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PURPOSE To quantitatively analyze and compare the novice vitreoretinal surgeons' performance after various types of external exposures. METHODS This prospective, self-controlled, cross-sectional study included 15 vitreoretinal fellows with less than 2 years of experience. Surgical performance was assessed using the Eyesi simulator after each exposure: Day 1, placebo, 2.5, and 5 mg/kg caffeine; Day 2, placebo, 0.2, and 0.6 mg/kg propranolol; Day 3, baseline simulation, breathalyzer reading of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentration; Day 4, baseline simulation, push-up sets with 50% and 85% repetition maximum; Day 5, 3-hour sleep deprivation. Eyesi-generated total scores were the main outcome measured (0-700, worst to best). RESULTS Performances worsened after increasing alcohol exposure based on the total score (χ2 = 7; degrees of freedom = 2; P = 0.03). Blood alcohol concentration 0.06% to 0.10% and 0.11% to 0.15% was associated with diminished performance compared with improvements after propranolol 0.6 and 0.2 mg/kg, respectively (∆1 = -22 vs. ∆2 = +13; P = 0.02; ∆1 = -43 vs. ∆2 = +23; P = 0.01). Propranolol 0.6 mg/kg was positively associated with the total score, compared with deterioration after 2.5 mg/kg caffeine (∆1 = +7 vs. ∆2 = -13; P = 0.03). CONCLUSION Surgical performance diminished dose dependently after alcohol. Caffeine 2.5 mg/kg was negatively associated with dexterity, and performance improved after 0.2 mg/kg propranolol. No changes occurred after short-term exercise or acute 3-hour sleep deprivation.

Leigh syndrome represents a complex inherited neurometabolic and neurodegenerative disorder associated with different clinical, genetic and neuroimaging findings in the context of bilateral symmetrical lesions involving the brainstem and basal ganglia. Heterogeneous neurological manifestations such as spasticity, cerebellar ataxia, dystonia, choreoathetosis and parkinsonism are associated with multisystemic and ophthalmological abnormalities due to >75 different monogenic causes. Here, we describe the clinical and genetic features of a Brazilian cohort of patients with Leigh Syndrome in which muscle biopsy analysis showed mitochondrial DNA defects and determine the utility of whole exome sequencing for a final genetic diagnostic in this cohort.

IMPORTANCE: Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. OBJECTIVES: To establish weight-adjusted cutoffs for caffeine and β-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. DESIGN, SETTINGS, AND PARTICIPANTS: This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). INTERVENTIONS: Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. MAIN OUTCOMES AND MEASURES: An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. RESULTS: Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, –53.0; 95% CI, –99.3 to –6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, –12.0; 95% CI, –21.2 to –2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, –51.0; 95% CI, –77.6 to –24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, –16.0; 95% CI, –31.8 to –0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). CONCLUSIONS AND RELEVANCE: The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.

Background Hypomyelinating leukodystrophies represent an expanding group of neurogenetic disorders characterized primarily by central nervous system hypomyelination and variable neurological and non-neurological involvement. Hypomyelinating disorders have been rarely associated with gonadal dysfunction, being mainly represented by hypogonadotrophic hypogonadism in 4H syndrome. WT1 gene-associated disorders are classically associated with complex phenotypes including early carcinogenic risk for gonadoblastoma and Wilms' tumor, chronic renal failure, nephrotic syndrome and sex developmental disorders in intersex disorders and ambiguous genitalia. Methods The authors describe three non-related Brazilian patients with hypomyelinating leukodystrophy associated with complex neurological and systemic dysfunction with WT1 gene mutations. Results All described patients presented with similar neuroimaging features including thin corpus callosum, mild to moderate cerebellar atrophy and diffuse periventricular and profound hypomyelinating leukodystrophy involving supratentorial white matter with classical compromise linked to inherited non-somatic WT1 gene mutations in a similar pattern to Denys-Drash syndrome, including nephrotic syndrome with different glomerular disease, chronic renal failure, intersex disorder with ambiguous genitalia, and early occurrence of specific tumors, such as Wilms' tumor and gonadoblastoma. Conclusions Clinicians must include WT1 gene mutations in the differential diagnosis of hypomyelinating leukodystrophy with nephrotic syndrome, chronic renal failure, ambiguous genitalia or sex developmental disorders.