K27me3) in single cells as an orthogonal approach to chromatin accessibility for identifying cell states. We show that scCUT&Tag profiling of H3K27me3 distinguishes cell types in human blood and allows the generation of cell-type-specific PcG landscapes from heterogeneous tissues. Furthermore, we used scCUT&Tag to profile H3K27me3 in a patient with a brain tumor before and after treatment, identifying cell types in the tumor microenvironment and heterogeneity in PcG activity in the primary sample and after treatment.

Timing of cranioplasty: a 10.75-year single-center analysis of 754 patients.

OBJECTIVE Despite their technical simplicity, cranioplasty procedures carry high reported morbidity rates. The authors here present the largest study to date on complications after cranioplasty, focusing specifically on the relationship between complications and timing of the operation. METHODS The authors retrospectively reviewed all cranioplasty cases performed at Harborview Medical Center over the past 10.75 years. In addition to relevant clinical and demographic characteristics, patient morbidity and mortality data were abstracted from the electronic medical record. Cox proportional-hazards models were used to analyze variables potentially associated with the risk of infection, hydrocephalus, seizure, hematoma, and bone flap resorption. RESULTS Over the course of 10.75 years, 754 cranioplasties were performed at a single institution. Sixty percent of the patients who underwent these cranioplasties were male, and the median follow-up overall was 233 days. The 30-day mortality rate was 0.26% (2 cases, both due to postoperative epidural hematoma). Overall, 24.6% percent of the patients experienced at least 1 complication including infection necessitating explantation of the flap (6.6%), postoperative hydrocephalus requiring a shunt (9.0%), resorption of the flap requiring synthetic cranioplasty (6.3%), seizure (4.1%), postoperative hematoma requiring evacuation (2.3%), and other (1.6%). The rate of infection was significantly higher if the cranioplasty had been performed < 14 days after the initial craniectomy (p = 0.007, Holm-Bonferroni-adjusted p = 0.028). Hydrocephalus was significantly correlated with time to cranioplasty (OR 0.92 per 10-day increase, p < 0.001) and was most common in patients whose cranioplasty had been performed < 90 days after initial craniectomy. New-onset seizure, however, only occurred in patients who had undergone their cranioplasty > 90 days after initial craniectomy. Bone flap resorption was the least likely complication for patients whose cranioplasty had been performed between 15 and 30 days after initial craniectomy. Resorption was also correlated with patient age, with a hazard ratio of 0.67 per increase of 10 years of age (p = 0.001). CONCLUSIONS Cranioplasty performed between 15 and 30 days after initial craniectomy may minimize infection, seizure, and bone flap resorption, whereas waiting > 90 days may minimize hydrocephalus but may increase the risk of seizure.

Interlaminar endoscopic lateral recess decompression-surgical technique and early clinical results.

BACKGROUND: Lateral recess stenosis is a common pathology causing de-novo or residual radicular pain following lumbar spine surgery. Diagnostic criteria and treatment strategies for symptomatic lateral recess stenosis are not well established. METHODS: We identified ten patients in our prospective patient database (n=146) who underwent endoscopic interlaminar decompression for unilateral symptomatic lateral recess stenosis. Lateral recess height and angle were measured on axial T2-weighted MRI. Values from the symptomatic side were compared to the contralateral side which served as asymptomatic control. Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) for back and leg pain were collected preoperatively, postoperatively and at last follow-up. RESULTS: Preoperative MRI revealed that both lateral recess angle and height were significantly smaller on the symptomatic compared to the asymptomatic side (angle: 19.3° vs. 35.7°; height: 2.9 vs. 5.7 mm; P<0.01). All patients tolerated endoscopic interlaminar decompression well and half of the patients were discharged on the day of surgery. At last follow-up (12.6±1.7 months), 8 out of 10 patients experienced a minimally clinically important improvement of their VAS for ipsilateral leg pain, which improved from 7.2±0.5 preoperatively to 2.5±0.8 postoperatively (P=0.001). The back pain VAS also improved (preoperatively 5.1±1.1 vs. postoperatively 1.7±0.9, P<0.05). The ODI improved from 50±5.8 preoperatively to 22.2±5.1 at last follow-up (P=0.001). One patient experienced persistent leg pain. CONCLUSIONS: Lateral recess height and angle correlate with symptomatic lateral recess stenosis which is effectively treated utilizing interlaminar endoscopic lateral recess decompression.

Risk of Complications with Simultaneous Cranioplasty and Placement of Ventriculoperitoneal Shunt.

BACKGROUND: The development of hydrocephalus (HCP) necessitating placement of a ventriculoperitoneal shunt (VPS) after decompressive hemicraniectomy occurs at a rate of approximately 5%-15%. The ideal approach for addressing both HCP and a cranial defect remains unclear, and whether concomitant VPS and cranioplasty (CP) increases the risk of complications is uncertain. METHODS: This is a retrospective cohort study of adult patients who underwent CP and VPS placement for any indication at Harborview Medical Center, Seattle between March 2004 and November 2014 with at least 30 days of follow-up. The primary variable of interest was the timing of CP relative to VPS placement. The outcomes of interest were CP- and VPS-related infections, early (within 1 year of placement) VPS obstruction, and a composite of any of these complications in a single patient. RESULTS: The rate of composite outcomes was 15% in the subgroup of patients with simultaneous CP and VPS placement, compared with 29% in the subgroup of patients in whom CP and VPS placement were performed separately, a non-statistically significant difference (P = 0.24). Similarly, there was no statistically significant difference between the subgroups in any of the 3 individual outcomes of interest, which remained after accounting for potential covariates in a multivariate regression model. CONCLUSIONS: In our study population, there was no difference between simultaneous and separate CP and VPS placement with respect to CP infection, VPS infection, and VPS mechanical failure/obstruction. There is equipoise in the current literature regarding the safety of performing these 2 common procedures simultaneously, with studies of similar size and design finding variable degrees of safety of this practice.