Surgery vs. Radiosurgery for Patients with Localized Metastatic Brain Disease: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.

Purpose: To analyze the efficacy and safety of surgery compared to radiosurgery (RS), combined or not with whole brain radiotherapy (WBRT), for localized metastatic brain disease. Methods: A systematic review with meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The inclusion criteria were limited to randomized controlled trials (RCTs) that compared surgery and RS for patients with up to 3 metastases (median diameter ≤ 4 cm). The primary outcomes were represented by overall survival (OS) and local brain progression-free survival (PFS), with the rate of complications as a secondary outcome. The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the RoB2 revised tool and the certainty of the evidence was assessed according to the GRADE guidelines. Results: In total, 11,256 records were identified through database and register searches. After study selection, 3 RCTs and 353 patients were included in the quantitative synthesis. Surgery and RS represented the main intervention arms in all the included RCTs. Conclusions: A low level of evidence suggests that RS alone and surgery followed by WBRT provide an equal rate of local brain PFS in patients with localized metastatic brain disease. There is a very low level of evidence that surgery and RS as main interventions offer equivalent OS in the population investigated. A reliable assessment of the complication rates among surgery and RS was not achievable. The lack of high-certainty evidence either for superiority or equivalence of these treatments emphasizes the need for further, more accurate, RCTs comparing surgery and RS as local treatment in patients with oligometastatic brain disease.

Intracranial Sonodynamic Therapy With 5-Aminolevulinic Acid and Sodium Fluorescein: Safety Study in a Porcine Model.

BACKGROUND: Sonodynamic therapy (SDT) is an emerging ultrasound-based treatment modality for malignant gliomas which combines ultrasound with sonosensitizers to produce a localized cytotoxic and modulatory effect. Tumor-specificity of the treatment is achieved by the selective extravasation and accumulation of sonosensitizers in the tumor-bearing regions. The aim of this study is to demonstrate the safety of low-intensity ultrasonic irradiation of healthy brain tissue after the administration of FDA-approved sonosensitizers used for SDT in experimental studies in an in vivo large animal model. METHODS: In vivo safety of fluorescein (Na-Fl)- and 5 aminolevulinic acid (5-ALA)-mediated low-intensity ultrasound irradiation of healthy brain parenchyma was assessed in two sets of four healthy swine brains, using the magnetic resonance imaging (MRI)-guided Insightec ExAblate 4000 220 kHz system. After administration of the sonosensitizers, a wide fronto-parietal craniotomy was performed in pig skulls to allow transmission of ultrasonic beams. Sonication was performed on different spots within the thalamus and periventricular white matter with continuous thermal monitoring. Sonication-related effects were investigated with MRI and histological analysis. RESULTS: Post-treatment MRI images acquired within one hour following the last sonication, on day one, and day seven did not visualize any sign of brain damage. On histopathology, no signs of necrosis or apoptosis attributable to the ultrasonic treatments were shown in target areas. CONCLUSIONS: The results of the present study suggest that either Na-FL or 5-ALA-mediated sonodynamic therapies under MRI-guidance with the current acoustic parameters are safe towards healthy brain tissue in a large in vivo model. These results further support growing interest in clinical translation of sonodynamic therapy for intracranial gliomas and other brain tumors.

Sonodynamic Therapy for the Treatment of Intracranial Gliomas.

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

High-Definition 4K 3D Exoscope (ORBEYETM) in Peripheral Nerve Sheath Tumor Surgery: A Preliminary, Explorative, Pilot Study.

BACKGROUND: Surgery for peripheral nerve sheath tumors aims to preserve functional fascicles achieving gross-total resection. Increasing the visualization of anatomic details helps to identify the different layers and the tumor-nerve interface. The traditional microscope can present some limitations in this type of surgery, such as its physical obstruction. OBJECTIVE: To present a proof-of-concept study about exoscope-guided surgery for schwannomas of the lower limbs, to analyze the advantages and disadvantages of the 4K, high-quality, 3-dimensional (3D) imaging. METHODS: We analyzed 2 consecutive surgical cases of suspected schwannomas of the lower limbs using the ORBEYE™ exoscope (Olympus). A standard operative microscope was also available in the operating room. All procedures were performed with neurophysiological monitoring, to identify functioning nerves and to localize the tumor capsule safest entry point. The cases are reported according to the PROCESS guidelines. RESULTS: In both cases, we achieved a gross total resection of the schwannomas; the exoscope provided an excellent view of the anatomic details at tumor-nerve interface, as visible in intraoperative images and in the 3D-4K video supporting these findings. The surgeon's position was comfortable in both cases, although if the co-surgeon positioned himself in front of the first surgeon, the comfort was slightly reduced. The 4K monitor allowed a realistic, nontiring 3D vision for all the team. CONCLUSION: The ORBEYETM, after an adequate learning curve, can represent a feasible and comfortable instrument for nerve tumor surgery, which is usually performed in a single horizontal plane. Further and wider clinical series are necessary to confirm this first impression.

Fluorescein-guided removal of peripheral nerve sheath tumors: a preliminary analysis of 20 cases.

OBJECTIVE: Benign peripheral nerve sheath tumors (PNSTs) include mainly schwannomas-the most common tumors arising from peripheral nerves-and neurofibromas. Due to their origin, distinguishing between functional intact nerve and the fibers from whence the PNST arose may not always be easy to perform. The introduction of intraoperative tools to better visualize these tumors could be helpful in achieving a gross-total resection. In this study, the authors present a series of patients harboring PNST in which the surgery was performed under fluorescein guidance. METHODS: Between September 2018 and February 2019, 20 consecutive patients with a total of 25 suspected PNSTs underwent fluorescein-guided surgery performed under microscopic view with a dedicated filter integrated into the surgical microscope (YELLOW 560) and with intraoperative monitoring. All patients presented with a different degree of contrast enhancement at preoperative MRI. Fluorescein was intravenously injected after intubation at a dose of 1 mg/kg. Preoperative clinical and radiological data, intraoperative fluorescein characteristics, and postoperative neurological and radiological outcomes were collected and analyzed. RESULTS: Six patients were affected by neurofibromatosis or schwannomatosis. There were 14 schwannomas, 8 neurofibromas, 1 myxoma, 1 reactive follicular hyperplasia, and 1 giant cell tumor of tendon sheath. No patient experienced worsening of neurological status after surgery. No side effects related to fluorescein injection were found in this series. Fluorescein allowed an optimal intraoperative distinction between tumor and surrounding nerves in 13 of 14 schwannomas and in all neurofibromas. In 6 neurofibromas and in 1 schwannoma, the final YELLOW 560 visualization showed the presence of small tumor remnants that were not visible under white-light illumination and that could be removed, obtaining a gross-total resection. CONCLUSIONS: Fluorescein was demonstrated to be a feasible, safe, and helpful intraoperative adjunct to better identify and distinguish PNSTs from intact functional nerves, with a possible impact on tumor resection, particularly in diffuse neurofibromas.

Deep brain stimulation of the posterior limb of the internal capsule in the treatment of central poststroke neuropathic pain of the lower limb: case series with long-term follow-up and literature review.

OBJECTIVE: Central poststroke neuropathic pain is a debilitating syndrome that is often resistant to medical therapies. Surgical measures include motor cortex stimulation and deep brain stimulation (DBS), which have been used to relieve pain. The aim of this study was to retrospectively assess the safety and long-term efficacy of DBS of the posterior limb of the internal capsule for relieving central poststroke neuropathic pain and associated spasticity affecting the lower limb. METHODS: Clinical and surgical data were retrospectively collected and analyzed in all patients who had undergone DBS of the posterior limb of the internal capsule to address central poststroke neuropathic pain refractory to conservative measures. In addition, long-term pain intensity and level of satisfaction gained from stimulation were assessed. Pain was evaluated using the visual analog scale (VAS). Information on gait improvement was obtained from medical records, neurological examination, and interview. RESULTS: Four patients have undergone the procedure since 2001. No mortality or morbidity related to the surgery was recorded. In three patients, stimulation of the posterior limb of the internal capsule resulted in long-term pain relief; in a fourth patient, the procedure failed to produce any long-lasting positive effect. Two patients obtained a reduction in spasticity and improved motor capability. Before surgery, the mean VAS score was 9 (range 8-10). In the immediate postoperative period and within 1 week after the DBS system had been turned on, the mean VAS score was significantly lower at a mean of 3 (range 0-6). After a mean follow-up of 5.88 years, the mean VAS score was still reduced at 5.5 (range 3-8). The mean percentage of long-term pain reduction was 38.13%. CONCLUSIONS: This series suggests that stimulation of the posterior limb of the internal capsule is safe and effective in treating patients with chronic neuropathic pain affecting the lower limb. The procedure may be a more targeted treatment method than motor cortex stimulation or other neuromodulation techniques in the subset of patients whose pain and spasticity are referred to the lower limbs.

Dorsal anterior cingulate cortex (ACC) deep brain stimulation (DBS): a promising surgical option for the treatment of refractory thalamic pain syndrome (TPS).

BACKGROUND: Neuroimaging evidences and previous successful case series of cingulotomy for cancer pain have disclosed the key-role of the dorsal anterior cingulate cortex (ACC) in the generation of the empathic and affective dimension of pain. The aim of this study is to assess the effectiveness and safety of ACC neuromodulation for the treatment of the thalamic pain syndrome (TPS), a chronic neuropathic disease often complicated by severe affective and emotional distress in the long term. METHOD: From January 2015 to April 2017, 5 patients with pure drug-refractory TPS underwent ACC deep brain stimulation (DBS) at our institution. Quantitative assessment of pain and health-related quality of life were performed 1 day before surgery and postoperatively at 6 and 18 months by using the numeric rating scale (NRS), the 36-item short-form health survey (SF-36), and the McGill pain and the EuroQol5-domain questionnaires. RESULTS: Mean age at surgery was 56.2 years (range, 47-66). NRS score improved by 37.9% at 6 months (range, - 22.2 to - 80%) and by 35% at 18 months (range, - 11.1 to - 80%). At the last follow-up, one patient reported a relevant pain reduction (NRS 2), only complaining of mild pain poorly interfering with activities of daily living. Concomitant improvements in the McGill and EuroQol5-domain pain questionnaires, SF-36 total and sub-item scores were also noticed at each follow-up. No surgical or stimulation-related complications occurred during the study period. CONCLUSIONS: ACC DBS may be a safe and promising surgical option to alleviate discomfort and improve the overall quality of life in a patient affected by drug-resistant TPS. Further prospective, larger, and randomized studies are needed to validate these findings.

The neurosurgical treatment of craniofacial pain syndromes: current surgical indications and techniques.

Craniofacial pain syndromes are comprised of multiple pathological entities resulting in pain referred to the scalp, face, or deeper cranial structures. In a small subset of patients affected by those syndromes, pharmacological and physical therapies fail in alleviating pain. In some of those refractory patients surgical procedures aimed at relieving pain are indicated and have been adopted with variable results and safety profiles. In this review, the authors describe craniofacial pain syndromes that most commonly fail to respond to pharmacological therapies and may be amenable to tailored surgical procedures. In particular, trigeminal, glossopharyngeal, and occipital neuralgias are considered, as well as some primary headache syndromes such as cluster headache, short unilateral neuralgiform headache with conjunctival injection and tearing/short unilateral neuralgiform headache with autonomic symptoms, and migraine. Surgical techniques, including the implantation of deep brain or peripheral nerve electrodes with subsequent chronic stimulation, microvascular decompression of neurovascular conflicts, and percutaneous lesioning of neural structures are described. Finally, surgical indications, outcomes, and safety of these procedures are presented.

Two-Staged Frontal Bone Defect Reconstruction: Perioperative Assessment of Scalp Vascularization Using Near-Infrared Indocyanine Green Video Angiography (Visionsense Iridium).

BACKGROUND: Head trauma and neurosurgical-related osteomyelitis are common causes of cranial bone defect. Even though cranioplasty is considered a safe and well-consolidated procedure, there are still some issues about the flap's vascularization assessment. In this paper we describe a 2-staged cranioplasty procedure, focusing on the perioperative evaluation of the skin flap vascularization. Our goal is to assess if the skin flap's perfusion measurement with indocyanine green fluorescence can be considered a reliable method to predict good outcome in cranioplasties. CASE DESCRIPTION: A 50-year-old patient presented with a wide frontal bone defect due to a prior surgery-related osteomyelitis. During the first operation, a tissue expander was placed under the scalp in order to grant an appropriate skin stretching. During the second operation the defect was repaired with a custom-made prosthesis after tissue expander removal. During all procedures, vascular integrity of the skin flap was intraoperatively assessed by means of indocyanine green fluorescence. CONCLUSIONS: Surgical procedures were well tolerated; at 1 year of follow-up the cosmetic defect was unremarkable. Indocyanine green fluorescence can be a good aid to predict the probability of the skin flap survival by measuring its perfusion.

Deep Brain Stimulation of the Caudal Zona Incerta and Motor Thalamus for Postischemic Dystonic Tremor of the Left Upper Limb: Case Report and Review of the Literature.

BACKGROUND: Dystonic tremor is defined as a tremor occurring in a body region affected by dystonia. The pathophysiologic mechanisms behind dystonic tremor supposedly involve anomalies affecting the pallidothalamic-receiving area (for the dystonic component) and the ventralis intermedius-cortical loop (for the tremor component). Interest in posterior subthalamic area stimulation for various types of involuntary abnormal movements has arisen owing to positive results in patients affected by tremor refractory to ventralis intermedius deep brain stimulation. CASE DESCRIPTION: A 23-year-old man, with a 15-year history of left upper limb dystonic tremor due to a stroke in the right thalamus, underwent deep brain stimulation with a single electrode passing through the right ventralis oralis anterior/ventralis oralis posterior nuclei and caudal zona incerta. Objective movement outcomes were assessed through the Unified Dystonia Rating Scale and Fahn-Tolosa-Marin Clinical Rating Scale for Tremor. The impact of tremor on activities of daily living was assessed with the ADL-T24 questionnaire, and quality of life was assessed with the Quality of Life Scale. All questionnaires were administered before deep brain stimulation and at 5-year follow-up. Unified Dystonia Rating Scale and Fahn-Tolosa-Marin Clinical Rating Scale for Tremor scores decreased from 14.5 to 4.5 and from 46 to 7, respectively. ADL-T24 score decreased from 19 to 3, whereas Quality of Life Scale score increased from 49 to 82. CONCLUSIONS: Stimulation of motor thalamus and caudal zona incerta could be a viable treatment for patients affected by tremor of various origins, including dystonic tremor, refractory to medical therapy.

Internal Pulse Generators in Deep Brain Stimulation: Rechargeable or Not?

OBJECTIVE: Deep brain stimulation (DBS) is a cost-effective strategy for the treatment of different neurologic disorders. However, DBS procedures are associated with high costs of implantation and replacement of the internal pulse generator (IPG). Different manufacturers propose the use of rechargeable IPGs. The objective of this study is to compare the implantation costs of nonrechargeable IPGs versus the estimated costs of rechargeable IPGs in different categories of patients to evaluate if an economic advantage for the health care system could be derived. METHODS: The study looked at 149 patients who underwent a surgical procedure for IPG replacement. In a hypothetical scenario, rechargeable IPGs were implanted instead of nonrechargeable IPGs at the time of DBS system implantation. Another scenario was outlined in a perspective period of time, corresponding to the patients' life expectancy. Costs were calculated, and inferential analysis was performed. RESULTS: A savings of €234,194, including the cost of management of complications, was calculated during a follow-up period of 7.9 years. In a comprehensive life expectancy period of 47 years, a savings of €5,918,188 would be obtained (P < 0.05). Long-term group data point out that a relevant savings would be expected from implantation of rechargeable IPGs in dystonic patients (P < 0.05) and patients with Parkinson disease (P < 0.05), and a savings is projected to occur in other categories of patients (P < 0.05). CONCLUSIONS: Implantation of rechargeable IPGs presents clinical advantages compared with nonrechargeable devices. A huge economic savings can be realized with the implantation of rechargeable IPGs in categories of patients implanted with IPGs for DBS.