Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

MRI and pathology comparisons in Rasmussen's encephalitis: a multi-institutional examination of hemispherotomy outcomes relative to imaging and histological severity.

PURPOSE: Rasmussen encephalitis (RE) is a very rare chronic neurological disorder of unilateral inflammation of the cerebral cortex. Hemispherotomy provides the best chance at achieving seizure freedom in RE patients, but with significant risks and variable long-term outcomes. The goal of this study is to utilize our multicenter pediatric cohort to characterize if differences in pathology and/or imaging characterization of RE may provide a window into post-operative seizure outcomes, which in turn could guide decision-making for parents and healthcare providers. METHODS: This multi-institutional retrospective review of medical record, imaging, and pathology samples was approved by each individual institution's review board. Data was collected from all known pediatric cases of peri-insular functional hemispherotomy from the earliest available electronic medical records. Mean follow-up time was 4.9 years. Clinical outcomes were measured by last follow-up visit using both Engel and ILAE scoring systems. Relationships between categorical and continuous variables were analyzed with Pearson correlation values. RESULTS: Twenty-seven patients met study criteria. No statistically significant correlations existed between patient imaging and pathology data. Pathology stage, MRI brain imaging stages, and a combined assessment of pathology and imaging stages showed no statistically significant correlation to post-operative seizure freedom rates. Hemispherectomy Outcome Prediction Scale scoring demonstrated seizure freedom in only 71% of patients receiving a score of 1 and 36% of patients receiving a score of 2 which were substantially lower than predicted. CONCLUSIONS: Our analysis did not find evidence for either independent or combined analysis of imaging and pathology staging being predictive for post peri-insular hemispherotomy seizure outcomes, prompting the need for other biomarkers to be explored. Our data stands in contrast to the recently proposed Hemispherectomy Outcome Prediction Scale and does not externally validate this metric for an RE cohort.

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

An unusual presentation of bilateral optic pathway glioma in Crouzon Syndrome.

Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Predictors of mortality and tumor recurrence in desmoplastic infantile ganglioglioma and astrocytoma-and individual participant data meta-analysis (IPDMA).

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Intraoperative Phase Contrast MRI Analysis of Cerebrospinal Fluid Velocities During Posterior Fossa Decompression for Chiari I Malformation.

BACKGROUND: Cerebrospinal fluid (CSF) velocity at the craniovertebral junction (CVJ) is known to be altered in patients with Chiari I malformation (CMI), and normalization of CSF velocities is associated with symptom resolution. However, preoperative and intraoperative prediction methods have thus far failed to identify patients in whom CSF velocities can be normalized with posterior fossa decompression (PFD) without duraplasty. Phase contrast MRI (PC-MRI) may assist not only in diagnosis of CMI but also in guiding the intraoperative decision to perform duraplasty during PFD. PURPOSE: To use intraoperative MRI data to quantify changes in CSF hydrodynamics at the CVJ during each step of PFD with duraplasty (PFDD) in 12 consecutive patients. STUDY TYPE: Retrospective case series with all patients imaged before, during and after decompression, and all data analyzed postprocedure. POPULATION/SUBJECTS: Pediatric patients, mean age 14 years (range 4-18), undergoing PFD for CMI. FIELD STRENGTH/SEQUENCE: Intraoperative studies involved a dedicated 1.5T Siemens MRI imager. PC-MRI scans were in the axial plane at the CVJ. ASSESSMENT: Two observers assessed measurements. STATISTICAL TEST: The equality of matched pairs of observations was tested using the Wilcoxon matched-pairs signed-ranks test. RESULTS: Data analyses of the PC-MRI demonstrated a marked and immediate increase in CSF velocity at the posterior CVJ during PFDD. Mean cranially-directed velocities increased by a mean of 1.049cm/s (P = 0.028) from preincision to postoperative measurement. There was a mean 0.45 cm/s (P = 0.022) increase in mean cranial velocity from preincision to bone decompression scans, and a mean 0.48 cm/s (P = 0.018) increase in mean velocity from preincision to duraplasty. DATA CONCLUSION: In all subjects, significant increases in the mean and peak velocities of cranially- and caudally-directed velocities were observed from preincision to post-PFDD scans at the posterior CVJ. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;51:1463-1470.

Detection of immune responses after immunotherapy in glioblastoma using PET and MRI.

Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.

Survival in pediatric medulloblastoma: a population-based observational study to improve prognostication.

Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30-0.46, p < 0.001) and Surgery (HR 0.42; 95% CI 0.30-0.58, p < 0.001) independently predict survival. The probability of mortality from a neurological cause is <5% in patients who are alive 8 years following diagnosis. The SEER cohort analysis demonstrates significant improvements in pediatric medulloblastoma survival. In contrast to previous reports, the majority of patients survive in the modern era, and those alive 8 years following initial diagnosis are likely a long-term survivor. The importance of minimizing treatment-related toxicity is increasingly apparent given the likelihood of long-term survival.

Lateral parietal arteriovenous malformation with feeding artery aneurysm.

Superficial arteriovenous malformations (AVMs) with favorable Spetzler-Martin grading are amenable to primary surgical resection. Careful preoperative workup including preoperative angiograms is essential to identify feeding artery aneurysms and deep venous drainage. The authors present a 37-year-old female who presented with a Spetzler-Martin Grade II right parietal superficial AVM with a 5-mm feeding artery aneurysm from the posterior cerebral artery. Given the risk of hemorrhage, the AVM was resected completely without any complications. On subsequent postoperative angiograms, the feeding artery aneurysm diminished in caliber. Feeding artery aneurysms may regress spontaneously after resection of an AVM due to flow-related changes. The video can be found here: https://youtu.be/PpwODc9iI3g .

Extradural clinoidectomy for resection of clinoidal meningioma.

Extradural anterior clinoidectomy is a versatile technique to increase exposure of the sellar and parasellar region. It is of particular use in the resection of clinoidal meningiomas, as sphenoidal and clinoidal hyperostosis can cause compression of the optic nerve. Extradural clinoidectomy follows a series of steps, consisting of (1) unroofing of the superior orbital fissure, (2) unroofing of the optic canal, (3) removal of the optic strut, and (4) removal of the anterior clinoid process. The authors show these steps in detail, as well as their application to the resection of a large clinoidal meningioma. The video can be found here: https://youtu.be/O1Fcef29ETg .

Efficacy and safety of endoscopic third ventriculostomy and choroid plexus cauterization for infantile hydrocephalus: a systematic review and meta-analysis.

PURPOSE: Endoscopic third ventriculostomy/choroid plexus cauterization (ETV/CPC) has gained popularity in its treatment of infantile hydrocephalus over the past decade. In this manuscript, we perform a systematic review and meta-analysis to determine the efficacy and safety of ETV/CPC, and to compare the procedural outcomes between North American and sub-Saharan African cohorts. METHODS: Systematic review was performed using four electronic databases and bibliographies of relevant articles, with no language or date restrictions. Cohort studies of participants undergoing ETV/CPC that reported outcome were included using MOOSE guidelines. The outcome was time to repeat CSF diversion or death. Forest plots were created for pooled mean and its 95 % CI of outcome and morbidity. RESULTS: Of 78 citations, 11 retrospective reviews (with 524 total participants) were eligible. Efficacy was achieved in 63 % participants at follow-up periods between 6 months and 8 years. Adverse events and mortality was reported in 3.7 and 0.4 % of participants, respectively. Publication bias was detected with respect to efficacy and morbidity of the procedure. A large discrepancy in success was identified between ETV/CPC in six studies from sub-Saharan Africa (71 %), compared to three studies from North America (49 %). CONCLUSIONS: The reported success of ETV/CPC for infantile hydrocephalus is higher in sub-Saharan Africa than developed nations. Large long-term prospective multi-center observational studies addressing patient-important outcomes are required to further evaluate the efficacy and safety of this re-emerging procedure.

Stereotactic laser ablation for hypothalamic and deep intraventricular lesions.

OBJECTIVE Laser ablation is a novel, minimally invasive procedure that utilizes MRI-guided thermal energy to treat epileptogenic and other brain lesions. In addition to treatment of mesial temporal lobe epilepsy, laser ablation is increasingly being used to target deep or inoperable lesions, including hypothalamic hamartoma (HH), subependymal giant cell astrocytoma (SEGA), and exophytic intrinsic hypothalamic/third ventricular tumors. The authors reviewed their early institutional experience with these patients to characterize clinical outcomes in patients undergoing this procedure. METHODS A retrospective cohort (n = 12) of patients undergoing laser ablation at a single institution was identified, and clinical and radiographic records were reviewed. RESULTS Laser ablation was successfully performed in all patients. No permanent neurological or endocrine complications occurred; 2 (17%) patients developed acute obstructive hydrocephalus or shunt malfunction following treatment. Laser ablation of HH resulted in seizure freedom (Engel Class I) in 67%, with the remaining patients having a clinically significant reduction in seizure frequency of greater than 90% compared with preoperative baseline (Engel Class IIB). Treatment of SEGAs resulted in durable clinical and radiographic tumor control in 2 of 3 cases, with one patient receiving adjuvant everolimus and the other receiving no additional therapy. Palliative ablation of hypothalamic/third ventricular tumors resulted in partial tumor control in 1 of 3 patients. CONCLUSIONS Early experience suggests that laser ablation is a generally safe, durable, and effective treatment for patients harboring HHs. It also appears effective for local control of SEGAs, especially in combination therapy with everolimus. Its use as a palliative treatment for intrinsic hypothalamic/deep intraventricular tumors was less successful and associated with a higher risk of serious complications. Additional experience and long-term follow-up will be beneficial in further characterizing the effectiveness and risk profile of laser ablation in treating these lesions in comparison with conventional resective surgery or stereotactic radiosurgery.

Failure of a polyether-ether-ketone expandable interbody cage following transforaminal lumbar interbody fusion.

PURPOSE: Expandable cages are a more recent option for maintaining or restoring disc height and segmental lordosis with transforaminal lumbar interbody fusion (TLIF). Complications associated with expandable cages have not yet been widely reported. We report a case of postoperative failure of a polyether-ether-ketone (PEEK) expandable interbody device used during TLIF. METHODS: A 50-year-old man presented with severe back and right leg pain after undergoing L4-5 and L5-S1 TLIFs with expandable cages and L3-S1 posterior instrumented fusion. Imaging showed retropulsion of a portion of the interbody cage into the spinal canal causing nerve compression. Displacement occurred in a delayed manner. In addition, pseudoarthrosis was present. RESULTS: The patient underwent re-exploration with removal of the retropulsed wafer and redo fusion. CONCLUSIONS: Expandable cages are a recent innovation; as such, efficacy and complication data are limited. As with any new device, there exists potential for mechanical failure, as occurred in the case presented.

Sleep apnea and cervical spine pathology.

PURPOSE: Sleep apnea is a multi-factorial disease with a variety of identified causes. With its close proximity to the upper airway, the cervical spine and its associated pathologies can produce sleep apnea symptoms in select populations. The aim of this article was to summarize the literature discussing how cervical spine pathologies may cause sleep apnea. METHODS: A search of the PubMed database for English-language literature concerning the cervical spine and its relationship with sleep apnea was conducted. Seventeen published papers were selected and reviewed. RESULTS: Single-lesion pathologies of the cervical spine causing sleep apnea include osteochondromas, osteophytes, and other rare pathologies. Multifocal lesions include rheumatoid arthritis of the cervical spine and endogenous cervical fusions. Furthermore, occipital-cervical misalignment pre- and post-cervical fusion surgery may predispose patients to sleep apnea. CONCLUSIONS: Pathologies of the cervical spine present significant additional etiologies for producing obstructive sleep apnea in select patient populations. Knowledge of these entities and their pathophysiologic mechanisms is informative for the clinician in diagnosing and managing sleep apnea in certain populations.

The human craniospinal venous system and its influence on postural intracranial pressure: a review.

OBJECTIVE: The cerebral and spinal venous systems have similar functions but unique anatomical and physiological properties. CSF occupies space in the cranial and spinal vaults, is continuously produced, and has many roles, including maintaining a favorable environment for CNS structures. The influence of the cerebrospinal venous system on CSF dynamics has been theorized since the 1940s. Newer studies suggest venous outflow pattern alterations in response to changes in body position. However, the relationship of postural cerebrospinal venous outflow shifts with and their influence on CSF homeostasis is not well understood. METHODS: The authors searched the published literature related to the anatomy and function of vertebral venous plexus (VVP), CSF, and positional cerebral venous flow characteristics. A comprehensive collection of literature was compiled and reviewed, and the relationship between cerebrospinal and venous system changes and alterations in body positions, with an emphasis on the craniocervical system, is discussed. RESULTS: The VVP is a network of valveless veins extending from the sacrum to the cranium that are interconnected with the cranial dural sinuses. The internal VVP occupies space within the extradural spinal canal and functions to return spinal venous blood to the heart, but it has additional properties, including the capability of bidirectional venous flow, an intraspinal dilatory capacity, and a role in cerebral venous outflow. When one rises to the upright position, CSF shifts toward the spinal canal and force vectors change, leading to reduced intracranial CSF pressure; simultaneously, cerebral venous outflow shifts from the jugular vein to the VVP outflow pathway. The venous outflow shift mechanism and its purpose are poorly understood. The authors review the known physiology of the system, identify gaps in knowledge to direct future research, and propose an interpretation of these data, concluding that position-dependent CSF and cerebrospinal venous shifts are part of a complementary positional craniospinal pressure regulation system that must be kept in balance for optimal CNS function. CONCLUSIONS: Current knowledge of the cerebrospinal venous anatomy, dynamic flow characteristics in response to gravity, and the venous system's influence on CSF suggests that the VVP plays a role in influencing CSF pressure, and the authors hypothesize that it plays a role in supporting intracranial pressure in the upright body posture. Further research is needed to better characterize the functional relationship of the VVP to CSF dynamics as well as identify potentially related disease states.

Arterial Bypass in the Treatment of Complex Middle Cerebral Artery Aneurysms: Lessons Learned from Forty Patients.

OBJECTIVE: Complex middle cerebral artery (MCA) aneurysms incorporating parent or branching vessels are often not amenable to standard microsurgical clipping or endovascular embolization treatments. We aim to discuss the treatment of such aneurysms via a combination of surgical revascularization and aneurysm exclusion based on our institutional experience. METHODS: Thirty-four patients with complex MCA aneurysms were treated with bypass and aneurysm occlusion, 5 with surgical clipping or wrapping only, and 1 with aneurysm excision and primary reanastomosis. Bypasses included superficial temporal artery (STA)-MCA, double-barrel STA-MCA, occipital artery-MCA, and external carotid artery-MCA. After bypass, aneurysms were treated by surgical clipping, Hunterian ligation, trapping, or coil embolization. RESULTS: The average age at diagnosis was 46 years. Of the aneurysms, 67% were large and most involved the MCA bifurcation. Most bypasses performed were STA-MCA bypasses, 12 of which were double-barrel. There were 2 wound-healing complications. All but 2 of the aneurysms treated showed complete occlusion at the last follow-up. There were 3 hemorrhagic complications, 3 graft thromboses, and 4 ischemic insults. The mean follow-up was 73 months. Of patients, 83% reported stable or improved symptoms from presentation and 73% reported a functional status (Glasgow Outcome Scale score 4 or 5) at the latest available follow-up. CONCLUSIONS: Cerebral revascularization by bypass followed by aneurysm or parent artery occlusion is an effective treatment option for complex MCA aneurysms that cannot be safely treated by standard microsurgical or endovascular techniques. Double-barrel bypass consisting of 2 STA branches to 2 MCA branches yields adequate flow replacement in most cases.

Single-nucleus expression characterization of non-enhancing region of recurrent high-grade glioma.

Background: Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. Methods: We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings. Results: Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions. Conclusions: This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.