Long-Term Globus Pallidus Internus Deep Brain Stimulation in Pediatric Non-Degenerative Dystonia: A Cohort Study and a Meta-Analysis.

BACKGROUND: The evidence in the effectiveness of deep brain stimulation in children with medication-refractory non-degenerative monogenic dystonia is heterogeneous and long-term results are sparse. OBJECTIVES: The objective is to describe long-term outcomes in a single-center cohort and compare our results with a meta-analysis cohort form literature. METHODS: We performed a retrospective single-center cohort study including consecutive pediatric patients with non-degenerative genetic or idiopathic dystonia treated with globus pallidus internus deep brain stimulation at our center and a systematic review and individual-patient data meta-analysis with the same inclusion criteria. The primary outcome was the change from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFMDRS-M) score. RESULTS: The clinical cohort included 25 patients with a mean study follow-up of 11.4 years. The meta-analysis cohort included 224 patients with a mean follow-up of 3 years. Overall, the BFMDRS-M mean improvements at 1 year and at last follow-up were 41% and 33% in the clinical cohort and 58.9% and 57.2% in the meta-analysis cohort, respectively. TOR1A-dystonia showed the greatest and most stable BFMDRS-M improvement in both cohorts at 1 year and at last follow-up (76.3% and 74.3% in the clinical cohort; 69.6% and 67.3% in the meta-analysis cohort), followed by SGCE-dystonia (63% and 63.9% in the meta-analysis cohort). THAP1-dystonia (70.1% and 29.8% in the clinical cohort; 52.3% and 42.0% in the meta-analysis cohort) and KMT2B-dystonia (33.3% and 41.3% in the clinical cohort; 38.0% and 26.7% in the meta-analysis cohort) showed a less pronounced or sustained response. CONCLUSION: Globus pallidus deep brain stimulation long-term treatment seems effective with a possible gene-specific differential effect. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Bilateral Simultaneous Magnetic Resonance-Guided Focused Ultrasound Pallidotomy for Life-Threatening Status Dystonicus.

BACKGROUND: Invasive treatments like radiofrequency stereotactic lesioning or deep brain stimulation of the globus pallidus internus can resolve drug-resistant status dystonicus (SD). However, these open procedures are not always feasible in patients with SD. OBJECTIVE: The aim was to report the safety and efficacy of simultaneous asleep bilateral transcranial magnetic resonance-guided focused ultrasound (MRgFUS) pallidotomy for life-threatening SD. METHODS: We performed bilateral simultaneous MRgFUS pallidotomy under general anesthesia in 2 young patients with pantothenate kinase-associated neurodegeneration and GNAO1 encephalopathy. Both patients had medically refractory SD and severe comorbidities contraindicating open surgery. RESULTS: SD resolved at 4 and 12 days after MRgFUS, respectively. Adverse events (intraoperative hypothermia and postoperative facial paralysis) were mild and transient. CONCLUSION: Bilateral simultaneous MRgFUS pallidotomy under general anesthesia is safe and may be a valid alternative therapeutic option for fragile patients. Further studies are needed to assess long-term efficacy of the procedure.

Posterior Hypothalamic Region Deep Brain Stimulation for the Treatment of Aggression Disorders in Patients with Intellectual Disability: A Systematic Review.

INTRODUCTION: Aggressive disorders, in patients with intellectual disability, are satisfactorily managed with an educational, psychological, and pharmacological approach. Posterior hypothalamic region deep brain stimulation emerged in the last two decades as a promising treatment for patients with severe aggressive disorders. However, limited experiences are reported in the literature. METHODS: A systematic review was performed following PRISMA guidelines and recommendations by querying PubMed and Embase on August 24th, 2022, with the ensuing string parameters: ([deep brain stimulation] OR [DBS]) AND ([aggressiv*] OR disruptive). Cochrane Library, DynaMed, and ClinicalTrials.gov were consulted using the combination of keywords "deep brain stimulation" and "aggressive" or "aggression". The clinical outcome at the last follow-up and the rate of complications were considered primary and secondary outcomes of interest. RESULTS: The initial search identified 1,080 records, but only 10 studies met the inclusion criteria and were considered. The analysis of clinical outcome and complications was therefore performed on a total of 60 patients. Quality of all selected studies was classified as high, but one. Mean Overt Aggression Scale (OAS) improvement was 68%, while Inventory for Client Agency Planning (ICAP) improvement ranged between 38.3% and 80%. Complications occurred in 4 patients (6.7%). CONCLUSION: Posterior hypothalamic region deep brain stimulation may be considered a valuable option for patients with severe aggression disorders and ID. This review can represent a mainstay for those who will be engaged in the surgical treatment of these patients.

High-Definition 4K-3D Exoscope in Spine Surgery: A Single-Center Experience and Review of the Literature.

Background and Objectives: Binocular optical microscopy (OM) paved the way for a new era in brain and spine neurosurgery fields with the introduction of microsurgery. Despite its enormous contribution to modern neurosurgery, OM presents some intrinsic limitations that surgeons need to face during procedures such as prolonged non-ergonomic positions and decreased vision quality to the assistant eyepiece. To overcome these limitations, in recent years, new operative tools have been introduced, such as exoscopes. Here, we present our experience with exoscopes in spine surgery. Materials and Methods: In the period between January 2022 and December 2023, we gradually implemented the use of a high-definition 4K-3D exoscope (ORBEYETM, Olympus, Japan) in patients undergoing spinal surgery. Results: A total of 243 patients underwent spine surgery with exoscope magnification (47 intradural tumors, 99 lumbar degenerative cases, 79 cervical degenerative cases, 5 dorsal calcified disk herniations, 4 dural arteriovenous fistulas (dAVFs), and 9 others). We compared this cohort with a similar cohort of patients operated in the same period using OM based on different endpoints: operating time, complication rate, and infection rate. We did not find any statistically significant difference in any of the endpoints between these two groups. Conclusions: In our experience, the exoscope provides a better resolution of spinal anatomy and higher quality real-time images of the surgery for the entire OR team and improves the ergonomic posture of both surgeons, without lengthening the operating time and without increasing the rate of adverse events. Prospective studies with a larger cohort of patients are needed to further validate these findings.

Microvascular decompression for trigeminal neuralgia: a single-center experience with 516 cases, including 32 patients with multiple sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the effectiveness and long-term pain relief of microvascular decompression (MVD) for "typical" trigeminal neuralgia (TN), including patients affected by multiple sclerosis (MS). METHODS: Between January 2011 and December 2022, 516 consecutive patients presenting with trigeminal neuralgia and a diagnosed neurovascular conflict at MRI underwent microvascular decompression surgery in our neurosurgery department. Ten surgeons with different ages and experiences performed the surgical procedures. Pain improvement, re-operation rate, and complication rates were retrospectively collected and analyzed. RESULTS: 516 patients were included (214 males 302 females, ranging from 12 to 87 years), including 32 patients with multiple sclerosis. Neurovascular compression was found in all cases during surgery. Barrow Neurological Institute pain intensity scale with a score of I was achieved in 404 patients (78,29%), a score II or III was obtained in 100 cases (19,37%) and a score of IV and V in 12 patients (2,32%). In the multiple sclerosis subset of patients, a BNI score of I was achieved in 21/32 (65.62%). The pain recurrence rate of our series was 15.11%. The follow-up for all patients was at least of 13 months, with a mean follow-up of 41.93 months (± 17.75 months, range 13-91 months). Neither intraoperative mortality nor major intra-operative complications occurred in the analyzed series. The re-operation rate was 12.98%. Thermorhizotomy, percutaneous balloon compression, cyber-knife radiosurgery, or new MVD were the surgical techniques utilized for re-operations. CONCLUSIONS: MVD may be considered an effective and safe surgical technique for TN, and in patients affected by multiple sclerosis, it may be proposed even if a less favorable outcome has to be expected with respect to classic TN patients. Larger studies focusing on the relation of multiple sclerosis with neurovascular compression are required.

3D4K exoscope in epilepsy surgery: a seminal experience.

BACKGROUND AND OBJECTIVES: To report the progressive introduction of the exoscope (EX) from surface lesionectomy to antero-mesial temporal lobectomy (AMTL) in an epilepsy surgery practice. METHODS: We describe a population of ten consecutive patients undergoing EX surgery, with a minimum follow-up of 6 months, that was compared to a similar population of patients referred to operative microscopic surgery (OM). RESULTS: All surgeries were performed with the use of EX or OM alone. Transient neurological complications for surgery in eloquent regions were recorded in one patient for each population. Nine and seven patients undergoing, respectively, EX and OM surgery resulted in Engel class Ia (90% vs. 70%). The mean duration of EX and OM surgery resulted in 265.5 and 237.9 min, respectively, with a mean of 308.3 and 253.3 min for AMTL cases, respectively. CONCLUSIONS: This preliminary study revealed that ORBEYE EX can be safe and effective in different types of epilepsy surgeries. The transition from OM to EX is fast, even though it is slower for the more challenging mesial temporal structure removal. Ergonomic and operative team interaction is improved by the use of EX. Our data need to be confirmed by larger studies.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy May Spare Dopaminergic Therapy in Early-Stage Tremor-Dominant Parkinson's Disease: A Pilot Study.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD). OBJECTIVE: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy. METHODS: We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy. RESULTS: We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy. CONCLUSIONS: In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Short- and long-term motor outcome of STN-DBS in Parkinson's Disease: focus on sex differences.

INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with Parkinson's disease (PD) with motor complications; the contribution of sex in determining the outcome is still not understood. METHODS: We included 107 patients (71 males) with PD consecutively implanted with STN-DBS at our center. We reviewed patient charts from our database and retrospectively collected demographical and clinical data at baseline and at three follow-up visits (1, 5 and 10 years). RESULTS: We found a long-lasting effect of DBS on motor complications, despite a progressive worsening of motor performances in the ON medication condition. Bradykinesia and non-dopaminergic features seem to be the major determinant of this progression. Conversely to males, females showed a trend towards worsening in bradykinesia already at 1-year follow-up and poorer scores in non-dopaminergic features at 10-year follow-up. Levodopa Equivalent Daily Dose (LEDD) was significantly reduced after surgery compared to baseline values; however, while in males LEDD remained significantly lower than baseline even 10 years after surgery, in females LEDD returned at baseline values. Males showed a sustained effect on dyskinesias, but this benefit was less clear in females; the total electrical energy delivered was consistently lower in females compared to males. The profile of adverse events did not appear to be influenced by sex. CONCLUSION: Our data suggest that there are no major differences on the motor effect of STN-DBS between males and females. However, there may be some slight differences that should be specifically investigated in the future and that may influence therapeutic decisions in the chronic follow-up.

Globus pallidus internus activity during simultaneous bilateral microelectrode recordings in status dystonicus.

Limited data are available regarding the electrophysiology of status dystonicus (SD). We report simultaneous microelectrode recordings (MERs) from the globus pallidus internus (GPi) of a patient with SD who was treated with bilateral deep brain stimulation (DBS). Mean neuronal discharge rate was of 30.1 ± 10.9 Hz and 38.5 Hz ± 11.1 Hz for the right and left GPi, respectively. On the right side, neuronal electrical activity was completely abolished at the target point, whereas the mean burst index values showed a predominance of bursting and irregular activity along trajectories on both sides. Our data are in line with previous findings of pallidal irregular hypoactivity as a potential electrophysiological marker of dystonia and thus SD, but further electrophysiological studies are needed to confirm our results.

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.

Staged pallidotomy: MRI and clinical follow-up in status dystonicus.

PURPOSE: We report on a patient affected by Status Distonicus who was treated with Deep Brain Stimulation electrodes implanted in the Globus Pallidus internus (Gpi) and used for serial radiofrequency lesions. MATERIALS AND METHODS: The evolution of radiofrequency lesions was monitored by post-operative and late Magnetic Resonance Imaging (MRI). After the first lesion the patient did improve, though not in a significant fashion. Therefore, three further radiofrequency lesions were delivered 2, 4 and 6 days respectively after surgery with subsequent improvement of dystonic movements. RESULTS: MRI scans performed at 8 days, 3 months, and 6 months after surgery showed a diffuse T2-hyperintense and T1-hypointense GPi signal alteration which progressively decreased over time. CONCLUSION: We confirm that the possibility to stage pallidotomies over time using a couple of new contacts is a safe and efficacious procedure in treating SD patients where the lesions themselves are limited by the appearance of side effects, or in patients showing a poor response to a single lesion. As far as we know, this is the first description of MRI evolution and monitoring of a staged pallidotomy.

An unusual surgical indication for cerebral tuberculosis: status dystonicus. Case report.

Actual indications for surgery in tuberculosis are limited to obtaining a diagnosis, acquiring tissue for culture studies, treating hydrocephalus, aspiring a brain abscess, and reducing intracranial pressure in patients with multiple tuberculomas. Tuberculosis-related movement disorders are usually treated pharmacologically. We report on a child affected by post-tubercular generalized dystonia, who progressed to status dystonicus (SD) and underwent stereotactic bilateral pallidotomy. After surgery, SD resolved, and drugs were rapidly tapered. The successful reversal of SD and the motor improvement observed in our patient demonstrate the safety, feasibility, and clinical efficacy of pallidotomy in post-tuberculous-meningoencephalitis dystonia and SD.

Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition.

BACKGROUND AND PURPOSE: Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy. METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control. RESULTS: We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-ß/p-Smad- and ß-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones. CONCLUSIONS: Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.

"Short term surgical complications after subthalamic deep brain stimulation for Parkinson's disease: does old age matter?".

BACKGROUND: Patients aged 65 years and older are not traditionally considered optimal candidates for subthalamic deep brain stimulation (STN-DBS), mainly for their presumed increased incidence of surgical complications. The aim of this study was to assess STN-DBS surgery safety in relation to age. METHODS: A total of 107 consecutive patients undergoing bilateral STN-DBS at our institution between 2002 and 2014 were retrospectively stratified according to age in two groups (Young group < 65 years old; Elderly group ≥ 65 years old;). Rate of short-term surgical complications (within 90 days) was reviewed and compared between the two groups. RESULTS: Pre-operative baseline data were comparable between the two groups. The 90-days post-operative mortality rate was 0%. Overall incidence of complications related to surgery was 6,54%. In the Elderly group we observed 3 post-operative intra-cerebral haematomas (7,89%), 1 requiring urgent surgical evacuation. In the Young group we observed 2 post-operative asymptomatic intra-cerebral haematomas (2,89%) and 2 wound infections (2,89%), 1 requiring system removal. No others surgical complications were noticed in both groups. CONCLUSIONS: Chronological age ≥ 65 years old should not be considered alone as exclusion criteria to STN-DBS surgery.

Integrative approaches in spinal cord stimulation: Neuropathic pain management and motor recovery in spinal cord injury. A narrative review.

Introduction: Spinal cord stimulation is a widespread treatment of chronic neuropathic pain from different conditions. Several novel and improving technologies have been recently developed to increase the effect of neuromodulation in patients refractory to pharmacological therapy. Research question: To explore spinal cord stimulation's mechanisms of action, indications, and management. Material and methods: The paper initially explores the mechanism of action of this procedure based on the generation of an electric field between electrodes placed on the posterior dural surface of the spinal cord probably interfering with the transmission of pain stimuli to the brain. Subsequently, the most consolidated criteria for selecting patients for surgery, which constitute a major issue of debate, were defined. Thereafter, the fundamental patterns of stimulation were summarized by exploring the advantages and side effects. Lastly, the most common side effects and the related management were discussed. Results: Proper selection of the patient is of paramount importance to achieve the best results from this specific neuromodulation treatment. Regarding the different types of stimulation patterns, no definite evidence-based guidelines exist on the most appropriate approach in relation to the specific type of neuropathic pain. Both burst stimulation and high-frequency stimulation are innovative techniques that reduce the risk of paresthesias compared with conventional stimulation. Discussion and conclusion: Novel protocols of stimulation (burst stimulation and high frequency stimulation) may improve the trade-off between therapeutic benefits and potential side effects. Likewise, decreasing the rates of hardware-related complications will be also useful to increase the application of neuromodulation in clinical settings.

Adaptive vs. Conventional Deep Brain Stimulation: One-Year Subthalamic Recordings and Clinical Monitoring in a Patient with Parkinson's Disease.

Conventional DBS (cDBS) for Parkinson's disease uses constant, predefined stimulation parameters, while the currently available adaptive DBS (aDBS) provides the possibility of adjusting current amplitude with respect to subthalamic activity in the beta band (13-30 Hz). This preliminary study on one patient aims to describe how these two stimulation modes affect basal ganglia dynamics and, thus, behavior in the long term. We collected clinical data (UPDRS-III and -IV) and subthalamic recordings of one patient with Parkinson's disease treated for one year with aDBS, alternated with short intervals of cDBS. Moreover, after nine months, the patient discontinued all dopaminergic drugs while keeping aDBS. Clinical benefits of aDBS were superior to those of cDBS, both with and without medications. This improvement was paralleled by larger daily fluctuations of subthalamic beta activity. Moreover, with aDBS, subthalamic beta activity decreased during asleep with respect to awake hours, while it remained stable in cDBS. These preliminary data suggest that aDBS might be more effective than cDBS in preserving the functional role of daily beta fluctuations, thus leading to superior clinical benefit. Our results open new perspectives for a restorative brain network effect of aDBS as a more physiological, bidirectional, brain-computer interface.

Quantitative Tractography-Based Evaluations in Essential Tremor Patients after MRgFUS Thalamotomy.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug-refractory essential tremor (ET). The relationship between lesion characteristics, dentate-rubro-thalamic-tract (DRTT) involvement and clinical benefit remains unclear. OBJECTIVES: To investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting. METHODS: Forty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion-tensor 3 T-images and location and volume of the lesion were calculated. RESULTS: Probabilistic tractography identified both decussating (d-DRTT) and non-decussating (nd-DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd-DRTT. Despite the lesions predominantly intersecting the medial portion of the d-DRTT, with a significantly greater overlap in responder patients, we observed only a non-significant correlation between tremor improvement and increased d-DRTT-lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1-day MRI (r = 0.42, P < 0.01). CONCLUSION: Variability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method.