Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Surgeon effects on cataract refractive outcomes are minimal compared with patient comorbidity and gender: an analysis of 490 987 cases.

AIM: To investigate effect of patient age, gender, comorbidities and surgeon on refractive outcomes following cataract surgery. METHODS: Study population: patients on UK national ophthalmic cataract database on cataract operations undertaken between 1 April 2010 and 31 August 2018. Variables examined included gender, age, diabetic retinopathy, glaucoma, high myopia, inherited retinal disease, optic nerve disease, uveitis, pseudoexfoliation, vitreous opacities, retinal pathology, cataract type, previous surgery and posterior capsular rupture. A multivariate normal cross-classified model was fitted to the refractive outcome using Markov Chain Monte Carlo (MCMC) methods with diffuse priors to approximate maximum likelihood estimation. A MCMC chain was generated with a burn-in of 5000 iterations and a monitoring chain of 50 000 iterations. RESULTS: 490 987 cataract operations were performed on 351 864 patients by 2567 surgeons. Myopic and astigmatic errors were associated with posterior capsule rupture (-0.38/+0.04×72), glaucoma (-0.10/+0.05×95), previous vitrectomy (-0.049/+0.03×66) and high myopia (-0.07/+0.03×57). Hyperopic and astigmatic errors were associated with diabetic retinopathy (+0.08/+0.03×104), pseudoexfoliation (+0.07/+0.01×158), male gender (+0.12/+0.05×91) and age (-0.01/+0.06×97 per increasing decade). Inherited retinal disease, optic nerve disease, previous trabeculectomy, uveitis, brunescent/white cataract had no significant impact on the error of the refractive outcome. The effect of patient gender and comorbidity was additive. Surgeons only accounted for 4% of the unexplained variance in refractive outcome. CONCLUSION: Patient comorbidities and gender account for small but statistically significant differences in refractive outcome, which are additive. Surgeon effects are very small.

Evaluating Refractive Outcomes after Cataract Surgery.

PURPOSE: To compare methods for evaluating refractive outcomes after cataract surgery to detect outliers. DESIGN: Case series database study of the evaluation of diagnostic technology. PARTICIPANTS: Consecutive patients who had uneventful cataract operations over a 5-year period. METHODS: The intended and postoperative refractive outcome and differences between these were analyzed as a spherical equivalent, cylinder, and spherocylinder. The average keratometry and differences between steep and flat keratometric meridians were used to calculate the intended refractive error. MAIN OUTCOME MEASURES: Outliers were defined as patients for whom the difference between the intended and postoperative refractive errors was more than 3 standard deviations (SDs) away from the mean. RESULTS: A total of 9000 patients were included. Twelve patients had missing data and were excluded. The mean intended refractive outcome was -0.12+0.12×2 (95% lower confidence limit [LCL], -1.94+1.06×44; 95% upper confidence limit [UCL], +0.77+1.05×140). The actual postoperative refractive error was -0.30+0.47×6 (95% LCL, -2.36+1.31×36; 95% UCL, +1.00+1.18×148) with a difference from the intended of -0.18+0.35×7 (95% LCL, -1.91+1.22×38; 95% UCL, +0.75+1.09×145). Treating the components of the refractive error independently, outliers were observed in 82 eyes (0.91%) based on the sphere, 46 eyes (0.51%) based on the spherical equivalent, 115 eyes (1.28%) based on treating the cylinder as a scalar, and 76 eyes (0.85%) based on treating the cylinder as a vector. When the differences between the intended and postoperative refractive errors were calculated as a compound spherocylinder, outliers were observed for 233 eyes (2.59%). CONCLUSIONS: Treating the intended refractive outcome as a spherocylinder improves the precision for detecting clinically significant refractive outliers.

2-0 Prolene brow suspension for paediatric ptosis: a retrospective case series of 37 eyes.

AIM: To assess the efficacy of 2-0 prolene brow suspension surgery in paediatric ptosis with poor levator function. MATERIALS AND METHODS: Retrospective review of cases that underwent 2-0 Prolene brow suspension surgery between 1997-2007. Primary surgical success was defined as post-operative lid height clear of the pupil and asymmetry of 2 mm or less. RESULTS: Twenty-seven patients (37 lids) were included in the study. The mean follow-up period was 71 months (range 2-173). There were 10 recurrences giving an overall success rate of 72.9%. The complication rate was 5.4%. CONCLUSIONS: Prolene brow suspension surgery in most patients has a long-lasting effect with a low complication rate. Success rates are comparable to other non-autogenous materials. This may obviate the need for a more definitive secondary procedure in the future.

First eye prediction error improves second eye refractive outcome results in 2129 patients after bilateral sequential cataract surgery.

OBJECTIVE: To define theoretical correction factors for second-eye intraocular lens (IOL) power adjustment based on first eye refractive prediction error (PE). DESIGN: Database study. PARTICIPANTS: We included 2129 patients who underwent bilateral sequential phacoemulsification cataract surgery with the same IOL model. METHODS: Retrospectively calculated PEs (Hoffer Q, Holladay 1, SRK/T) were analyzed for association between paired eyes, examining the effect of interocular differences in axial length (AL) and corneal power. A range of correction factors (CF) derived from the first eye PE were applied to the second eye PE using optimized and non-optimized IOL constants (IOLCs). MAIN OUTCOME MEASURES: Second eye mean absolute error (MAE). RESULTS: Prediction errors of paired eyes were correlated. Interocular corneal power differences exceeding 0.60 diopters (D) were associated with a weaker correlation but interocular AL differences did not affect the correlation. When a 50% CF was applied to second eyes of patients with a first eye PE between ±0.50 and ±1.50 D, it improved refractive outcomes from 30%, 56%, and 92% to 42%, 75%, and 96% within ±0.25 D, ±0.50 D and ±1.00 D, respectively, and reduced the MAE from 0.49 to 0.37 D (P<0.0001). For first eye PE below ±0.50 D, a 50% CF reduced the MAE from 0.32 to 0.30 D (P<0.00001). A 50% CF also reduces second eye MAE for eyes with nonoptimized IOLCs. CONCLUSIONS: A 50% CF reduces second eye PE when either first eye optimized PE is within ±1.50 D or when nonoptimized IOLCs are used. The correlation is weaker when interocular corneal power differences are >0.60 D.

Intraocular lens formula constant optimization and partial coherence interferometry biometry: Refractive outcomes in 8108 eyes after cataract surgery.

PURPOSE: To assess the benefits of intraocular lens (IOL)-constant optimization for IOLMaster biometry on refractive outcomes after cataract surgery for all surgeons and individual surgeons, define acceptable levels of error in IOL-constant optimization, and calculate the minimum number of eyes required for IOL-constant optimization. SETTING: Department of Ophthalmology, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, United Kingdom. DESIGN: Database study. METHODS: Hypothetical prediction errors were retrospectively calculated on prospectively collected data extracted from electronic medical records using manufacturers' and optimized IOL constants with Hoffer Q, Holladay 1, and SRK/T formulas for 2 IOLs. The acceptable IOL-constant optimization error margins, personalized IOL constants for individual surgeons, and minimum sample sizes for IOL-constant optimization were evaluated. RESULTS: Optimization of IOL constants reduced the mean absolute errors from 0.66 diopters (D) and 0.52 D to 0.40 D and 0.42 D for the Sofport AO IOL and Akreos Fit IOL, respectively. The percentage of eyes within ±0.25 D, ±0.50 D, and ±1.00 D of target refraction improved from for both IOL models. The IOL-constant errors exceeding 0.09 for the Hoffer Q, 0.09 for the Holladay 1, and 0.15 for the SRK/T produced inferior outcomes. Differences in personalized IOL constants between most surgeons were clinically insignificant. Calculating IOL constants to within 0.06, 0.06, and 0.10 for the Hoffer Q, Holladay 1, and SRK/T, respectively, required 148 to 257 eyes. CONCLUSIONS: Optimizing IOL constants for IOLMaster biometry substantially improved refractive outcomes, far exceeding any additional benefit of personalizing IOL constants for individual surgeons. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosure is found in the footnotes.

Formula choice: Hoffer Q, Holladay 1, or SRK/T and refractive outcomes in 8108 eyes after cataract surgery with biometry by partial coherence interferometry.

PURPOSE: To assess how intraocular lens (IOL) formula choice affects refractive outcomes after cataract surgery using IOLMaster biometry. SETTING: Department of Ophthalmology, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, United Kingdom. DESIGN: Database study. METHODS: Hypothetical prediction errors were retrospectively calculated on prospectively collected data from electronic medical records using optimized Hoffer Q, Holladay 1, and SRK/T formulas (Sofport AO and Akreos Fit IOLs) across a range of 0.5 mm or 1.0 mm axial length (AL) subgroups. RESULTS: In short eyes, the Hoffer Q had the lowest mean absolute error (MAE) for ALs from 20.00 to 20.99 mm. The Hoffer Q and Holladay 1 had a lower MAE than the SRK/T for ALs from 21.00 to 21.49 mm. There were no statistically significant differences in MAE for ALs from 21.50 to 21.99 mm. In medium eyes, there were no statistically significant differences in MAE for any IOL formula for ALs from 22.00 to 23.49 mm. For ALs from 23.50 to 25.99 mm, there was a trend toward lower MAEs for the Holladay 1, with statistically significant differences in 2 subgroups. In long eyes, the SRK/T had the lowest MAE, with statistically significant differences for ALs of 27.00 mm or longer. CONCLUSIONS: The Hoffer Q performed best for ALs from 20.00 to 20.99 mm, the Hoffer Q and Holladay 1 for ALs from 21.00 to 21.49 mm, and the SRK/T for ALs of 27.00 mm or longer. Using optimized constants, refractive outcomes of 40%, 75%, and 95% within ±0.25 diopter (D), ±0.50 D, and ±1.00 D, respectively, were achievable. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosure is found in the footnotes.

Reversible cicatricial ectropion precipitated by topical brimonidine eye drops.

Bilateral cicatricial ectropian was precipitated by topical brimonidine eye drops. On discontinuation of the drug, the ectropian resolved. Patients on brimonidine who develop cicatricial ectropian should not be managed surgically at first presentation.

Therapy insight: The recognition and treatment of retinal manifestations of systemic vasculitis.

A variety of retinal signs can occur in patients who have systemic vasculitides, or who experience complications of these diseases or their treatment. Although treatment of these retinal manifestations is usually the treatment of the systemic disease, specific treatment is occasionally indicated to preserve vision. The more prevalent of the systemic vasculitides are giant cell arteritis, polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, relapsing polychondritis and systemic lupus erythematosus. Less frequently occurring vasculitides include Takayasu's arteritis, Goodpasture's disease, microscopic polyangiitis and Henoch-Schönlein purpura, as well as vasculitis secondary to scleroderma and rheumatoid arthritis. This article describes the pathogenesis, clinical features and treatment of retinal manifestations of systemic vasculitides.

Diplopia associated with the cosmetic use of botulinum toxin a for facial rejuvenation.

We report three cases in which cosmetic injections of botulinum toxin A around the eye caused diplopia. Diplopia was due to inferior oblique paresis, which was bilateral in two cases. We suggest that consent for periocular botulinum toxin procedures should include a warning about diplopia.