Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons.

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.

Retinal Detachments after Open-Globe Injury: Risk Factors and Outcomes.

PURPOSE: To identify risk factors for retinal detachment (RD) after open-globe injury (OGI) and evaluate outcomes of RD repair after OGI. DESIGN: Case-control study. PARTICIPANTS: Overall, 769 patients presented with 786 OGIs, which were surgically managed with ≥ 30 days of follow-up. Of the 786 eyes, 223 developed RD, the other 551 served as controls, and RD status of 12 eyes was unknown. METHODS: A retrospective chart review was performed of all OGIs presented to the University of Michigan between 2000 and 2022. Multivariable regression identified risk factors for RD after OGI and predictors of poor vision after RD repair. Kaplan-Meier analysis estimated time from OGI to RD. MAIN OUTCOME MEASURE: Predictors of visual outcome after RD repair after OGI. RESULTS: After OGI, 223 (28.4%) of 786 eyes were diagnosed with RD, with > 73% diagnosed within a month. Predictors of RD include posterior injury (zone II vs. I odds ratio [OR], 1.60 [95% confidence interval {CI}, 1.04-2.46]; P = 0.0331; zone III vs. I OR, 2.29 [1.53-3.41]; P < 0.0001), vitreous hemorrhage (OR, 2.29 [1.54-3.1]; P < 0.0001), and presenting acuity worse than count fingers (CFs) (OR, 2.65 [1.69 - 4.16]; P < 0.0001). Retinal detachment repair took place in 142 of 223 eyes. The mean logarithm of minimal angle of resolution visual acuity (VA) improved from 2.3 ± 0.8 to 1.7 ± 0.9 after RD repair at 6-month follow-up, with 51.2% of eyes achieving CF or better vision. Single surgery anatomic success rate was 69.7% and final anatomic success was 88%. Predictors of vision worse than CF include history of ocular surgery (OR, 0.32 [0.11-0.94]; P = 0.039), proliferative vitreoretinopathy (PVR; OR, 0.39 [0.16 - 0.92]; P = 0.032), aphakia (OR, 0.25 [0.08 - 0.77]; P = 0.016), and redetachment (OR, 0.26 [0.1 - 0.63]; P = 0.003). CONCLUSIONS: Most RD occur within the first month after OGI. Patients with posterior injuries, vitreous hemorrhage, or poor presenting VA were more likely to develop RD after OGI. Anatomic success was achieved in the majority, as was final VA of CF vision or better. History of ocular surgery, PVR at time of repair, aphakia, and redetachment were risk factors for a poor outcome. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Secondary Choroidal Neovascularization in Combined Hamartoma of the Retina and Retinal Pigment Epithelium.

Purpose: To report a 4-year-old boy with a large, macula-involving combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) lesion with an associated choroidal neovascular membrane involving the fovea, characterized with multimodal imaging. Methods: Case report. Results: Given the low likelihood of visual improvement with intervention, observation was recommended and the CHRRPE remained stable on follow-up 4 months after presentation. Conclusion: CHRRPE is a rare congenital retinal lesion that is variably pigmented. Awareness of rare complications, such as CNVM, as seen in this pediatric case is paramount.

Outcomes of Penetrating Keratoplasty After Open Globe Injury.

PURPOSE: The purpose of this study was to investigate the clinical features, surgical outcomes, and prognostic factors of penetrating keratoplasty (PKP) after open globe injury (OGI). METHODS: A retrospective review of all patients treated for OGI between January 2000 and July 2017 was conducted. Demographic, preoperative, perioperative, and postoperative data were collected for those who underwent PKP after OGI. The predictive value of each preoperative variable on graft failure was assessed using univariate and multivariable Cox proportional hazards models, and the predictive value of variables on post-PKP visual outcome was assessed using both univariate and multivariable logistic regression models. All eyes that underwent PKP after OGI were included unless they had less than 365 days of follow-up. RESULTS: Forty-six eyes that underwent PKP met inclusion criteria. The median age was 46 years (interquartile range = 23.00-61.25), median follow-up was 78.5 months (interquartile range = 38.63-122.02), and 37 of 46 subjects (80.4%) were male. The observed 1- and 5-year graft survival estimates were 80.4% and 41.7%, respectively. Factors statistically associated with graft failure in multivariable analyses were rejection episode, hazard ratio (HR) = 3.29; retinal detachment (RD), HR = 3.47; and endophthalmitis, HR = 6.27. Fifteen of 42 eyes (35.7%) regained ambulatory vision (20/200 or better). The strongest predictors of vision worse than 20/200 at the last follow-up were RD, odds ratio (OR) = 43.88; graft rejection, OR = 12.42; and injury outside the workplace, OR = 25.05. CONCLUSIONS: Despite a high graft survival at 1 year, most of the patients did not regain ambulatory vision. Graft rejection, RD, and endophthalmitis were risk factors for graft failure. These factors should be considered when counseling patients regarding PKP after OGI.

Concentric Macular Rings Without Ocular Pathology.

Concentric macular rings (CMRs) of Henle's fiber layer (HFL) are an uncommon imaging phenomenon previously associated with foveal hypoplasia and epiretinal membrane. Here, we present a case of a 15-year-old boy with bilateral CMRs, normal visual function, and no ocular pathology. These bilateral findings in the absence of vitreomacular traction, foveal hypoplasia, or any other ocular abnormality suggest that macular rings may occur as a normal but rare variant of HFL architecture. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:353-355.].

Clinical Presentation and Outcomes of Rhegmatogenous Retinal Detachments During the COVID-19 Lockdown and Its Aftermath at a Tertiary Care Center in Michigan.

BACKGROUND AND OBJECTIVE: To investigate the effect of the coronavirus disease 2019 (COVID-19) lockdown on the presentation and management of acute, primary rhegmatogenous retinal detachment (RRD). PATIENTS AND METHODS: This was a single-center, consecutive case series with historic controls, examining patients during the COVID-19 "stay-at-home" order (March 24 to June 1, 2020), the subsequent reopening phase (June 1 to July 31, 2020), and corresponding preceding intervals (March 24 to July 31, 2016 to 2019). RESULTS: Despite a significant increase in patients presenting with macula-off RRD during the COVID-19 lockdown compared to the 2016 to 2019 timeframe (P = .03), the rate of single surgery anatomical success was similar between all groups (P = .66), as was final visual acuity (P = .61). No delays between presentation and surgical intervention were observed during the lockdown (P = .49). CONCLUSIONS: Despite the limitations of the COVID-19 lockdown, patients underwent surgery in a timely manner and achieved comparable visual outcomes to controls before COVID-19. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:593-600.].

Contemporary Management of Complex and Non-Complex Rhegmatogenous Retinal Detachment Due to Giant Retinal Tears.

PURPOSE: To investigate the clinical features and surgical outcomes of rhegmatogenous retinal detachment (RRD) associated with giant retinal tears (GRTs) at a tertiary referral center. PATIENTS AND METHODS: A retrospective, non-consecutive interventional case series of GRT-associated RRDs that underwent primary surgical repair at the University of Michigan W.K. Kellogg Eye Center between January 1, 2011 and July 1, 2020. Clinical characteristics and preoperative, perioperative, and postoperative data were collected. RESULTS: Forty-eight eyes of 47 patients with GRT-associated RRDs met inclusion criteria, including those that were children (under 12 years, N=4, 8.3%), associated with a history of trauma (N=20, 41.7%) or with grade C proliferative vitreoretinopathy (PVR-C) (N=7, 14.6%) at baseline. Median age was 46 years (interquartile range (IQR): 29 years, range: 4 to 72 years), median follow-up was 28 months (IQR: 43 months, range: 3-124 months), and 83.3% (N=40) of subjects were male. Primary surgical repair for GRT-associated RRDs included pars plana vitrectomy (PPV) (N=40, 83.3%), scleral buckle (SB) (N=1, 2.1%), or combined PPV/SB (N=7, 14.6%). Surgical approach commonly involved the use of perfluorocarbon liquid (N=43, 90%) and gas tamponade (N=39, 81%). Single surgery anatomic success (SSAS) was 75% (95% CI: 60%, 85%) at 3 months and 65% (95 CI: 47%, 78%) at 2 years. Final anatomic success was achieved in all 48 eyes (100%). Median visual acuity improved from 20/250 preoperatively to 20/60 at final follow-up, with 44% (N=20) of eyes achieving postoperative visual acuity of 20/40 or better. CONCLUSION: In this series from a tertiary referral center, both complex and non-complex GRT-associated RRDs were most commonly managed with PPV alone, perfluorocarbon liquid, and gas tamponade with favorable final anatomic and visual outcomes comparable to other modern GRT series.

Epigenomic analysis of Parkinson's disease neurons identifies Tet2 loss as neuroprotective.

Parkinson's disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover, Tet2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. Tet2 loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.