Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision ...loss or worsening diabetic macular edema (DME).
To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy.
Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.
Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.
The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.
Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.
Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.
clinicaltrials.gov Identifier: NCT01489189.
Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed.
To evaluate efficacy and safety of 0.5-mg ...intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR.
Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018.
Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group.
Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety.
The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified.
Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR.
ClinicalTrials.gov Identifier: NCT01489189.
To compare rates and identify predictive factors for events that represent worsening of proliferative diabetic retinopathy (PDR) in eyes treated with panretinal photocoagulation (PRP) or ranibizumab.
...Randomized clinical trial (55 United States sites).
Three hundred ninety-four study eyes from 305 adults with PDR, visual acuity (VA) 20/320 or better, and no history of PRP.
Panretinal photocoagulation or intravitreous ranibizumab injections (0.5 mg/0.05 ml).
Time from randomization to a composite PDR-worsening outcome defined as the first occurrence of vitreous hemorrhage, retinal detachment, anterior segment neovascularization, or neovascular glaucoma.
Through 2 years, the cumulative probability of worsening PDR was 42% (PRP) versus 34% (ranibizumab; hazard ratio HR, 1.33; 99% confidence interval CI, 0.90 to 1.98; P = 0.063). Worse baseline levels of diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study scale) were associated with increased risk of worsening PDR, regardless of treatment group (64% high-risk PDR or worse vs. 23% moderate PDR or better; HR, 3.97; 99% CI, 2.48 to 6.36; P < 0.001). In the PRP group, eyes receiving pattern scan versus conventional single-spot PRP also were at higher risk for worsening PDR (60% vs. 39%; HR, 2.04; 99% CI, 1.02 to 4.08; P = 0.008), regardless of the number of spots placed or the number of sittings to complete the initial PRP. Eyes in both groups with vision-impairing (VA 20/32 or worse) center-involved diabetic macular edema (DME) at baseline were required to receive ranibizumab for center-involved DME. Therefore the composite outcome was compared by treatment in the subgroup of eyes that did not have vision-impairing center-involved DME at baseline. For these eyes, the rate of PDR-worsening was greater with PRP than ranibizumab (45% vs. 31%; HR, 1.62; 99% CI, 1.01 to 2.60; P = 0.008).
In eyes with PDR, ranibizumab resulted in less PDR worsening compared with PRP, especially in eyes not required to receive ranibizumab for center-involved DME. Although anti-vascular endothelial growth factor therapy requires a more frequent visit schedule than PRP, these findings provide additional evidence supporting the use of ranibizumab as an alternative therapy to PRP for PDR, at least through 2 years.
To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S.
Post ...hoc analyses from a randomized clinical trial.
Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP).
Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria.
Neovascularization status through 2 years.
At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years.
The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.
Summary
Objectives
Patients with temporal lobe epilepsy (TLE) experience significant deficits in category‐related object recognition and naming following standard surgical approaches. These deficits ...may result from a decoupling of core processing modules (e.g., language, visual processing, and semantic memory), due to “collateral damage” to temporal regions outside the hippocampus following open surgical approaches. We predicted that stereotactic laser amygdalohippocampotomy (SLAH) would minimize such deficits because it preserves white matter pathways and neocortical regions that are critical for these cognitive processes.
Methods
Tests of naming and recognition of common nouns (Boston Naming Test) and famous persons were compared with nonparametric analyses using exact tests between a group of 19 patients with medically intractable mesial TLE undergoing SLAH (10 dominant, 9 nondominant), and a comparable series of TLE patients undergoing standard surgical approaches (n = 39) using a prospective, nonrandomized, nonblinded, parallel‐group design.
Results
Performance declines were significantly greater for the patients with dominant TLE who were undergoing open resection versus SLAH for naming famous faces and common nouns (F = 24.3, p < 0.0001, η2 = 0.57, and F = 11.2, p < 0.001, η2 = 0.39, respectively), and for the patients with nondominant TLE undergoing open resection versus SLAH for recognizing famous faces (F = 3.9, p < 0.02, η2 = 0.19). When examined on an individual subject basis, no SLAH patients experienced any performance declines on these measures. In contrast, 32 of the 39 patients undergoing standard surgical approaches declined on one or more measures for both object types (p < 0.001, Fisher's exact test). Twenty‐one of 22 left (dominant) TLE patients declined on one or both naming tasks after open resection, while 11 of 17 right (nondominant) TLE patients declined on face recognition.
Significance
Preliminary results suggest (1) naming and recognition functions can be spared in TLE patients undergoing SLAH, and (2) the hippocampus does not appear to be an essential component of neural networks underlying name retrieval or recognition of common objects or famous faces.
Abstract Purpose Compare patient-centered outcomes in patients with proliferative diabetic retinopathy (PDR) treated with ranibizumab versus panretinal photocoagulation (PRP). Design Randomized ...clinical trial. Methods Setting : Multicenter (55 US sites). Patient Population : 216 adults with one study eye out of 305 adults (excluding participants with two study eyes since each eye received a different treatment) with PDR, visual acuity 20/320 or better, no history of PRP. Intervention : Ranibizumab (0.5-mg/0.05mL) versus PRP. Main Outcome Measures : Change from baseline to 2 years in composite and pre-specified subscale scores from the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), University of Alabama Low Luminance Questionnaire (UAB-LLQ), Work Productivity and Activity Impairment Questionnaire (WPAIQ). Results For the NEI VFQ-25 and UAB-LLQ composite scores, ranibizumab-PRP treatment group differences (95% CI) were +4.0 (-0.2, +8.3, P =0.06) and +1.8 (-3.5, +7.1, P =0.51) at 1 year, and +2.9 (-1.5, +7.2, P =0.20) and +2.3 (-2.9, +7.5, P =0.37) at 2 years, respectively. Work productivity loss measured with the WPAIQ was 15.6% less with ranibizumab (-26.3%, -4.8%, P =0.005) at 1 year and 2.9% (-12.2%, +6.4%, P =0.54) at 2 years. Eighty-three ranibizumab participants (97%) were 20/40 or better in at least one eye (visual acuity requirement to qualify for an unrestricted driver license in many states) at 2 years compared with 82 PRP participants (87%, adjusted risk ratio=1.1, 95% CI: 1.0, 1.2 P =0.005). Conclusions While differences in some work productivity and driving-related outcomes favored ranibizumab over PRP, no differences between treatment regimens for PDR were identified for most of the other patient-centered outcomes considered.
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as ...nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.
► Excess of rare complete knockouts provides support for inherited component in ASD ► Estimate a 3% contribution to ASD risk for rare autosomal complete knockouts ► A further 2% contribution to ASD risk in males from X-linked complete knockouts ► Discovered ASD candidate genes from screen of rare human knockouts
Lim et al. characterize the role of rare complete knockouts (autosomal genes with homozygous and compound heterozygous loss-of-function variants and hemizygous X chromosome knockouts in males) in ASD and estimate that 5% of cases may have a significant contribution from such alleles.
Removal of the anterior temporal lobe (ATL) is an effective surgical treatment for intractable temporal lobe epilepsy but carries a risk of language and verbal memory deficits. Preoperative ...localization of functional zones in the ATL might help reduce these risks, yet fMRI protocols in current widespread use produce very little activation in this region. Based on recent evidence suggesting a role for the ATL in semantic integration, we designed an fMRI protocol comparing comprehension of brief narratives (Story task) with a semantically shallow control task involving serial arithmetic (Math task). The Story > Math contrast elicited strong activation throughout the ATL, lateral temporal lobe, and medial temporal lobe bilaterally in an initial cohort of 18 healthy participants. The task protocol was then implemented at 6 other imaging centers using identical methods. Data from a second cohort of participants scanned at these centers closely replicated the results from the initial cohort. The Story–Math protocol provides a reliable method for activation of surgical regions of interest in the ATL. The bilateral activation supports previous claims that conceptual processing involves both temporal lobes. Used in combination with language lateralization measures, reliable ATL activation maps may be useful for predicting cognitive outcome in ATL surgery, though the validity of this approach needs to be established in a prospective surgical series.
► An fMRI protocol emphasizing semantic integration activates the anterior temporal lobe. ► ATL activation was consistently observed in individual participants. ► The results were successfully replicated at 6 other imaging centers. ► The methods provide a valuable tool for studying cognitive effects of ATL resection.
PDF
