Novel Extranasal Tear Stimulation: Pivotal Study Results.

Purpose: To evaluate the efficacy and safety of iTEAR, a novel, portable, sonic external neuromodulation device, for the treatment of dry eye disease (DED). Methods: This was a multicenter, open-label, single-arm clinical trial that included adult patients with DED with a Schirmer score of ≤10 mm in at least one eye. Enrolled subjects were instructed to apply the study device at least twice per day for 30 seconds bilaterally to the external nasal nerve. After the initial baseline visit, patients were followed up at days 3, 14, 30, 90, and 180. The primary efficacy endpoint was the Schirmer index (change from unstimulated to stimulated tear production as measured by the Schirmer test) at day 30. The major secondary endpoint was the change in symptoms of DED at day 30 evaluated using the Ocular Surface Disease Index (OSDI). Results: A total of 101 subjects evaluated at day 30 had a mean Schirmer index of 9.4 mm (95% confidence interval [CI], 7.4-11.3), and the baseline OSDI improved by an average of 14.4 (95% CI, 11.1-17.7). Both endpoints were highly statistically and clinically significant at all time points. There were two mild unanticipated adverse events definitely related to the device. Conclusions: The safety and efficacy of the iTEAR device observed in this study support its indication for treating DED. Translational Relevance: Neurostimulation has the potential to improve signs and symptoms of DED.

Phase II randomized sham-controlled study of renal denervation for individuals with uncontrolled hypertension - WAVE IV.

OBJECTIVES: The aim of this double-blind, randomized, sham-controlled study was to verify the blood pressure (BP)-lowering efficacy of externally delivered focused ultrasound for renal denervation (RDN). BACKGROUND: Nonrandomized, first proof-of-concept study and experimental evidence suggested that noninvasive techniques of RDN emerged as an alternative approach of RDN to invasive technologies. METHODS: WAVE IV, an international, randomized (1 : 1) sham-controlled, double-blind prospective clinical study, was prematurely stopped. Patients were enrolled if office BP was at least 160 mmHg and 24-h ambulatory BP was at least 135 mmHg, while taking three or more antihypertensive medications. The treatment consisted of bilateral RDN using therapeutic levels of ultrasound energy and the sham consisted of bilateral application of diagnostic levels of ultrasound energy. RESULTS: In the 81 treated patients neither changes in office BP at 12 and 24 weeks, nor changes in 24-h ambulatory BP at 24-week follow-up visit differed between the two groups significantly. Of note, no safety signal was observed. Adherence analysis disclosed full adherence in 77% at baseline and 82% at 6 months' follow-up visit. Post hoc analysis revealed that stricter criteria for stabilization of BP at baseline were associated with a numerically greater change in 24-h ambulatory BP in the RDN group than in the sham group. CONCLUSION: Our data did not prove that antihypertensive efficacy of the externally delivered focused ultrasound for RDN was greater than the sham effect. Stabilization of BP at baseline was identified as an important determinant of BP changes.

Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die.

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated. Here we show that global ischemia triggers a transient increase in mTOR phosphorylation at S2448, whereas decreasing p-mTOR and functional activity in selectively vulnerable hippocampal CA1 neurons. The decrease in mTOR coincides with an increase in biochemical markers of autophagy, pS317-ULK-1, pS14-Beclin-1, and LC3-II, a decrease in the cargo adaptor p62, and an increase in autophagic flux, a functional readout of autophagy. This is significant in that autophagy, a catabolic process downstream of mTORC1, promotes the formation of autophagosomes that capture and target cytoplasmic components to lysosomes. Inhibitors of the lysosomal (but not proteasomal) pathway rescued the ischemia-induced decrease in mTOR, consistent with degradation of mTOR via the autophagy/lysosomal pathway. Administration of the mTORC1 inhibitor rapamycin or acute knockdown of mTOR promotes autophagy and attenuates ischemia-induced neuronal death, indicating an inverse causal relation between mTOR, autophagy, and neuronal death. Our findings identify a novel and previously unappreciated mechanism by which mTOR self-regulates its own levels in hippocampal neurons in a clinically relevant model of ischemic stroke.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

Externally Delivered Focused Ultrasound for Renal Denervation.

OBJECTIVES: The aim of this study was to assess clinical safety and efficacy outcomes of renal denervation executed by an externally delivered, completely noninvasive focused therapeutic ultrasound device. BACKGROUND: Renal denervation has emerged as a potential treatment approach for resistant hypertension. METHODS: Sixty-nine subjects received renal denervation with externally delivered focused ultrasound via the Kona Medical Surround Sound System. This approach was investigated across 3 consecutive studies to optimize targeting, tracking, and dosing. In the third study, treatments were performed in a completely noninvasive way using duplex ultrasound image guidance to target the therapy. Short- and long-term safety and efficacy were evaluated through use of clinical assessments, magnetic resonance imaging scans prior to and 3 and 24 weeks after renal denervation, and, in cases in which a targeting catheter was used to facilitate targeting, fluoroscopic angiography with contrast. RESULTS: All patients tolerated renal denervation using externally delivered focused ultrasound. Office blood pressure (BP) decreased by 24.6 ± 27.6/9.0 ± 15.0 mm Hg (from baseline BP of 180.0 ± 18.5/97.7 ± 13.7 mm Hg) in 69 patients after 6 months and 23.8 ± 24.1/10.3 ± 13.1 mm Hg in 64 patients with complete 1-year follow-up. The response rate (BP decrease >10 mm Hg) was 75% after 6 months and 77% after 1 year. The most common adverse event was post-treatment back pain, which was reported in 32 of 69 patients and resolved within 72 h in most cases. No intervention-related adverse events involving motor or sensory deficits were reported. Renal function was not altered, and vascular safety was established by magnetic resonance imaging (all patients), fluoroscopic angiography (n = 48), and optical coherence tomography (n = 5). CONCLUSIONS: Using externally delivered focused ultrasound and noninvasive duplex ultrasound, image-guided targeting was associated with substantial BP reduction without any major safety signals. Further randomized, sham-controlled trials will be needed to validate this unique approach.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

Estradiol pretreatment ameliorates impaired synaptic plasticity at synapses of insulted CA1 neurons after transient global ischemia.

Global ischemia in humans or induced experimentally in animals causes selective and delayed neuronal death in pyramidal neurons of the hippocampal CA1. The ovarian hormone estradiol administered before or immediately after insult affords histological protection in experimental models of focal and global ischemia and ameliorates the cognitive deficits associated with ischemic cell death. However, the impact of estradiol on the functional integrity of Schaffer collateral to CA1 (Sch-CA1) pyramidal cell synapses following global ischemia is not clear. Here we show that long term estradiol treatment initiated 14 days prior to global ischemia in ovariectomized female rats acts via the IGF-1 receptor to protect the functional integrity of CA1 neurons. Global ischemia impairs basal synaptic transmission, assessed by the input/output relation at Sch-CA1 synapses, and NMDA receptor (NMDAR)-dependent long term potentiation (LTP), assessed at 3 days after surgery. Presynaptic function, assessed by fiber volley and paired pulse facilitation, is unchanged. To our knowledge, our results are the first to demonstrate that estradiol at near physiological concentrations enhances basal excitatory synaptic transmission and ameliorates deficits in LTP at synapses onto CA1 neurons in a clinically-relevant model of global ischemia. Estradiol-induced rescue of LTP requires the IGF-1 receptor, but not the classical estrogen receptors (ER)-α or ß. These findings support a model whereby estradiol acts via the IGF-1 receptor to maintain the functional integrity of hippocampal CA1 synapses in the face of global ischemia. This article is part of a Special Issue entitled SI: Brain and Memory.

Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study.

PURPOSE: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS: A total of 230 participants with neovascular AMD who received ≥ 3 ranibizumab or bevacizumab injections within the preceding year and requiring treatment at enrollment. METHODS: Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) ranibizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. MAIN OUTCOME MEASURES: Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. RESULTS: At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P = 0.008; mean 5.4, P = 0.09; and mean 6.6, respectively). Change in mean BCVA was -10.0, -7.5, and -6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 µm, 55.4 µm, and 33.3 µm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm(2), respectively. Mean CNV area decreased by 0.1 mm(2) in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension ≤ 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm(3)) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P = 0.001) and mean BCVA 4.4 letters superior to sham (P = 0.24). CONCLUSIONS: A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking.

Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death.

Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown. Here, we show that REST is controlled at the level of protein stability via ß-TrCP-dependent, ubiquitin-based proteasomal degradation in differentiated neurons under physiological conditions and identify Casein Kinase 1 (CK1) as an upstream effector that bidirectionally regulates REST cellular abundance. CK1 associates with and phosphorylates REST at two neighboring, but distinct, motifs within the C terminus of REST critical for binding of ß-TrCP and targeting of REST for proteasomal degradation. We further show that global ischemia in rats in vivo triggers a decrease in CK1 and an increase in REST in selectively vulnerable hippocampal CA1 neurons. Administration of the CK1 activator pyrvinium pamoate by in vivo injection immediately after ischemia restores CK1 activity, suppresses REST expression, and rescues neurons destined to die. Our results identify a novel and previously unappreciated role for CK1 as a brake on REST stability and abundance in adult neurons and reveal that loss of CK1 is causally related to ischemia-induced neuronal death. These findings point to CK1 as a potential therapeutic target for the amelioration of hippocampal injury and cognitive deficits associated with global ischemia.

16 and 24 Gy low-voltage X-ray irradiation with ranibizumab therapy for neovascular age-related macular degeneration: 12-month outcomes.

PURPOSE: To describe the 12-month safety and efficacy outcomes of 16 or 24 Gy radiation using low-voltage x-ray irradiation in conjunction with intravitreal ranibizumab for neovascular age-related macular degeneration (AMD). DESIGN: Prospective, phase I, open-label, nonrandomized uncontrolled safety study. METHODS: setting: Institutional. study population: Neovascular AMD patients. intervention: One x-ray irradiation treatment at 16 or 24 Gy was administered externally through 3 locations in the inferior pars plana. After 2 initial monthly loading doses of ranibizumab, subsequent ranibizumab was administered according to predetermined criteria. main outcome measures: Visual acuity, number of ranibizumab injections, safety and efficacy metrics at 12 months. RESULTS: Forty-seven eyes of 47 patients were enrolled and completed 12 months of follow-up: 16 Gy (n = 28) and 24 Gy (n = 19). There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean visual acuity improved in both groups: +8.4 ± 11.9 letters and +7.8 ± 12 letters for 16 and 24 Gy, respectively. In both groups, 100% of subjects lost <15 letters, with 76% and 79% gaining ≥0 letters in the 16 Gy and 24 Gy groups, respectively. Patients received a mean of 1.0 additional injection over 12 months. The mean change in optical coherence tomography central subfield thickness from baseline to month 12 was -107 and -87 µm for the 16 Gy and 24 Gy groups, respectively. CONCLUSION: One treatment of 16 or 24 Gy low-voltage x-ray therapy with as-needed ranibizumab appears safe in subjects with neovascular AMD at 12 months. An overall improvement in visual acuity was observed. No radiation-related adverse effects were reported.

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.

The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.

Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID study.

PURPOSE: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (nvAMD). DESIGN: Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS: Two hundred thirty patients with onset of nvAMD within 3 years who received 3 or more injections of ranibizumab or bevacizumab within the preceding year and who needed continuing ranibizumab or bevacizumab treatment. INTERVENTIONS: Participants were randomized 2:1:2:1 to 16 Gy plus pro re nata (PRN) ranibizumab, sham 16 Gy plus PRN ranibizumab, 24 Gy plus PRN ranibizumab, or sham 24 Gy plus PRN ranibizumab, respectively. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean number of ranibizumab injections at 52 weeks. Secondary end points were change in mean best-corrected visual acuity (VA), loss of fewer than 15 Early Treatment Diabetic Retinopathy Study letters, gain of 0 or more and 15 or more letters, and change in angiographic total lesion size and choroidal neovascularization (CNV) lesion size. RESULTS: Both the 16-Gy and 24-Gy SRT arms received significantly fewer ranibizumab treatments compared with the sham arms: mean number of treatments, 2.64 (median, 2), 2.43 (median, 2), and 3.74 (median, 3.5), respectively (P = 0.013 and P = 0.004, respectively, vs. sham). Change in mean VA was -0.28, +0.40, and -1.57 letters for the 16-Gy, 24-Gy, and sham arms, respectively. The 16-Gy, 24-Gy, and sham arms lost fewer than 15 letters in 93%, 89%, and 91% of eyes, respectively, with 53%, 57%, and 56% gaining 0 or more letters, respectively, and 4% gaining 15 letters or more in all arms. Mean total angiographic lesion area changed by -1.15 mm(2), +0.49 mm(2), and +0.75 mm(2), respectively; mean CNV lesion area decreased by 0.16 mm(2), 0.18 mm(2), and 0.10 mm(2), respectively. Optical coherence tomography central subfield thickness decreased by 85.90 µm, 70.39 µm, and 33.51 µm, respectively. The number of adverse events (AEs) and number of serious AEs (SAEs) were similar across arms. No AEs were attributed to radiation. No SAEs occurred in the study eye. CONCLUSIONS: A single dose of SRT significantly reduces ranibizumab retreatment for patients with nvAMD, with a favorable safety profile at 1 year. Whereas chronic nvAMD typically results in loss of VA over time, SRT is associated with relatively well-preserved VA over 1 year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a 'radiation-first' strategy.

BACKGROUND AND OBJECTIVE: To describe 'radiation-first' combination treatment with a non-invasive, low-voltage x-ray irradiation system followed by as needed ranibizumab for neovascular age-related macular degeneration (AMD). STUDY DESIGN AND METHODS: Phase I study of non-invasive, low-voltage 16 Gy x-ray irradiation delivered in three beams via the inferior pars plana in patients with active neovascular AMD. Ranibizumab was administered as needed per protocol. Patients were followed monthly for safety and efficacy over 12 months. RESULTS: 13 patients were enrolled and completed 12 months follow-up. Safety was good with no serious ocular/non-ocular adverse events or radiation-related ocular complications. 11 patients lost <15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, seven gained ≥0 ETDRS letters and 0 gained ≥15 ETDRS letters. Patients received a total of 31 subsequent ranibizumab injections (of possible 156) over the 12 months following x-ray irradiation. Mean time to first injection was 3.9 months. One patient received no ranibizumab injections, three patients received one injection, four patients received two injections, and five patients received three or more injections. CONCLUSIONS: After 12 months, non-invasive, low-voltage x-ray irradiation with as needed ranibizumab rescue therapy demonstrated good safety with a visual acuity stabilising effect and reduction in retinal thickness in patients with neovascular AMD.

Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes: 270-day analysis.

Objective. To determine the dose response and toxicity threshold of micro-collimated X-rays delivered to porcine maculae by a stereotactic radiosurgical system after 270 days. Methods. Twelve eyes of six Yucatan mini-swine were randomized to receive up to 90 Gy to the retina, using an office-based trans-pars plana delivery system. To determine the safety profile of this radiation delivery, ophthalmic examination, fundus photography, fluorescein angiography (FA), and spectral domain optical coherence tomography (SD-OCT) were obtained at multiple time points up to 270 days post treatment. Results. No abnormalities were noted on external examination. Cataracts were noted in 4 of 12 eyes. Dose and time-dependent changes were noted on fundus examination, FA, ICG and SD-OCT. No significant abnormalities were seen in the control, 16 Gy or 24 Gy groups using any modality. Histopathology revealed a dose response effect with no discernable lesions in the 16 Gy group. Conclusion. The X-ray delivery system precisely targets the porcine retina in vivo with little effect on surrounding structures. No ophthalmic or intracranial adverse effects were noted at clinically relevant doses at 270 days following radiation delivery.

24-Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular AMD: 6-month safety and functional outcomes.

BACKGROUND AND OBJECTIVE: To describe the 6-month safety and preliminary efficacy outcomes of the use of 24-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: A single treatment of a non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 24 Gy was administered in one session through three locations in the inferior pars plana in a consecutive series of patients with neo-vascular AMD (treatment naïve and previously treated). Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity examinations were performed at 1 week, 1 month, and monthly thereafter with quarterly fluorescein angiography. RESULTS: Nineteen patients completed 6 months of follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 38.3 ± 19.5 letters. At 6 months, the corresponding ETDRS score was 44.7 ± 16.8 letters. At 6 months, the mean change in visual acuity was 6.4 ± 9.8 ETDRS letters. Patients received an average of 0.4 additional ranibizumab injections following the initial two mandated injections. CONCLUSION: A single treatment of external 24-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement in visual acuity in patients with neovascular AMD at 6 months, with no radiation-related adverse effects.

16-Gy low-voltage x-ray irradiation followed by as-needed ranibizumab therapy for AMD: 6-month outcomes of a "radiation-first" strategy.

BACKGROUND AND OBJECTIVE: To describe the effect of a "radiation-first" combination treatment strategy for neovascular age-related macular degeneration (AMD) with ranibizumab rescue therapy. PATIENTS AND METHODS: Non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 16 Gy was given in a single session through three locations in the inferior pars plana in a consecutive series of patients with neovascular AMD. Ranibizumab was administered according to prospectively determined criteria. RESULTS: Thirteen patients completed a 6-month follow-up. All patients lost 15 or fewer ETDRS letters, 7 gained 0 or more ETDRS letters, and 0 gained more than 15 ETDRS letters. Patients received a total of 15 ranibizumab injections following x-ray irradiation at baseline. Two patients received no ranibizumab injections, seven patients received 1 injection, and four patients received 2 injections. CONCLUSION: Low-voltage x-ray treatment followed by ranibizumab rescue demonstrates an independent visual acuity stabilizing effect for patients with wet AMD.

16-Gy low-voltage x-ray irradiation with ranibizumab therapy for AMD: 6-month safety and functional outcomes.

BACKGROUND AND OBJECTIVE: To describe the 6-month safety and preliminary efficacy outcomes of the use of 16-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: A single treatment of a non-invasive, externally delivered low-voltage 16-Gy x-ray irradiation was administered in one session through three locations in the inferior pars plana. Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) examinations were performed at 1 week, 1 month, and monthly thereafter, with quarterly fluorescein angiography (FA). After the two initial ranibizumab injections, subsequent injections were administered according to the following criteria: VA decline of 10 ETDRS letters compared with baseline, increase of 100-µm central foveal thickness on OCT compared with baseline, the development of new submacular hemorrhage, and the development of a new area of classic choroidal neovascularization on FA. RESULTS: Twenty-six patients completed a 6-month follow-up. There was no evidence of radiation retinopathy, optic neuropathy, or cataract. The mean baseline ETDRS score was 46.6 letters (range: 5 to 80; standard deviation [SD]: 21.5). At 6 months, the corresponding ETDRS score was 55.6 letters (range: 25 to 80; SD: 18.9) and the mean change in VA was 9.5 ETDRS letters (SD: 10.3). On responder analysis, 96% lost 15 or fewer ETDRS letters, 81% gained 0 or more ETDRS letters, and 50% gained 15 or more ETDRS letters. Patients received a total of 13 ranibizumab injections following two initial injections. At 6 months, patients received an average of 0.5 additional injections following the initial two mandated injections. CONCLUSION: A single treatment of externally applied, non-invasive 16-Gy low-voltage x-ray therapy in conjunction with ranibizumab demonstrated an overall improvement of VA in patients with neovascular AMD at 6 months with no radiation-related adverse effects.

Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes.

OBJECTIVE: To investigate the effects of a novel stereotactic radiosurgical system for pars plana delivery of microcollimated x-rays to the retina and determine the retinal radiological dose response and toxicity threshold in a pig model. METHODS: The x-rays were delivered through the pars plana to the maculae of Yucatan miniswine to verify the targeting and safety of a cornea-scleral, stabilized, office-based delivery system. Twelve eyes were randomized to receive 0, 16, 24, 42, 60, or 90 Gy in a single dose to the retina. Eye examinations, fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were obtained at days 7, 30, 60, and 90. Indocyanine green angiography was done at day 90. RESULTS: Through day 90 interim analysis, no abnormalities of external structures were noted. A small cortical lens opacity was noted in the 60-Gy group. Fundus evaluation revealed no abnormalities at 16 or 24 Gy. Beginning at day 30, circular pale retinal lesions with sharp margins were noted in the maculae of the eyes that received 42, 60, and 90 Gy. Higher-dose lesions showed late staining on fluorescein angiography, choroidal hypoperfusion on indocyanine green angiography, and defined photoreceptor loss and retinal thinning on spectral-domain optical coherence tomography. CONCLUSION: Transscleral stereotactic radiation dosing of porcine eyes demonstrates no apparent clinical abnormalities in doses less than 24 Gy. Doses of 42 Gy or higher led to focal choroidal and retinal damage within the target area. CLINICAL RELEVANCE: Radiation can induce small-blood vessel closure and thereby has therapeutic potential in neovascular diseases such as age-related macular degeneration.

Stereotactic low-voltage x-ray irradiation for age-related macular degeneration.

The IRay stereotactic low-voltage x-ray irradiation treatment system for age-related macular degeneration consists of a low voltage x-ray tube, an eye tracking system, a robotically controlled delivery system, a coupling device to facilitate tracking and stabilisation, a graphical user interface and gating software. Low-voltage x-rays are delivered in a series of three spots to the macula in a non-invasive manner through the inferior pars plana. These beams are designed to overlap on the centre of the macula. Each beam delivers one-third of the total dose, such that the total macula dose is three times an individual beam's dose. The device is designed to run off standard domestic electrical power, and no special shielding is necessary for the room. This system has been validated in Monte Carlo simulations, human cadaver eye studies, pre-clinical animal studies and in a phase I clinical trial.

Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment.

Fragile X syndrome is the leading single gene cause of intellectual disabilities. Treatment of a Drosophila model of Fragile X syndrome with metabotropic glutamate receptor (mGluR) antagonists or lithium rescues social and cognitive impairments. A hallmark feature of the Fragile X mouse model is enhanced mGluR-dependent long-term depression (LTD) at Schaffer collateral to CA1 pyramidal synapses of the hippocampus. Here we examine the effects of chronic treatment of Fragile X mice in vivo with lithium or a group II mGluR antagonist on mGluR-LTD at CA1 synapses. We find that long-term lithium treatment initiated during development (5-6 weeks of age) and continued throughout the lifetime of the Fragile X mice until 9-11 months of age restores normal mGluR-LTD. Additionally, chronic short-term treatment beginning in adult Fragile X mice (8 weeks of age) with either lithium or an mGluR antagonist is also able to restore normal mGluR-LTD. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of Fragile X syndrome is an important advance, in that this identifies and validates these targets as potential therapeutic interventions for the treatment of individuals afflicted with Fragile X syndrome.