A Proposal for the Use of a Fixed Low-Energy Selective Laser Trabeculoplasty for Open Angle Glaucoma.

Selective laser trabeculoplasty (SLT) has been in routine clinical use for over 20 years with millions of patients successfully treated and a low rate of clinically significant complications. The procedure requires the clinician to manually position the laser beam on the trabecular meshwork using a gonioscopy lens and to titrate the SLT laser energy based on the amount of pigmentation in the angle, as well as the observation of small bubbles produced by the laser effect. We propose that SLT energy titration is unnecessary either to achieve intraocular pressure (IOP) reduction or to minimize potential side effects. Ample evidence to support our proposal includes multiple clinical reports demonstrating comparable levels of IOP reduction resulting from different laser energies, a large variety of energy and other laser parameters used in commercially available SLT lasers, and the nature of the laser-induced changes in the trabecular meshwork tissue with respect to energy. Despite these variations in laser parameters, SLT consistently reduces IOP with a low complication rate. We propose that using low fixed energy for all patients will effectively and safely lower patients' IOP while reducing the complexity of the SLT procedure, potentially making SLT accessible to more patients.

Direct selective laser trabeculoplasty in open angle glaucoma study design: a multicentre, randomised, controlled, investigator-masked trial (GLAUrious).

INTRODUCTION: Laser trabeculoplasty is an effective and widely used treatment for glaucoma. A new laser technology, the Eagle direct selective laser trabeculoplasty (DSLT) device, may provide automated, fast, simple, safe and effective laser treatment for glaucoma in a broader range of clinical settings. This trial aims to test the hypothesis that translimbal DSLT is effective and not inferior to selective laser trabeculoplasty (SLT) in reducing intraocular pressure (IOP) in open angle glaucoma (OAG). METHODS AND ANALYSIS: This is a multicentre, randomised, controlled, investigator-masked study. The primary efficacy outcome is intergroup difference in mean change from baseline IOP measured at 6 months. Secondary outcomes include mean percentage reduction in IOP at 3, 6 and 12 months; proportion of participants with at least 20% reduction in IOP from baseline at 6 months; change in ocular hypotensive medications at 12 months and evaluation of safety. Participants were aged >= 40 years with OAG, including exfoliative or pigmentary glaucoma, or ocular hypertension with untreated or washed out IOP 22-35 mm Hg. TREATMENTS: DSLT: 120 shots, 3 ns, 400 µm spot size, energy 1.4-1.8 mJ delivered at the limbus over 2 s. SLT: approximately 100 shots, 3 ns, 400 µm spot size administered 360 degrees at the limbus using any gonioscopy lens, energy 0.3-2.6 mJ. A sample size of 164 is sufficient to detect a non-inferiority margin of 1.95 mm Hg for change from baseline IOP. CLINICAL TRIAL REGISTRATION NUMBER: NCT03750201, ISRCTN14033075.

Energy Dose-Response in Selective Laser Trabeculoplasty: A Review.

PRCIS: A literature review of selective laser trabeculoplasty (SLT) energy dose-response found no definitive relationship between intraocular pressure (IOP) reduction with respect to total or pulse energy, race, pigmentation, or application pattern. PURPOSE: SLT is a safe and effective treatment for lowering IOP. Although evidence is mounting for the advantage of its use as a first-line treatment for IOP reduction, the SLT procedures in use vary widely. The purpose of this literature review was to investigate whether there were any relationships between SLT energy and efficacy for lowering IOP in the published literature. METHODS: A literature review was undertaken that included studies in which energy levels required for successful SLT treatment were investigated: in general, with respect to angle pigmentation, race or ethnicity, and treatment arc extent. RESULTS: There was no indication that higher (or lower) energy used in the treatment leads to greater (or less) IOP reduction. Similar results were obtained regarding the level of trabecular meshwork pigmentation. Race was not found to be associated with altered dose response in SLT. There were indications that treating the full 360 degrees, as opposed to smaller arcs, could be beneficial for more IOP reduction. IOP reduction from SLT was found to be similar to that provided by topical medications. CONCLUSIONS: The optimal energy level of SLT needed for IOP reduction has not yet been definitively established, with all reported pulse energies resulting in similar IOP reduction. Furthermore, similar lack of conclusive findings exists regarding optimal SLT energy dosage for use in different races and degrees of trabecular meshwork pigmentation. This parameter and each of the abovementioned factors requires further research.

Refined Sphenopalatine Ganglion Stimulator Placement and Intensity Setting to Augment Blood Flow and Neurologic Function.

Background and Purpose- Two large, randomized trials indicated that sphenopalatine ganglion (SPG) stimulation improves final disability outcome in acute anterior circulation patients with ischemic stroke with confirmed cortical involvement. This study evaluated 2 refinements in SPG stimulation treatment technique: (1) SPG electrode placement with real-time optical tracking guidance; and (2) stimulation intensity comfortable tolerance level selection using non-noxious facial physiological markers. Methods- This study was a single, active arm trial at 4 centers, enrolling patients with anterior circulation ischemic stroke, National Institutes of Health Stroke Scale 1 to 6 including arm weakness subitem score ≥1, not receiving recanalization therapies, and within 24 hours of onset. Stimulation level was set based on ipsilateral facial tingling sensation or lacrimation. SPG stimulation effects were assessed by measuring volumetric blood flow in the ipsilateral common carotid artery by ultrasound and grasp and pinch strength in the affected hand before and during stimulation, and by change in National Institutes of Health Stroke Scale from day 1 to 7. Results- Among 50 enrolled patients, age was median 66 years (interquartile range, 60-74), 44% were female, National Institutes of Health Stroke Scale median was 5 (interquartile range, 4-5), and median onset-to-screening time was 18 hours (interquartile range, 9-20). Median implantation skin-to-skin time was 4 minutes (interquartile range, 3-7), and all 50 implants were placed correctly. Comfortable tolerance level was found based on physiological biomarkers in 96% of patients, including 86% in the optimal, low-medium intensity range. SPG stimulation significantly increased common carotid artery peak systolic and end-diastolic blood flow (44%, P<0.0001; and 52%, P<0.0001) and improved pinch strength (42%, P<0.0001) and grasp strength (26%, P<0.0001). Degree of National Institutes of Health Stroke Scale recovery by day 7 was greater than in matched historic controls, median 75% versus 50%, P=0.0003. Conclusions- SPG stimulator placement with real-time optical tracking guidance was fast and accurate, and selection of stimulation intensity levels based on non-noxious facial tingling and lacrimation was feasible in nearly all patients. SPG stimulation led to cervico-cranial blood flow augmentation and improved hand motor function. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03551093.

Sphenopalatine Ganglion Stimulation to Augment Cerebral Blood Flow: A Randomized, Sham-Controlled Trial.

Background and Purpose- Many patients with acute ischemic stroke are not eligible for thrombolysis or mechanical reperfusion therapies due to contraindications, inaccessible vascular occlusions, late presentation, or large infarct core. Sphenopalatine ganglion (SPG) stimulation to enhance collateral flow and stabilize the blood-brain barrier offers an alternative, potentially more widely deliverable, therapy. Methods- In a randomized, sham-controlled, double-masked trial at 41 centers in 7 countries, patients with anterior circulation ischemic stroke not treated with reperfusion therapies within 24 hours of onset were randomly allocated to active SPG stimulation or sham control. The primary efficacy outcome was improvement beyond expectations on the modified Rankin Scale of global disability at 90 days (sliding dichotomy), assessed in the modified intention-to-treat population. The initial planned sample size was 660 patients, but the trial was stopped early when technical improvements in device placement occurred, so that analysis of accumulated experience could be conducted to inform a successor trial. Results- Among 303 enrolled patients, 253 received at least one active SPG or sham stimulation, constituting the modified intention-to-treat population (153 SPG stimulation and 100 sham control). Age was median 73 years (interquartile range, 64-79), 52.6% were female, deficit severity on the National Institutes of Health Stroke Scale was median 11 (interquartile range, 9-15), and time from last known well median 18.6 hours (interquartile range, 14.5-22.5). For the primary outcome, improved 3-month disability beyond expectations, rates in the SPG versus sham treatment groups were 49.7% versus 40.0%; odds ratio, 1.48 (95% CI, 0.89-2.47); P=0.13. A significant treatment interaction with stroke location (cortical versus noncortical) was noted, P=0.04. In the 87 patients with confirmed cortical involvement, rates of improvement beyond expectations were 50.0% versus 27.0%; odds ratio, 2.70 (95% CI, 1.08-6.73); P=0.03. Similar response patterns were observed for all prespecified secondary efficacy outcomes. No differences in mortality or serious adverse event safety end points were observed. Conclusions- SPG stimulation within 24 hours of onset is safe in acute ischemic stroke. SPG stimulation was not shown to statistically significantly improve 3-month disability above expectations, though favorable outcomes were nominally higher with SPG stimulation. Beneficial effects may distinctively be conferred in patients with confirmed cortical involvement. The results of this study need to be confirmed in a larger pivotal study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03767192.

An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial.

BACKGROUND: Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood-brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8-24 h after acute ischaemic stroke improved functional outcome. METHODS: ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40-80 years and women aged 40-85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8-24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059. FINDINGS: Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89-1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05-2·10; p=0·0258). There was an inverse U-shaped dose-response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low-midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population. INTERPRETATION: Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8-24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial's results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome. FUNDING: BrainsGate Ltd.