Analysis of alpha-synuclein harvested from intracranial instruments used in deep brain stimulation surgery for Parkinson's disease.

Alpha-synuclein (αSyn) forms pathologic aggregates in Parkinson's disease (PD) and is implicated in mechanisms underlying neurodegeneration. While pathologic αSyn has been extensively studied, there is currently no method to evaluate αSyn within the brains of living patients. Patients with PD are often treated with deep brain stimulation (DBS) surgery in which surgical instruments are in direct contact with neuronal tissue; herein, we describe a method by which tissue is purified from DBS surgical instruments in PD and essential tremor (ET) patients and demonstrate that αSyn is robustly detected. 24 patients undergoing DBS surgery for PD (17 patients) or ET (7 patients) were enrolled; from patient samples, 81.2 ± 44.8 µg protein (n=15) is able to be purified, with immunoblot assays specific for αSyn reactive in all tested samples. Light microscopy revealed axons and capillaries as the primary components of purified tissue (n=3). Further analysis was conducted using western blot, demonstrating that truncated αSyn (1-125 αSyn) was significantly increased in PD (n=5) compared to ET (n=3), in which αSyn misfolding is not expected (0.64 ± 0.25 vs. 0.25 ± 0.12, P = 0.046), thus showing that pathologic αSyn can be reliably purified from living PD patients with this method.

Management of essential tremor deep brain stimulation-induced side effects.

Deep brain stimulation (DBS) is an effective surgical therapy for carefully selected patients with medication refractory essential tremor (ET). The most popular anatomical targets for ET DBS are the ventral intermedius nucleus (VIM) of the thalamus, the caudal zona incerta (cZI) and the posterior subthalamic area (PSA). Despite extensive knowledge in DBS programming for tremor suppression, it is not uncommon to experience stimulation induced side effects related to DBS therapy. Dysarthria, dysphagia, ataxia, and gait impairment are common stimulation induced side effects from modulation of brain tissue that surround the target of interest. In this review, we explore current evidence about the etiology of stimulation induced side effects in ET DBS and provide several evidence-based strategies to troubleshoot, reprogram and retain tremor suppression.

Active recharge biphasic stimulation for the intraoperative monopolar review in deep brain stimulation.

Introduction: Charge balancing is used in deep brain stimulation (DBS) to avoid net charge accumulation at the tissue-electrode interface that can result in neural damage. Charge balancing paradigms include passive recharge and active recharge. In passive recharge, each cathodic pulse is accompanied by a waiting period before the next stimulation, whereas active recharge uses energy to deliver symmetric anodic and cathodic stimulation pulses sequentially, producing a net zero charge. We sought to determine differences in stimulation induced side effect thresholds between active vs. passive recharge during the intraoperative monopolar review. Methods: Sixty-five consecutive patients undergoing DBS from 2021 to 2022 were retrospectively reviewed. Intraoperative monopolar review was performed with both active recharge and passive recharge for all included patients to determine side effect stimulation thresholds. Sixteen patients with 64 total DBS contacts met inclusion criteria for further analysis. Intraoperative monopolar review results were compared with the monopolar review from the first DBS programming visit. Results: The mean intraoperative active recharge stimulation threshold was 4.1 mA, while the mean intraoperative passive recharge stimulation threshold was 3.9 mA, though this difference was not statistically significant on t-test (p = 0.442). Mean stimulation threshold at clinic follow-up was 3.2 mA. In Pearson correlation, intraoperative passive recharge thresholds had stronger correlation with follow-up stimulation thresholds (Pearson r = 0.5281, p < 0.001) than intraoperative active recharge (Pearson r = 0.340, p = 0.018), however the difference between these correlations was not statistically significant on Fisher Z correlation test (p = 0.294). The mean difference between intraoperative passive recharge stimulation threshold and follow-up stimulation threshold was 0.8 mA, while the mean difference between intraoperative active recharge threshold and follow-up threshold was 1.2 mA. This difference was not statistically significant on a t-test (p = 0.134). Conclusions: Both intraoperative active recharge and passive recharge stimulation were well-correlated with the monopolar review at the first programming visit. No statistically significant differences were observed suggesting that either passive or active recharge may be utilized intraoperatively.

Risk factors for postoperative urinary retention after deep brain stimulation surgery: the role of the subthalamic nucleus.

OBJECTIVE: Deep brain stimulation (DBS) is a common procedure in neurosurgery used for the treatment of Parkinson's disease (PD) and essential tremor (ET) among other disorders. Lower urinary tract dysfunction is a common complication in PD, and this study aimed to evaluate the risk factors of postoperative urinary retention (POUR) after DBS surgery in patients with PD compared with patients with ET. Understanding the risk factors associated with this complication may help in the development of strategies to minimize its occurrence and improve patient outcomes. METHODS: The study was a retrospective analysis of patients who underwent DBS surgery for PD and ET at the University of Florida between 2010 and 2021. The surgical technique used has been described in previous articles and included a two-stage procedure, with stage 1 involving burr hole placement, microelectrode recording, and electrode implantation and stage 2 involving the placement of an implantable pulse generator (IPG). Data were collected on patient characteristics and surgical details and analyzed using univariate and mixed-linear models. Post hoc propensity score matching was used to confirm the association between subthalamic nucleus (STN)-DBS and POUR. RESULTS: The study included 350 patients (153 with PD and 197 with ET) who underwent 1086 DBS surgeries (lead implantations, IPG placement, and IPG replacements). The POUR rates were 16.6% (79/477), 5.2% (19/363), and 0.4% (1/246) for stage 1, stage 2, and IPG replacement procedures, respectively. Optimal mixed-effects logistic modeling revealed history of urinary retention (OR 9.3, p = 0.004), male sex (OR 2.7, p = 0.011), having an electrode placed or connected for the first time (OR 2.2, p = 0.014), anesthesia time (OR 1.5 for each 30-minute increase, p < 0.0001), preoperative opioid use (OR 1.4 for each additional 10 morphine milligram equivalents, p = 0.032), and Charlson Comorbidity Index (OR 1.4 per comorbidity, p = 0.017) to be significant risk factors for POUR. Having an electrode in the STN was found to be protective of POUR (propensity score-matched analysis: OR 0.2, p = 0.010). CONCLUSIONS: Most risk factors found to increase the risk of POUR in DBS are not modifiable but are still important to consider in preoperative planning. Opioid use reduction and shorter anesthesia time may be modifiable risk factors to weigh against their alternative. Targeting the STN during DBS may result in decreased rates of POUR. This highlights the potential for STN-targeted DBS in reducing POUR risk in PD and ET patients.

Neural Bypasses: Literature Review and Future Directions in Developing Artificial Neural Connections.

Reported neuro-modulation schemes in the literature are typically classified as closed-loop or open-loop. A novel group of recently developed neuro-modulation devices may be better described as a neural bypass, which attempts to transmit neural data from one location of the nervous system to another. The most common form of neural bypasses in the literature utilize EEG recordings of cortical information paired with functional electrical stimulation for effector muscle output, most commonly for assistive applications and rehabilitation in spinal cord injury or stroke. Other neural bypass locations that have also been described, or may soon be in development, include cortical-spinal bypasses, cortical-cortical bypasses, autonomic bypasses, peripheral-central bypasses, and inter-subject bypasses. The most common recording devices include EEG, ECoG, and microelectrode arrays, while stimulation devices include both invasive and noninvasive electrodes. Several devices are in development to improve the temporal and spatial resolution and biocompatibility for neuronal recording and stimulation. A major barrier to entry includes neuroplasticity and current decoding mechanisms that regularly require retraining. Neural bypasses are a unique class of neuro-modulation. Continued advancement of neural recording and stimulating devices with high spatial and temporal resolution, combined with decoding mechanisms uninhibited by neuroplasticity, can expand the therapeutic capability of neural bypassing. Overall, neural bypasses are a promising modality to improve the treatment of common neurologic disorders, including stroke, spinal cord injury, peripheral nerve injury, brain injury and more.

Growth Analysis of Untreated Meningiomas under Observation.

BACKGROUND: When meningiomas are small or asymptomatic, the decision to observe rather than treat requires balancing the growth potential of the lesion with the outcome and side effects of treatment. The aim of this study is to characterize the growth patterns of untreated meningiomas to better inform the clinical decision-making process. METHODS: Patients with meningiomas were identified from 2005 to 2015. Those without treatment who had been followed for 1.5 years, with three magnetic resonance imaging (MRI) scans, were identified. Scans were measured with orthogonal diameters, geometric mean diameters, and volumes using the ABC/2 method. Regression modeling determined what growth pattern these parameters best approximated. RESULTS: Two hundred and fifteen MRI scans for 34 female (82.9%) and 7 male (17%) patients with 43 tumors were evaluated. Initial tumor volumes ranged from 0.13 to 9.98 mL. The mean and median initial volumes were 2.44 and 1.52 mL, respectively. Follow-up times ranged from 21 to 144 months, with a median of 70 months. There were 12 tumors (28%) whose growth rates were significantly greater than zero. For all tumors, use of a linear regression model allowed accurate prediction of the future size using prior data. CONCLUSION: Three-quarters of presumptive meningiomas managed conservatively do not grow significantly. The remainder have significant growth over time, and the behavior could be approximated with linear regression models.

Treatment of breast cancer brain metastases: radiotherapy and emerging preclinical approaches.

The breast is one of the common primary sites of brain metastases (BM). Radiotherapy for BM from breast cancer may include whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT), but a consensus is difficult to reach because of the wide and varied protocols, indications, and outcomes of these interventions. Overall, dissemination of disease, patient functional status, and tumor size are all important factors in the decision of treatment with WBRT or SRS. Thus far, previous studies indicate that WBRT can improve tumor control compared to SRS, but increase side effects, however no randomized trials have compared the efficacy of these therapies in BM from breast cancer. Therapies targeting long non-coding RNAs and transcription factors, such as MALAT1, HOTAIR, lnc-BM, TGL1, and ATF3, have the potential to both prevent metastatic spread and treat BM with improved radiosensitivity. Given the propensity for HER2+ breast cancer to develop BM, the above-mentioned cell lines may represent an important target for future investigations, and the development of everolimus and pyrotinib are equally important.

Deep brain stimulation for the treatment of tremor.

This review article provides a brief historical perspective on the use of DBS for tremor, reviews the various etiologies for tremor that can be effectively managed with DBS therapy, discusses the DBS targets that have been used for suppression of tremor, and reviews in detail important aspects of DBS surgical technique, including significant technological advances over the past several years that, when applied, can substantially improve the outcomes of DBS for tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

Focused ultrasound: Innovation in use for neurologic conditions.

Focused ultrasound has emerged as a key tool for neurologic disorders. In this focused review, we discuss the utility in disrupting the blood brain barrier to maximize treatment. This can facilitate creating direct coagulative lesions and aid in the administration of chemotherapy. Furthermore, it can facilitate neuromodulation when used in pulse sequencing. The current literature regarding brain tumors, essential tremor, and obsessive-compulsive disorder is reviewed. Additionally, concepts and experimental outcomes for neurodegenerative disease such as Alzheimer's is presented. Focused ultrasound as a tool is still in its infancy but the potential for adjuvant and direct therapy is promising. More clinical uses will become apparent in coming decades.

Concomitant parasagittal meningioma and adjacent intracranial abscess of occult etiology.

INTRODUCTION: Abscesses associated with tumors are a rare entity. Imaging to differentiate abscess from other entities is often non-diagnostic, and often the source of infection is unknown. We present an unusual case of peritumoral abscess infected with both gram-negative and gram-positive bacteria. METHODS: A 70-year-old, previously healthy male presented with a 1-day history of right-sided facial weakness sparing the forehead, as well as concomitant right upper and lower extremity numbness. A homogenously enhancing mass with adjacent rim-enhancing lesion with diffusion restricting cavity seen on magnetic resonance imaging (MRI) raised the possibility of abscess. RESULTS: Separate biopsy specimens of both the tumor and adjacent fluid collection during drainage of the collection confirmed World Health Organization (WHO) grade I meningioma and bacterial abscess containing Streptococcus constellatus, Fusobacterium species, Prevotella dentalis, and Parvimonas micra. The histologic diagnosis therefore confirmed the preoperative radiologic findings of two different but associated lesions. Investigations to determine a definitive source of infection were inconclusive, including urinalysis, blood cultures, respiratory cultures, endoscopy, and an orthopantomogram. CONCLUSIONS: Gram-negative and gram-positive bacteria can both be culprits in the formation of peritumoral abscess. Although the source of infection is unconfirmed, the presence of oropharyngeal flora in the abscess suggests a subclinical odontogenic infection with hematogenous spread to the tumor and adjacent brain.

Comparison of ABC/2 estimation and a volumetric computerized method for measurement of meningiomas using magnetic resonance imaging.

INTRODUCTION: Measurement of tumor growth rates over time for patients with meningiomas has important prognostic and therapeutic implications. Our objective was to compare two methods of measuring meningioma volume: (1) the simplified ellipsoid (ABC/2) method; and (2) perimetric volume measurements using imaging software modules. METHODS: Patients with conservatively managed meningiomas for at least 1.5 years were retrospectively identified from the VCU Brain and Spine Tumor Registry over a 10-year period (2005-2015). Tumor volumes were independently measured using the simplified ellipsoid and computerized perimetric methods. Intra class correlations (CC) and Bland-Altman analyses were performed. RESULTS: A total of 26 patients representing 29 tumors were identified. Across 146 images, there were 24 (16%) images that were non-measurable using standard application commands with the computerized perimetric method. The mean volume obtained using the ABC/2 and computerized perimetric methods were 3.2 ± 3.4 cm3 and 3.4 ± 3.5 cm3, respectively. The mean volume difference was 0.2 cm3 (SE = 0.12; p = 0.10) across measurement methods. The concordance correlation coefficient (CCC) between methods was 0.95 (95% CI 0.91, 0.98). CONCLUSIONS: There is excellent correlation between the simplified ellipsoid and computerized perimetric methods of volumetric analysis for conservatively managed meningiomas. The simplified ellipsoid method remains an excellent method for meningioma volume assessment and had an advantage over the perimetric method which failed to allow measurement of roughly one in six tumors on imaging.

A systematic review of perioperative seizure prophylaxis during brain tumor resection: the case for a multicenter randomized clinical trial.

OBJECTIVE The majority of neurosurgeons administer antiepileptic drugs (AEDs) prophylactically for supratentorial tumor resection without clear evidence to support this practice. The putative benefit of perioperative seizure prophylaxis must be weighed against the risks of adverse effects and drug interactions in patients without a history of seizures. Consequently, the authors conducted a systematic review of prospective randomized controlled trials (RCTs) that have evaluated the efficacy of perioperative seizure prophylaxis among patients without a history of seizures. METHODS Five databases (PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL/Academic Search Complete, Web of Science, and ScienceDirect) were searched for RCTs published before May 2017 and investigating perioperative seizure prophylaxis in brain tumor resection. Of the 496 unique research articles identified, 4 were selected for inclusion in this review. RESULTS This systematic review revealed a weighted average seizure rate of 10.65% for the control groups. There was no significant difference in seizure rates among the groups that received seizure prophylaxis and those that did not. Further, this expected incidence of new-onset postoperative seizures would require a total of 1258 patients to enroll in a RCT, as determined by a Farrington-Manning noninferiority test performed at the 0.05 level using a noninferiority difference of 5%. CONCLUSIONS According to a systematic review of major RCTs, the administration of prophylactic AEDs after brain tumor resection shows no significant reduction in the incidence of seizures compared with that in controls. A large multicenter randomized clinical trial would be required to assess whether perioperative seizure prophylaxis provides benefit for patients undergoing brain tumor resection.

Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma.

Targeting tumor angiogenesis is a potential therapeutic strategy for glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma angiogenesis. We conducted a phase II study to test the effectiveness of tivozanib in patients with recurrent glioblastoma. Ten adult patients were enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at baseline, within 24-72 h of treatment initiation, and monthly thereafter. Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel architecture imaging were used to assess vascular effects. Resting state MRI was used to assess brain connectivity. Best RANO criteria responses were: 1 complete response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). Two patients were taken off study for toxicity and 8 patients were taken off study for PD. Median progression-free survival was 2.3 months and median overall survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of tivozanib. However, there were no clear structural changes in vasculature as vessel caliber and enhancing tumor volume did not significantly change. Despite functional changes in tumor vasculature, tivozanib had limited anti-tumor activity, highlighting the limitations of anti-VEGF monotherapy. Future studies in glioblastoma should leverage the anti-vascular activity of agents targeting VEGF to enhance the activity of other therapies.