Stereotactic Radiosurgery for Intermediate (III) or High (IV-V) Spetzler-Martin Grade Arteriovenous Malformations: International Stereotactic Radiosurgery Society Practice Guideline.

BACKGROUND AND OBJECTIVES: Consensus guidelines do not exist to guide the role of stereotactic radiosurgery (SRS) in the management of patients with Spetzler-Martin Grade III-V arteriovenous malformations (AVMs). We sought to establish SRS practice guidelines for Grade III-V AVMs based on a critical systematic review of the published literature. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant search of Medline, Embase, and Scopus, 1986 to 2023, for publications reporting post-SRS outcomes in ≥10 Grade III-V AVMs with the median follow-up ≥24 months was performed. Primary end points were AVM obliteration and post-SRS hemorrhage. Secondary end points included dosimetric variables, Spetzler-Martin parameters, and neurological outcome. RESULTS: : In total, 2463 abstracts were screened, 196 manuscripts were reviewed, and 9 met the strict inclusion criteria. The overall sample of 1634 AVMs consisted of 1431 Grade III (88%), 186 Grade IV (11%), and 11 Grade V lesions (1%). Total median post-SRS follow-up was 53 months for Grade III and 43 months for Grade IV-V AVMs (ranges, 2-290; 12-262). For Grade III AVMs, the crude obliteration rate was 72%, and among Grade IV-V lesions, the crude obliteration rate was 46%. Post-SRS hemorrhage was observed in 7% of Grade III compared with 17% of Grade IV-V lesions. Major permanent deficits or death from hemorrhage or radiation-induced complications occurred in 86 Grade III (6%) and 22 Grade IV-V AVMs (12%). CONCLUSION: Most patients with Spetzler-Martin Grade III AVMs have favorable SRS treatment outcomes; however, the obliteration rate for Grade IV-V AVMs is less than 50%. The available studies are heterogenous and lack nuanced, long-term, grade-specific outcomes.

Repeat Single-Session Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations: A Systematic Review, Meta-Analysis, and International Stereotactic Radiosurgery Society Practice Guidelines.

BACKGROUND AND OBJECTIVES: Repeat stereotactic radiosurgery (SRS) for residual arteriovenous malformations (AVMs) can be considered as a salvage approach after failure of initial SRS. There are no published guidelines regarding patient selection, timing, or SRS parameters to guide clinical practice. This systematic review aimed to review outcomes and complications from the published literature to inform practice recommendations provided on behalf of the International Stereotactic Radiosurgery Society. METHODS: We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of MEDLINE, Scopus, Web of Science, and Embase was conducted. Fourteen studies with 925 patients met the inclusion criteria. Patients were treated between 1985 and 2022. All studies were retrospective, except for one prospective cohort. RESULTS: The median patient age at repeat SRS ranged from 32 to 60 years. Four studies (630 patients) reported detailed information on Spetzler-Martin grade at the time of repeat SRS; 12.54% of patients had Spetzler-Martin grade I AVMs (79/630 patients), 46.51% had grade II (293/630), 34.92% had grade III (220/630), 5.08% had grade IV (32/630), and 0.95% had grade V (6/630). The median prescription doses varied between 15 and 25 Gy (mean, 13.06-22.8 Gy). The pooled overall obliteration rate at the last follow-up after repeat SRS was 59% (95% CI 51%-67%) with a median follow-up between 21 and 50 months. The pooled hemorrhage incidence at the last follow-up was 5% (95% CI 4%-7%), and the pooled overall radiation-induced change incidence was 12% (95% CI 7%-20%). CONCLUSION: For an incompletely obliterated AVM, repeat radiosurgery after 3 to 5 years of follow-up from the first SRS provides a reasonable benefit to the risk profile. After repeat SRS, obliteration is achieved in the majority of patients. The risk of hemorrhage or radiation-induced change appears low, and International Stereotactic Radiosurgery Society recommendations are presented.

Management of sporadic intracanalicular vestibular schwannomas: A critical review and International Stereotactic Radiosurgery Society (ISRS) practice guidelines.

BACKGROUND: The choice of an appropriate strategy for intracanalicular vestibular schwannoma (ICVS) is still debated. We conducted a systematic review and meta-analysis with the aim to compare treatment outcomes amongst management strategies (conservative surveillance (CS), microsurgical resection (MR), or stereotactic radiosurgery (SRS)) aiming to inform guideline recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2021 referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies or case series reporting a cohort of ICVS managed with CS, MR, or SRS. Primary outcome measures included tumor control, the need for additional treatment, hearing outcomes, and posttreatment neurological deficits. These were pooled using meta-analytical techniques and compared using meta-regression with random effect. RESULTS: Forty studies were included (2371 patients). The weighted pooled estimates for tumor control were 96% and 65% in SRS and CS series, respectively (P < .001). Need for further treatment was reported in 1%, 2%, and 25% for SRS, MR, and CS, respectively (P = .001). Hearing preservation was reported in 67%, 68%, and 55% for SRS, MR, and CS, respectively (P = .21). Persistent facial nerve deficit was reported in 0.1% and 10% for SRS and MR series, respectively (P = .01). CONCLUSIONS: SRS is a noninvasive treatment with at least equivalent rates of tumor control and hearing preservation as compared to MR, with the caveat of better facial nerve preservation. As compared to CS, upfront SRS is an effective treatment in achieving tumor control with similar rates of hearing preservation.

Modern neurosurgical techniques for psychiatric disorders.

Psychosurgery refers to an ensemble of more or less invasive techniques designed to reduce the burden caused by psychiatric diseases in patients who have failed to respond to conventional therapy. While most surgeries are designed to correct apparent anatomical abnormalities, no discrete cerebral anatomical lesion is evident in most psychiatric diseases amenable to invasive interventions. Finding the optimal surgical targets in mental illness is troublesome. In general, contemporary psychosurgical procedures can be classified into one of two primary modalities: lesioning and stimulation procedures. The first group is divided into (a) thermocoagulation and (b) stereotactic radiosurgery or recently introduced transcranial magnetic resonance-guided focused ultrasound, whereas stimulation techniques mainly include deep brain stimulation (DBS), cortical stimulation, and the vagus nerve stimulation. The most studied psychiatric diseases amenable to psychosurgical interventions are severe treatment-resistant major depressive disorder, obsessive-compulsive disorder, Tourette syndrome, anorexia nervosa, schizophrenia, and substance use disorder. Furthermore, modern neuroimaging techniques spurred the interest of clinicians to identify cerebral regions amenable to be manipulated to control psychiatric symptoms. On this way, the concept of a multi-nodal network need to be embraced, enticing the collaboration of psychiatrists, psychologists, neurologists and neurosurgeons participating in multidisciplinary groups, conducting well-designed clinical trials.

Safety and Feasibility of Nucleus Accumbens Surgery for Drug Addiction: A Systematic Review.

BACKGROUND: Substance addiction encompasses the incapacity to discontinue urgent drug use; many severely disabled patients might be considered appropriate candidates for surgery due to the high rates of relapse despite conservative treatment. A crucial finding in the brain of these patients is increased extracellular concentrations of dopamine in the nucleus accumbens (NAcc). OBJECTIVES: To determine the efficacy and safety of NAcc surgery for the treatment of substance dependence. MATERIALS AND METHODS: Adhering to PRISMA guidelines, we performed a systematic review to identify all original studies in which NAcc surgery was performed to treat relapsing drug addiction with a minimum follow-up of six months. From database inception to April 10, 2020, we searched PubMed, Scopus, and LILACS. Two reviewers independently selected studies and extracted data. The main outcome was the relapse rate. The GRADE methods were applied to evaluate the quality of evidence. This study was registered with PROSPERO CRD42020177054. RESULTS: Fifteen studies involving 359 participants met inclusion criteria; eight (56%) included NAcc deep brain stimulation (DBS) in 13 patients with addiction for alcohol (N = 6, 46.1%), opioid (N = 4, 30.7%), and nicotine (N = 3, 15.3%); seven studies (N = 346, 44%) performed NAcc radiofrequency (RF) ablation for opioid (N = 334) and alcohol (N = 12) dependence. Relapse rates were 38.4% for DBS and 39% for RF ablation. CONCLUSIONS: Despite available studies reporting a benefit in the treatment of drug addictions with NAcc surgery, this systematic review stresses the need for carefully planned prospective studies in order to further address the efficacy and indications.

Linear accelerator-based radiosurgery for trigeminal neuralgia: comparative outcomes of frame-based and mask-based techniques.

OBJECTIVE: Precise and accurate targeting is critical to optimize outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). The aim of this study was to compare the outcomes after SRS for TN in which two different techniques were used: mask-based 4-mm cone versus frame-based 5-mm cone. METHODS: The authors performed a retrospective review of patients who underwent SRS for TN at their institution between 1996 and 2019. The Barrow Neurological Institute (BNI) pain score and facial hypesthesia scale were used to evaluate pain relief and facial numbness. RESULTS: A total of 234 patients were included in this study; the mean age was 67 years. In 97 patients (41.5%) radiation was collimated by a mask-based 4-mm cone, whereas a frame-based 5-mm cone was used in the remaining 137 patients (58.5%). The initial adequate pain control rate (BNI I-III) was 93.4% in the frame-based 5-mm group, compared to 87.6% in the mask-based 4-mm group. This difference between groups lasted, with an adequate pain control rate at ≥ 24 months of 89.9% and 77.8%, respectively. Pain relief was significantly different between groups from initial response until the last follow-up (≥ 24 months, p = 0.02). A new, permanent facial hypesthesia occurred in 30.3% of patients (33.6% in the frame-based 5-mm group vs 25.8% in the mask-based 4-mm group). However, no significant association between the BNI facial hypesthesia score and groups was found. Pain recurrence occurred earlier (median time to recurrence 12 months vs 29 months, p = 0.016) and more frequently (38.1% vs 20.4%, p = 0.003) in the mask-based 4-mm than in the frame-based 5-mm group. CONCLUSIONS: Frame-based 5-mm collimator SRS for TN resulted in a better long-term pain relief with similar toxicity profiles to that seen with mask-based 4-mm collimator SRS.

Gamma Ray Radiosurgery for Trigeminal Neuralgia: Targeting Proximal or Distal to the Dorsal Root Entry Zone.

Introduction Stereotactic radiosurgery for trigeminal neuralgia (TN) has gained interest among patients who are not suitable for surgical procedures. Although two target zones are more recognized - dorsal root entry zone (DREZ) and retrogasserian zone (RGZ) - the optimal targeting technique remains controversial in terms of clinical outcomes and rates of complications. Therefore, various modifications to the radiosurgical technique for TN have been made. Objective This study aimed to determine the differences in shoot location (i.e., RGZ vs. DREZ) regarding effectiveness and adverse effects in patients with medically refractory TN. Additionally, we evaluated the effect of the integral dose (ID) on treatment outcomes and complications. Methods We present a retrospective cohort study of 49 patients with primary, drug-resistant TN treated with gamma knife radiosurgery targeting the distal and proximal parts of the nerve regarding the DREZ with a prescription dose of 90 Gy (80 to 96 Gy). A subset of these patients (n=38) where the ID could be measured to the nerve was correlated to treatment outcomes and complications. Results The median follow-up time was 36 months for RGZ and 51 months for DREZ targets. Neurovascular conflict was identified in 87.5% of the RGZ group and 88.2% of the DREZ group. Using the Barrow Neurological Institute (BNI) pain score, 26 (81.3%) RGZ and 12 (70.6%) DREZ patients were successfully treated (BNI I-IIIb; p=0.02). Seven (21.9%) RGZ and eight (47.1%) DREZ patients reported complete pain relief without medication (BNI I). Time response was 22.3 days for RGZ and 34.1 days for DREZ (p=0.277). There were 10 (31.3%) patients in the RGZ group with associated complications versus six (35.3%) patients in the DREZ group (χ2=0.0826, degree of freedom=1, p=0.773). Treatment outcomes using higher ID were better in the RGZ than DREZ (81.8% vs. 57.1, respectively), and a significant association was found between a higher ID delivered to the nerve and the development of complications (p=0.02). Conclusion Based on the obtained results, the RGZ was a more effective targeting area with better treatment outcomes without significant differences in complication rates than DREZ. A higher ID at the RGZ than DREZ had a greater therapeutical effect. Further investigation regarding the optimal target area along the ID delivered and clinical outcomes are required.

Delayed Brain Cyst Formation After Gamma Knife Anterior Capsulotomy.

BACKGROUND: Gamma Knife ventral anterior capsulotomy is an effective option to treat refractory obsessive-compulsive disorder. Although well tolerated, complications can develop years after radiosurgery. We describe a case in which abnormal complications induced by very high doses of radiation evolved. CASE DESCRIPTION: A 55-year-old man with refractory obsessive-compulsive disorder was treated with Gamma Knife ventral anterior capsulotomy using a dose of 180 Gy. His obsessive-compulsive symptoms improved, but his condition evolved with a manic episode, cognitive memory changes, visual hallucinations, confabulation, and frontal lobe symptoms. Magnetic resonance imaging showed brain edema in the left hemisphere and a 6-mm brain cyst in the right hemisphere at postoperative month 20. CONCLUSIONS: This case shows the consequences of affecting more fibers related to the anterior frontal region than intended with a radiosurgical procedure and illustrates the importance of careful clinical and imaging follow-up after Gamma Knife ventral anterior capsulotomy.

Upholding Scientific Duty Amidst Poisonous Disinformation.

Because of a recent politically-biased Lancet editorial, the world's opinion has been directed against the Brazilian government over the rising numbers of COVID-19 cases in the country. This is an example of reporting data without accounting for important covariates. Epidemiological figures should always be corrected for population size. In fact, Brazil is not even on the list of the 10 countries with the highest number of deaths per 100,000 people. Belgium, the United Kingdom, and Spain are the most affected countries in this regard. The disinformation presented by a renowned medical journal has ignited severe criticisms against a Chief-of-State for not promoting a generalized lockdown in a country of continental size. As scientists, we have a duty to stress the caveats of science instead of fueling political attacks, and we should refrain from jumping to uninformed conclusions without considering well-analyzed data. Moreover, while there is no evidence to endorse the efficacy of a generalized lockdown in socioeconomically vulnerable populations, it is undoubtedly associated with severe nationwide adverse effects.

Gamma Knife Radiosurgery for Transmodiolar Schwannoma.

BACKGROUND: Rare and deep located tumors are surgical challenge with high morbidity. Minimal invasive techniques should be encouraged for a better outcome. Intralabyrinthine schwannoma (ILS) is a rare benign tumor that usually presents with hearing loss and tinnitus. Surgery is associated with high rate of facial paralysis and deafness. Radiosurgery is an option for tinnitus treatment, without the risk of facial paralysis. CASE DESCRIPTION: A young male patient presented with severe hearing loss and incapacitating tinnitus. Magnetic resonance revealed the presence of a small ILS. Radiosurgery was performed and obtained tinnitus control without complications and no further tumor growth. CONCLUSIONS: Tumor control and symptoms relief could be safely achieved through a precisely plan using Gamma Knife radiosurgery, decreasing morbidity. This is the first radiosurgical description for a transmodiolar schwannoma.

Understanding gamma ventral capsulotomy: Potential implications of diffusion tensor image tractography on target selectivity.

BACKGROUND: The role of tractography in gamma ventral capsulotomy (GVC) planning is still unclear. This paper aims to describe the spatial distribution of medial orbitofrontal cortex (OFC) and lateral OFC fibers passing through the anterior limb of the internal capsule (ALIC) and analyze quantitative tractography parameters that differentiate obsessive-compulsive disorder (OCD) individuals from other neurosurgery functional patients (morbid obesity and Parkinson's disease [PD]). METHODS: Twenty patients undergoing functional stereotactic procedures, between 2013 and 2016, were included in this study. OCD patients underwent GVC (single shot 150 Gy and 4-mm collimators). PD and morbid obesity patients were submitted to deep brain stimulation implants. Diffusion tensor image tractography was reconstructed using Brainlab Elements software (Brainlab AG, Munich, Germany). RESULTS: Nine PD, six morbid obesity, and five OCD patients were included with a mean age of 65.4 ± 9.1, 41.0 ± 8.2, and 31.2 ± 5.5, respectively, which are statistically different from each other (P < 0.001). Fourteen patients (70%) were men. A total of 40 cerebral hemispheres were analyzed. Medial OFC fibers are localized more inferior in the ALIC than the lateral OFC fibers in all hemispheres, but the level of intersection and exact topography of fiber bundles are variable among individuals. Both medial and lateral OFC fiber tracts of PD and morbid obesity patients have lower volume than, respectively, medial and lateral counterparts of OCD patients (P < 0.001). CONCLUSIONS: Medial and lateral OFC tract fibers have a general standard distribution in the anterior internal capsule (lateral OFC higher than medial OFC fibers). There are differences between obesity, Parkinson, and OCD patients regarding fiber tract statistics.

Immediate Pain Relief Elicited After Radiosurgery for Classical and Symptomatic Trigeminal Neuralgia.

Background Immediate relief following radiosurgery for trigeminal neuralgia (TN) has been observed in a minority of cases. Objective Our goals were to determine the occurrence of immediate pain relief as real vs. placebo effect and to search for factors associated with this desirable outcome. Methods Between January 2003 and June 2008, 150 patients were treated with radiosurgery for classical or symptomatic TN. A commercially available linear accelerator (Novalis®, BrainLab) device was used to deliver 90 Gy to the root-entry zone with a 4- or 5-mm collimator. Pain outcomes were graded using a four-point scale. Complications were recorded through standardized follow-up evaluations. Treatment plans were retrieved and brainstem/trigeminal nerves were retrospectively re-contoured using standard anatomical landmarks. Dose-volume histograms were used to calculate the volume of brainstem/trigeminal nerve receiving 20%, 30%, and 50% of the prescribed radiation doses. Results Twenty-five (19.84%) patients presented with immediate pain relief, defined as pain cessation within 48 hours post-radiosurgery. Kaplan-Meier analysis showed that good/excellent pain outcomes were sustained and significantly better in the immediate pain relief group (p = 0.006) compared to non-immediate relief. Univariate and multivariate logistic regression analyses failed to show the correlation between brainstem/trigeminal nerve volumes, trigeminal nerve-pontine angle, prior surgical procedures, TN etiology, age, gender, and immediate pain relief. Neither post-radiosurgery complications nor recurrence rates were different between groups. Conclusion Immediate pain relief leads to sustained relief and patients present significantly better pain outcomes in comparison to those without immediate relief. The mechanism triggering immediate relief is still unknown and did not correlate with the volume of brainstem/trigeminal nerve receiving pre-specified doses of radiation.

Effect of a Quality Improvement Intervention on Adherence to Therapies for Patients With Acute Ischemic Stroke and Transient Ischemic Attack: A Cluster Randomized Clinical Trial.

IMPORTANCE: Translating evidence into clinical practice in the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA) is challenging, especially in low- and middle-income countries. OBJECTIVE: To assess the effect of a multifaceted quality improvement intervention on adherence to evidence-based therapies for care of patients with AIS and TIA. DESIGN, SETTING AND PARTICIPANTS: This 2-arm cluster-randomized clinical trial assessed 45 hospitals and 2336 patients with AIS and TIA for eligibility before randomization. Eligible hospitals were able to provide care for patients with AIS and TIA in Brazil, Argentina, and Peru. Recruitment started September 12, 2016, and ended February 26, 2018; follow-up ended June 29, 2018. Data were analyzed using the intention-to-treat principle. INTERVENTIONS: The multifaceted quality improvement intervention included case management, reminders, a roadmap and checklist for the therapeutic plan, educational materials, and periodic audit and feedback reports to each intervention cluster. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite adherence score for AIS and TIA performance measures. Secondary outcomes included an all-or-none composite end point of performance measures, the individual process measure components of the composite end points, and clinical outcomes at 90 days after admission (stroke recurrence, death, and disability measured by the modified Rankin scale). RESULTS: A total of 36 hospitals and 1624 patients underwent randomization. Nineteen hospitals were randomized to the quality improvement intervention and 17 to routine care. The overall mean (SD) age of patients enrolled in the study was 69.4 (13.5) years, and 913 (56.2%) were men. Overall mean (SD) composite adherence score for the 10 performance measures in the intervention group hospitals compared with control group hospitals was 85.3% (20.1%) vs 77.8% (18.4%) (mean difference, 4.2%; 95% CI, -3.8% to 12.2%). As a secondary end point, 402 of 817 patients (49.2%) at intervention hospitals received all the therapies that they were eligible for vs 203 of 807 (25.2%) in the control hospitals (odds ratio, 2.59; 95% CI, 1.22-5.53; P = .01). CONCLUSIONS AND RELEVANCE: A multifaceted quality improvement intervention did not result in a significant increase in composite adherence score for evidence-based therapies in patients with AIS or TIA. However, when using an all-or-none approach, the intervention resulted in improved adherence to evidence-based therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02223273.

Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder.

For more than half a century, stereotactic neurosurgical procedures have been available to treat patients with severe, debilitating symptoms of obsessive-compulsive disorder (OCD) that have proven refractory to extensive, appropriate pharmacological, and psychological treatment. Although reliable predictors of outcome remain elusive, the establishment of narrower selection criteria for neurosurgical candidacy, together with a better understanding of the functional neuroanatomy implicated in OCD, has resulted in improved clinical efficacy for an array of ablative and non-ablative intervention techniques targeting the cingulum, internal capsule, and other limbic regions. It was against this backdrop that gamma knife capsulotomy (GKC) for OCD was developed. In this paper, we review the history of this stereotactic radiosurgical procedure, from its inception to recent advances. We perform a systematic review of the existing literature and also provide a narrative account of the evolution of the procedure, detailing how the procedure has changed over time, and has been shaped by forces of evidence and innovation. As the procedure has evolved and adverse events have decreased considerably, favorable response rates have remained attainable for approximately one-half to two-thirds of individuals treated at experienced centers. A reduction in obsessive-compulsive symptom severity may result not only from direct modulation of OCD neural pathways but also from enhanced efficacy of pharmacological and psychological therapies working in a synergistic fashion with GKC. Possible complications include frontal lobe edema and even the rare formation of delayed radionecrotic cysts. These adverse events have become much less common with new radiation dose and targeting strategies. Detailed neuropsychological assessments from recent studies suggest that cognitive function is not impaired, and in some domains may even improve following treatment. We conclude this review with discussions covering topics essential for further progress of this therapy, including suggestions for future trial design given the unique features of GKC therapy, considerations for optimizing stereotactic targeting and dose planning using biophysical models, and the use of advanced imaging techniques to understand circuitry and predict response. GKC, and in particular its modern variant, gamma ventral capsulotomy, continues to be a reliable treatment option for selected cases of otherwise highly refractory OCD.

Double Blinded Randomized Trial of Subcutaneous Trigeminal Nerve Stimulation as Adjuvant Treatment for Major Unipolar Depressive Disorder.

BACKGROUND: More than 30% of major depressive disorder patients fail to respond to adequate trials of medications and psychotherapy. While modern neuromodulation approaches (ie, vagal nerve stimulation, deep brain stimulation) are yet to prove their efficacy for such cases in large randomized controlled trials, trigeminal nerve stimulation (TNS) has emerged as an alternative with promising effects on mood disorders. OBJECTIVE: To assess efficacy, safety, tolerability, and placebo effect duration of continuous subcutaneous TNS (sTNS) in treatment-resistant depression (TRD). METHODS: The TREND study is a single-center, double-blind, randomized, controlled, phase II clinical trial. Twenty unipolar TRD patients will receive V1 sTNS as adjuvant to medical therapy and randomized to active vs sham stimulation throughout a 24-wk period. An additional 24-wk open-label phase will follow. Data concerning efficacy, placebo response, relapse, and side effects related to surgery or electrical stimulation will be recorded. We will use the HDRS-17, BDI-SR, IDS_SR30, and UKU scales. EXPECTED OUTCOMES: The main outcome measure is improvement in depression scores using HAM-17 under continuous sTNS as adjuvant to antidepressants. Active stimulation is expected to significantly impact response and remission rates. Minor side effects are expected due to the surgical procedure and electrical stimulation. The open-label phase should further confirm efficacy and tolerability. DISCUSSION: This study protocol is designed to define efficacy of a novel adjuvant therapy for TRD. We must strive to develop safe, reproducible, predictable, and well-tolerated neuromodulation approaches for TRD patients impaired to manage their lives and contribute with society.

An international cluster-randomized quality improvement trial to increase the adherence to evidence-based therapies for acute ischemic stroke and transient ischemic attack patients: Rationale and design of the BRIDGE STROKE Trial.

BACKGROUND: Translating evidence into clinical practice in the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA) is challenging especially in low- and middle-income countries. OBJECTIVES: The aim of this study is to assess the effect of a multifaceted quality improvement intervention on adherence to evidence-based therapies for AIS and TIA patients care. DESIGN: We designed a pragmatic, 2-arm cluster-randomized trial involving 36 clusters and 1624 patients from Brazil, Argentina, and Peru. Hospitals are randomized to receive a multifaceted quality improvement intervention (intervention group) or to routine care (control group). The BRIDGE Stroke multifaceted quality improvement intervention includes case management, reminders, health care providers' educational materials (including treatment algorithms), interactive workshops, and audit and feedback reports. Primary outcome is a composite adherence score to AIS and TIA performance measures. Secondary outcomes include an "all or none" composite end point to performance measures, the individual components of the composite end points, and clinical outcomes at 90 days following admission (stroke recurrence, death, and disability measured by the modified Rankin scale). SUMMARY: The BRIDGE Stroke Trial is an international pragmatic evaluation of a multifaceted quality improvement intervention. If effective, this intervention could be potentially extended widely to improve the quality of care and outcomes of patients with AIS or TIA.

An Open-Label Clinical Trial of Hypothalamic Deep Brain Stimulation for Human Morbid Obesity: BLESS Study Protocol.

BACKGROUND: Human morbid obesity is increasing worldwide in an alarming way. The hypothalamus is known to mediate its mechanisms. Deep brain stimulation (DBS) of the ventromedial hypothalamus (VMH) may be an alternative to treat patients refractory to standard medical and surgical therapies. OBJECTIVE: To assess the safety, identify possible side effects, and to optimize stimulation parameters of continuous VMH-DBS. Additionally, this study aims to determine if continuous VMH-DBS will lead to weight loss by causing changes in body composition, basal metabolism, or food intake control. METHODS: The BLESS study is a feasibility study, single-center open-label trial. Six patients (body mass index > 40) will undergo low-frequency VMH-DBS. Data concerning timing, duration, frequency, severity, causal relationships, and associated electrical stimulation patterns regarding side effects or weight changes will be recorded. EXPECTED OUTCOMES: We expect to demonstrate the safety, identify possible side effects, and to optimize electrophysiological parameters related to VMH-DBS. No clinical or behavioral adverse changes are expected. Weight loss ≥ 3% of the basal weight after 3 mo of electrical stimulation will be considered adequate. Changes in body composition and increase in basal metabolism are expected. The amount of food intake is likely to remain unchanged. DISCUSSION: The design of this study protocol is to define the safety of the procedure, the surgical parameters important for target localization, and additionally the safety of long-term stimulation of the VMH in morbidly obese patients. Novel neurosurgical approaches to treat metabolic and autonomic diseases can be developed based on the data made available by this investigation.

Asymmetric neuromodulation of motor circuits in Parkinson's disease: The role of subthalamic deep brain stimulation.

Whereas hemispheric dominance is well-established for appendicular motor control in humans, the evidence for dominance in axial motor control is still scarce. In Parkinson's disease (PD), unilateral (UL) onset of appendicular motor symptoms corresponds with asymmetric neurodegeneration predominantly affecting contralateral nigrostriatal circuits. Disease progression yields bilateral and axial motor symptoms but the initial appendicular asymmetry usually persists. Furthermore, there is evidence for hemispheric dominance for axial motor dysfunction in some of these patients. Dopaminergic medications improve appendicular symptoms but can also produce motor complications over time. Once these complications develop, bilateral (BL) deep brain stimulation (DBS) of the subthalamic nuclei (STN) can significantly improve appendicular symptoms while reducing medication doses and motor complications. Conversely, axial motor symptoms remain a significant source of disability, morbidity, and mortality for patients with PD. These axial symptoms do not necessarily improve with dopaminergic therapy, might not respond, and could even worsen after BL-DBS. In contrast to medications, DBS provides the opportunity to modify stimulation parameters for each cerebral hemisphere. Identical, BL-DBS of motor circuits with hemispheric dominance in PD might produce overstimulation on one side and/or understimulation on the other side, which could contribute to motor dysfunction. Several studies based on asymmetry of appendicular motor symptoms already support an initial UL rather than BL approach to DBS in some patients. The response of axial motor symptoms to UL versus BL-DBS remains unclear. Nonetheless, UL-DBS, staged BL-DBS, or asymmetric programming of BL-DBS could also be considered in patients with PD.

The hypothalamus at the crossroads of psychopathology and neurosurgery.

The neurosurgical endeavor to treat psychiatric patients may have been part of human history since its beginning. The modern era of psychosurgery can be traced to the heroic attempts of Gottlieb Burckhardt and Egas Moniz to alleviate mental symptoms through the ablation of restricted areas of the frontal lobes in patients with disabling psychiatric illnesses. Thanks to the adaptation of the stereotactic frame to human patients, the ablation of large volumes of brain tissue has been practically abandoned in favor of controlled interventions with discrete targets. Consonant with the role of the hypothalamus in the mediation of the most fundamental approach-avoidance behaviors, some hypothalamic nuclei and regions, in particular, have been selected as targets for the treatment of aggressiveness (posterior hypothalamus), pathological obesity (lateral or ventromedial nuclei), sexual deviations (ventromedial nucleus), and drug dependence (ventromedial nucleus). Some recent improvements in outcomes may have been due to the use of stereotactically guided deep brain stimulation and the change of therapeutic focus from categorical diagnoses (such as schizophrenia) to dimensional symptoms (such as aggressiveness), which are nonspecific in terms of formal diagnosis. However, agreement has never been reached on 2 related issues: 1) the choice of target, based on individual diagnoses; and 2) reliable prediction of outcomes related to individual targets. Despite the lingering controversies on such critical aspects, the experience of the past decades should pave the way for advances in the field. The current failure of pharmacological treatments in a considerable proportion of patients with chronic disabling mental disorders is reminiscent of the state of affairs that prevailed in the years before the early psychosurgical attempts. This article reviews the functional organization of the hypothalamus, the effects of ablation and stimulation of discrete hypothalamic regions, and the stereotactic targets that have most often been used in the treatment of psychopathological and behavioral symptoms; finally, the implications of current and past experience are presented from the perspective of how this fund of knowledge may usefully contribute to the future of hypothalamic psychosurgery.

The role of diffusion tensor imaging tractography for Gamma Knife thalamotomy planning.

OBJECTIVE The role of tractography in Gamma Knife thalamotomy (GK-T) planning is still unclear. Pyramidal tractography might reduce the risk of radiation injury to the pyramidal tract and reduce motor complications. METHODS In this study, the ventralis intermedius nucleus (VIM) targets of 20 patients were bilaterally defined using Iplannet Stereotaxy Software, according to the anterior commissure-posterior commissure (AC-PC) line and considering the localization of the pyramidal tract. The 40 targets and tractography were transferred as objects to the GammaPlan Treatment Planning System (GP-TPS). New targets were defined, according to the AC-PC line in the functional targets section of the GP-TPS. The target offsets required to maintain the internal capsule (IC) constraint of < 15 Gy were evaluated. In addition, the strategies available in GP-TPS to maintain the minimum conventional VIM target dose at > 100 Gy were determined. RESULTS A difference was observed between the positions of both targets and the doses to the IC. The lateral (x) and the vertical (z) coordinates were adjusted 1.9 mm medially and 1.3 mm cranially, respectively. The targets defined considering the position of the pyramidal tract were more medial and superior, based on the constraint of 15 Gy touching the object representing the IC in the GP-TPS. The best strategy to meet the set constraints was 90° Gamma angle (GA) with automatic shaping of dose distribution; this was followed by 110° GA. The worst GA was 70°. Treatment time was substantially increased by the shaping strategy, approximately doubling delivery time. CONCLUSIONS Routine use of DTI pyramidal tractography might be important to fine-tune GK-T planning. DTI tractography, as well as anisotropy showing the VIM, promises to improve Gamma Knife functional procedures. They allow for a more objective definition of dose constraints to the IC and targeting. DTI pyramidal tractography introduced into the treatment planning may reduce the incidence of motor complications and improve efficacy. This needs to be validated in a large clinical series.