Sonodynamic therapy for adult-type diffuse gliomas: past, present, and future.

BACKGROUND: Intra-axial brain tumors persist as significant clinical challenges. Aggressive surgical resection carries risk of morbidity, and the blood-brain barrier (BBB) prevents optimal pharmacological interventions. There is a clear clinical demand for innovative and less invasive therapeutic strategies for patients, especially those that can augment established treatment protocols. Focused ultrasound (FUS) has emerged as a promising approach to manage brain tumors. Sonodynamic therapy (SDT), a subset of FUS, utilizes sonosensitizers activated by ultrasound waves to generate reactive oxygen species (ROS) and induce tumor cell death. OBJECTIVE: This review explores the historical evolution and rationale behind SDT, focusing on its mechanisms of action and potential applications in brain tumor management. METHOD: A systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Preclinical studies have demonstrated the efficacy of various sonosensitizers, including 5-aminolevulinic acid (5-ALA), fluorescein, porphyrin derivatives, and nanoparticles, in conjunction with FUS for targeted tumor therapy and BBB disruption. Clinical trials have shown promising results in terms of safety and efficacy, although further research is needed to fully understand the potential adverse effects and optimize treatment protocols. Challenges such as skull thickness affecting FUS penetration, and the kinetics of BBB opening require careful consideration for the successful implementation of SDT in clinical practice. Future directions include comparative studies of different sonosensitizers, optimization of FUS parameters, and exploration of SDT's immunomodulatory effects. CONCLUSION: SDT represents a promising frontier in the treatment of aggressive brain tumors, offering hope for improved patient outcomes.

Gamma knife radiosurgery for clival metastasis: case series and systematic review.

PURPOSE: Clival metastatic cancer is rare and has limited literature to guide management. We describe management of clival metastasis with Gamma Knife radiosurgery (GKRS). We augment our findings with a systematic review of all forms of radiation therapy for clival metastasis. METHODS: Records of 14 patients with clival metastasis who underwent GKRS at the University of Pittsburgh Medical Center from 2002 to 2023 were reviewed. Treatment parameters and clinical outcomes were assessed. A systematic review was conducted using evidence-based guidelines. RESULTS: The average age was 61 years with male predominance (n = 10) and average follow-up of 12.4 months. The most common primary cancers were prostate (n = 3) and lung (n = 3). The average time from cancer diagnosis to clival metastasis was 34 months. The most common presenting symptoms were headache (n = 9) and diplopia (n = 7). Five patients presented with abducens nerve palsies, and two presented with oculomotor nerve palsies. The median tumor volume was 9.3 cc, and the median margin dose was 15 Gy. Eleven patients achieved tumor control after one procedure, and three with progression obtained tumor control after repeat GKRS. One patient recovered abducens nerve function. The median survival from cancer diagnosis and GKRS were 49.7 and 15.3 months, respectively. The cause of death was progression of systemic cancer in six patients, clival metastasis in one, and unknown in four. The systematic review included 31 studies with heterogeneous descriptions of treatment and outcomes. CONCLUSION: Clival metastasis is rare and associated with poor prognosis. GKRS is a safe, effective treatment for clival metastasis.

Atlantoaxial facet fixation using cervical facet cage: technical case report and review of the literature.

In 1994, the use of interfacet spacer placement was for joint distraction, reduction, and fusion to supplement atlantoaxial or occipitocervical fixation. Here, we present a unique case of bilateral atlantoaxial interfacet fixation using cervical facet cages (CFC) in a pediatric patient with basilar invagination. In addition, we review the literature on atlantoaxial facet fixation. We present a 12-year-old boy with Wiedemann-Steiner syndrome who presented with multiple episodes of sudden neck jerking, described as in response to a sensation of being shocked, and guarding against neck motion, found to have basilar invagination with cervicomedullary compression. He underwent an occiput to C3 fusion with C1-C2 CFC fixation. We also conducted a literature review identifying all publications using the following keywords: "C1" AND "C2" OR "atlantoaxial" AND "facet spacer" OR "DTRAX." The patient demonstrated postoperative radiographic reduction of his basilar invagination from 6.4 to 4.1 mm of superior displacement above the McRae line. There was a 4.5 mm decrease in the atlantodental interval secondary to decreased dens retroflexion. His postoperative course was complicated by worsening of his existing dysphagia but was otherwise unremarkable. His neck symptoms completely resolved. We illustrate the safe use of CFC for atlantoaxial facet distraction, reduction, and instrumented fixation in a pediatric patient with basilar invagination. Review of the literature demonstrates that numerous materials can be safely placed as a C1-C2 interfacet spacer including bone grafts, titanium spacers, and anterior cervical discectomy and fusion cages. We argue that CFC may be included in this arsenal even in pediatric patients.

Neurosurgical Management of Rubinstein-Taybi Syndrome: An Institutional Experience.

INTRODUCTION: Rubinstein-Taybi syndrome (RTS) is a rare genetic condition with a distinctive set of physical features. This case series reports a single institutional experience of RTS cases, highlighting the role of neurosurgery in the comprehensive management of RTS patients. METHODS: A retrospective review of patients with genetically confirmed RTS presenting between 2010 and 2023 at Children's Hospital of Pittsburgh was performed. Patient demographics, genetic profile, clinical symptoms, radiographic characteristics, and neurosurgical management were recorded for all patients. RESULTS: Twenty-one patients (13 females, 8 males) aged 0 to 22 years presented for formal genetic counseling and diagnosis. Twenty patients (95%) had CREBBP pathogenic variants (RTS type 1), and 1 patient (5%) had EP300 pathogenic variants (RTS type 2). Ten patients (48%) had a low-lying conus medullaris, and 3 patients (30%) underwent subsequent spinal cord detethering. Four patients (19%) had a Chiari malformation, and three (75%) underwent Chiari decompression surgeries. One patient (5%) had Chiari-associated syringomyelia. CONCLUSIONS: RTS patients have an increased rate of tethered cord syndrome requiring detethering. The incidence of symptomatic Chiari I malformation requiring decompression has not been previously reported. The RTS series presented here demonstrates a high incidence of symptomatic Chiari I malformation in addition to tethered cord syndrome.

Radiosurgery outcomes in infratentorial juvenile pilocytic astrocytomas.

PURPOSE: To assess survival and neurological outcomes for patients who underwent primary or salvage stereotactic radiosurgery (SRS) for infratentorial juvenile pilocytic astrocytomas (JPA). METHODS: Between 1987 and 2022, 44 patients underwent SRS for infratentorial JPA. Twelve patients underwent primary SRS and 32 patients underwent salvage SRS. The median patient age at SRS was 11.6 years (range, 2-84 years). Prior to SRS, 32 patients had symptomatic neurological deficits, with ataxia as the most common symptom in 16 patients. The median tumor volume was 3.22 cc (range, 0.16-26.6 cc) and the median margin dose was 14 Gy (range, 9.6-20 Gy). RESULTS: The median follow-up was 10.9 years (range, 0.42-26.58 years). Overall survival (OS) after SRS was 97.7% at 1-year, and 92.5% at 5- and 10-years. Progression free survival (PFS) after SRS was 95.4% at 1-year, 79.0% at 5-years, and 61.4% at 10-years. There is not a significant difference in PFS between primary and salvage SRS patients (p = 0.79). Younger age correlated with improved PFS (HR 0.28, 95% CI 0.063-1.29, p = 0.021). Sixteen patients (50%) had symptomatic improvements while 4 patients (15.6%) had delayed onset of new symptoms related to tumor progression (n = 2) or treatment related complications (n = 2). Tumor volumetric regression or disappearance after radiosurgery was found in 24 patients (54.4%). Twelve patients (27.3%) had delayed tumor progression after SRS. Additional management of tumor progression included repeat surgery, repeat SRS, and chemotherapy. CONCLUSIONS: SRS was a valuable alternative to initial or repeat resection for deep seated infratentorial JPA patients. We found no survival differences between patients who had primary and salvage SRS.

Current trends, molecular insights, and future directions toward precision medicine in the management of pediatric cerebral arteriovenous malformations.

Pediatric arteriovenous malformations (AVMs) are rare but carry a risk of devastating neurological morbidity and mortality. Rupture of a cerebral AVM is the most common cause of spontaneous intracranial hemorrhage in children, with an unruptured AVM having an approximate hemorrhage risk of 2%-4% per year. The complex etiology of pediatric AVMs persists as an impediment to a comprehensive understanding of pathogenesis and subsequent targeted gene therapies. While AVMs secondary to vascular malformation syndromes have a clearer pathogenesis, a variety of gene mutations have been identified within sporadic AVM cases. The Ephrin B2/EphB4 (RASA-1, KRAS, and MEK) signaling axis, hemorrhagic telangiectasia, NOTCH, and TIE2 receptor complexes (PIK3CA and mTOR), in addition to other isolated gene variants, have been implicated in AVM pathogenesis. Furthering the understanding of the molecular mechanisms of AVM pathogenesis will lead to future novel therapies and treatment paradigms. Given the expected lifespan of a child, pediatric patients have an unacceptably high cumulative lifetime risk of hemorrhage. AVM treatment strategies are dependent on AVM grade, provider preference, and institutional resources. While open microsurgery is the mainstay of treatment for some AVMs, radiosurgery for definitive treatment and adjunctive endovascular embolization are also used extensively. There is increasing evidence indicating that all three modalities play important and potentially synergistic roles in the armamentarium for pediatric AVM treatment. This review serves to report current understanding in the genetic and molecular mechanisms of pediatric AVMs, review clinical diagnostic and classification criteria, and detail treatment options and subsequent outcomes of pediatric AVM patients.

Pharmaceutical Modulation of Intracranial Aneurysm Development and Rupture.

Management of intracranial aneurysms (IAs) is determined by patient age, risk of rupture, and comorbid conditions. While endovascular and microsurgical interventions offer solutions to mitigate the risk of rupture, pharmacological management strategies may complement these approaches or serve as alternatives in appropriate cases. The pathophysiology of IAs allows for the targeting of inflammation to prevent the development and rupture of IAs. The aim of this review is to provide an updated summary of different pharmaceutical management strategies for IAs. Acetylsalicylic acid and renin-angiotensin-aldosterone system (RAAS) inhibitor antihypertensives have some evidence supporting their protective effect. Studies of selective cyclooxygenase-2 (COX-2) inhibitors, statins, ADP inhibitors, and other metabolism-affecting drugs have demonstrated inconclusive findings regarding their association with aneurysm growth or rupture. In this manuscript, we highlight the evidence supporting each drug's effectiveness.

Comparing reactive versus empiric cerebrospinal fluid drainage strategies for spinal perfusion pressure optimization in patients with acute traumatic spinal cord injuries.

BACKGROUND: Spinal cord hypoperfusion undermines clinical recovery in acute traumatic spinal cord injuries. New guidelines suggest cerebrospinal fluid (CSF) drainage is an important strategy for preventing spinal cord hypoperfusion in the acute post-injury phase. METHODS: This study included participants presenting to a single level 1 trauma center between 2018 and 2022 with cervical or thoracic traumatic spinal cord injury severity grade A-C, as evaluated by the American spinal injury association impairment scale (AIS). The primary objective of this study was to compare the efficacy of two CSF drainage protocols in preventing spinal cord hypoperfusion; 1) draining CSF only when spinal cord perfusion pressure (SCPP) drops below 65 mmHg (i.e. reactive) versus 2) empiric CSF drainage of 5-10 mL every hour. Intrathecal pressure, spinal cord perfusion pressure (SCPP), mean arterial pressure (MAP), and vasopressor utilization were compared using univariate T-test statistical analysis. RESULTS: While there was no difference in the incidence of sub-optimal SCPP (<65 mmHg; p = 0.1658), reactively drained participants were more likely to exhibit critical hypoperfusion (<50 mmHg; p = 0.0030) despite also having lower average intrathecal pressures (p < 0.001). There were no differences in average SCPP, mean arterial pressure (MAP), or vasopressor utilization between the two groups (p > 0.05). CONCLUSIONS: Empiric (vs reactive) CSF drainage resulted in fewer incidences of critical spinal cord hypoperfusion for patients with acute traumatic spinal cord injuries.

Machine Learning in Spine Surgery: A Narrative Review.

Artificial intelligence and machine learning (ML) can offer revolutionary advances in their application to the field of spine surgery. Within the past 5 years, novel applications of ML have assisted in surgical decision-making, intraoperative imaging and navigation, and optimization of clinical outcomes. ML has the capacity to address many different clinical needs and improve diagnostic and surgical techniques. This review will discuss current applications of ML in the context of spine surgery by breaking down its implementation preoperatively, intraoperatively, and postoperatively. Ethical considerations to ML and challenges in ML implementation must be addressed to maximally benefit patients, spine surgeons, and the healthcare system. Areas for future research in augmented reality and mixed reality, along with limitations in generalizability and bias, will also be highlighted.

Preinjury Frailty Predicts 1-Year Mortality in Older Adults With Traumatic Spine Fractures.

BACKGROUND AND OBJECTIVES: Nearly 30% of older adults presenting with isolated spine fractures will die within 1 year. Attempts to ameliorate this alarming statistic are hindered by our inability to identify relevant risk factors. The primary objective of this study was to develop a prediction model that identifies feasible targets to limit 1-year mortality. METHODS: This retrospective cohort study included 703 older adults (65 years or older) admitted to a level I trauma center with isolated spine fractures, without neural deficit, from January 2013 to January 2018. Multivariable analysis was used to select for independently significant patient demographics, frailty variables, injury metrics, and management decisions to incorporate into distinct logistic regression models predicting 1-year mortality. Variables were considered significant, if P < .05. RESULTS: Of the 703 older adults, 199 (28.3%) died after hospital discharge, but within 1 year of index trauma. Risk Analysis Index (RAI; odds ratio [OR]: 1.116; 95% CI: 1.087-1.149; P < .001) and ambulation requiring a cane (OR: 2.601; 95% CI: 1.151-5.799; P = .02) or walker (OR: 4.942; 95% CI: 2.698-9.196; P < .001), ie, frailty variables, were associated with increased odds of 1-year mortality. Spine trauma scales were not associated with 1-year mortality. Longer hospital stays (OR: 1.112; 95% CI: 1.034-1.196; P = .004) and nursing home discharge (OR: 3.881; 95% CI: 2.070-7.378; P < .001) were associated with increased odds, while discharge to rehab (OR: 0.361; 95% CI: 0.155-0.799; P = .014) decreased 1-year mortality odds. A "preinjury" regression model incorporating Risk Analysis Index and ambulation status resulted in an area under receiver operating characteristic curve (AUROCC) of 0.914 (95% CI: 0.863-0.965). A "postinjury" model incorporating Glasgow Coma Scale, hospital stay duration, and discharge disposition resulted in AUROCC of 0.746 (95% CI: 0.642-0.849). Combining elements of the preinjury and postinjury models into an "integrated model" produced an AUROCC of 0.908 (95% CI: 0.852-0.965). CONCLUSION: Preinjury frailty measures are most strongly associated with 1-year mortality outcomes in older adults with isolated spine fractures. Incorporating injury metrics or management decisions did not enhance predictive accuracy. Further work is needed to understand how targeting frailty may reduce mortality.

Single institution series describing external ventricular drain (EVD) placement and short- and long-term complications related to placement accuracy.

Background: The placement of an external ventricular drain (EVD) for the treatment of acute hydrocephalus is one of the most common life-saving procedures that neurosurgeons perform worldwide. There are many well-known complications associated with EVD placement, including tract hemorrhages, intra-parenchymal and subdural hemorrhages, infection, and catheter misplacement. Given the variety of complications associated with EVD placement and the inconsistent findings on the relationship of accuracy to complications, the present study reviewed short- and long-term complications related to EVD placement at our institution. Methods: A retrospective review was conducted for all consecutive patients who underwent bedside EVD placement for any indication between December 2020 and December 2021. Collected variables included demographic information, etiology of disease state, pre-and post-operative head computed tomography measurements, and post-procedural metrics (immediate and delayed complications). Results: A total of 124 patients qualified for inclusion in our study. EVDs that were non-functioning/exchanged were not significantly related to age, accuracy, ventriculomegaly, sex, disposition, laterality, type of EVD used, intraventricular hemorrhage (IVH), etiology, or Kakarla Grade (KG) (all P > 0.17). The need for a second EVD was similarly not related to age, accuracy, ventriculomegaly, sex, disposition, location, laterality, type of EVD used, IVH, etiology, or KG (all P > 0.130). Patients who died, however, were significantly more likely to have a second contralateral EVD placed (18.2% vs. 4.9% P = 0.029). We also found that left-sided EVDs were significantly more likely to fail within seven days of placement (29.4% vs 13.3%, P = 0.037; relative risk (RR) 1.93, 95% confidence interval: 1.09-3.43), unrelated to age, sex, etiology, type of EVD, IVH, location of the procedure, or accuracy (all P > 0.07). This remained significant when using a binary logistic regression to control for ventriculomegaly, accuracy, mortality, age, sex, and etiology (P = 0.021, B = 3.43). Conclusion: In our cohort, although a clear relationship between inaccuracy and complication rates was not found, our data did demonstrate that left-sided EVDs were more likely to fail within the immediate postoperative time point, and patients who died were more likely to have a second, contralateral EVD placed.

Pleomorphic Xanthoastrocytoma: Multi-Institutional Evaluation of Stereotactic Radiosurgery.

BACKGROUND AND OBJECTIVES: Pleomorphic xanthoastrocytoma (PXA) is a rare low-grade glial tumor primarily affecting young individuals. Surgery is the primary treatment option; however, managing residual/recurrent tumors remains uncertain. This international multi-institutional study retrospectively assessed the use of stereotactic radiosurgery (SRS) for PXA. METHODS: A total of 36 PXA patients (53 tumors) treated at 11 institutions between 1996 and 2023 were analyzed. Data included demographics, clinical variables, SRS parameters, tumor control, and clinical outcomes. Kaplan-Meier estimates summarized the local control (LC), progression-free survival, and overall survival (OS). Secondary end points addressed adverse radiation effects and the risk of malignant transformation. Cox regression analysis was used. RESULTS: A total of 38 tumors were grade 2, and 15 tumors were grade 3. Nine patients underwent initial gross total resection, and 10 received adjuvant therapy. The main reason for SRS was residual tumors (41.5%). The median follow-up was 34 months (range, 2-324 months). LC was achieved in 77.4% of tumors, with 6-month, 1-year, and 2-year LC estimates at 86.7%, 82.3%, and 77.8%, respectively. Younger age at SRS (hazard ratios [HR] 3.164), absence of peritumoral edema (HR 4.685), and higher marginal dose (HR 6.190) were significantly associated with better LC. OS estimates at 1, 2, and 5 years were 86%, 74%, and 49.3%, respectively, with a median OS of 44 months. Four patients died due to disease progression. Radiological adverse radiation effects included edema (n = 8) and hemorrhagic change (n = 1). One grade 3 PXA transformed into glioblastoma 13 months after SRS. CONCLUSION: SRS offers promising outcomes for PXA management, providing effective LC, reasonable progression-free survival, and minimal adverse events.

Surgical management of metastatic Hürthle cell carcinoma to the skull base, cortex, and spine: illustrative case.

BACKGROUND: Hürthle cell carcinoma (HCC) is an unusual and aggressive variant of the follicular type of differentiated thyroid cancer (DTC), accounting for less than 3% of DTCs but posing the highest risk of metastasis. Brain metastases are uncommonly reported in the literature but pose a poor prognosis. The low rate of brain metastases from HCC coupled with ambiguous treatment protocols for the extracranial disease complicate successful disease management and definitive treatment strategy. The authors present the case of a patient with HCC metastasis to the skull base, cortex, and spine with recent tibial metastasis. OBSERVATIONS: Despite the presence of metastasis to the cortex, skull base, and spine, the patient responded very well to radiation therapy, sellar mass resection, and cervical spine decompression and fixation and has made a remarkable recovery. LESSONS: The authors' multidisciplinary approach to the patient's care, including a diverse team of specialists from oncology, neurosurgery, orthopedic surgery, radiology, endocrinology, and collaboration with clinical trial researchers, was fundamental to her successful outcome, demonstrating the utility of intersecting specialties in successful outcomes in neuro-oncological patient care.

Sex-specific molecular differences in glioblastoma: assessing the clinical significance of genetic variants.

Introduction: Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, and despite rigorous research, patient prognosis remains poor. The characterization of sex-specific differences in incidence and overall survival (OS) of these patients has led to an investigation of the molecular mechanisms that may underlie this dimorphism. Methods: We reviewed the published literature describing the gender specific differences in GBM Biology reported in the last ten years and summarized the available information that may point towards a patient-tailored GBM therapy. Results: Radiomics analyses have revealed that imaging parameters predict OS and treatment response of GBM patients in a sex-specific manner. Moreover, gender-based analysis of the transcriptome GBM tumors has found differential expression of various genes, potentially impacting the OS survival of patients in a sex-dependent manner. In addition to gene expression differences, the timing (subclonal or clonal) of the acquisition of common GBM-driver mutations, metabolism requirements, and immune landscape of these tumors has also been shown to be sex-specific, leading to a differential therapeutic response by sex. In male patients, transformed astrocytes are more sensitive to glutaminase 1 (GLS1) inhibition due to increased requirements for glutamine uptake. In female patients, GBM is more sensitive to anti-IL1ß due to an increased population of circulating granulocytic myeloid-derived suppressor cells (gMDSC). Conclusion: Moving forward, continued elucidation of GBM sexual dimorphism will be critical in improving the OS of GBM patients by ensuring that treatment plans are structured to exploit these sex-specific, molecular vulnerabilities in GBM tumors.

Infant Rudimentary Meningocele with Tethering of the Cervical Cord: A Case Report.

Rudimentary meningoceles of the spine with dural extension are very rare and warrant surgical excision to prevent infection and long-term neurological deficits in pediatric patients. We present the case of a 5-month-old infant with a tethered spinal cord secondary to a rudimentary meningocele. The patient presented shortly after birth with a midline cervical dimple that was evaluated for a suspected dermal sinus tract. Magnetic resonance imaging scan of the spine showed a sinus tract with intradural extension to C2-3 and external opening at the level of spinous process C5. En bloc surgical excision and spinal cord release were successfully performed. Histological analysis of the specimen confirmed the presence of two blunt sinus tracts and staining was consistent with a rudimentary meningocele. Intradural rudimentary meningoceles in infants can successfully be managed with surgical intervention. Surgery is indicated to prevent future motor complications from spinal cord tethering and neoplastic growth from the rudimentary meningocele.