Macular thickness fluctuation in neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor.

OBJECTIVE: To establish whether increased variability in macular thickness in neovascular age-related macular degeneration (nAMD) patients affects visual outcomes in clinical practice DESIGN: Retrospective cohort study PARTICIPANTS: Treatment-naive nAMD patients studied over 24 months METHODS: Central subfield thickness (CST) values from optical coherence tomography were collected quarterly from baseline to 24 months, and standard deviations (SDs) were calculated. The relationship was modeled with mixed-effects regression between CST SD and 24-month change in visual acuity (VA). Linear regression modeling determined predictors of CST SD. RESULTS: A total of 422 eyes with nAMD were studied. Baseline and 24-month CST values (mean ± SD) were 331.2 ± 97.6 and 253.4 ± 53.6 µm (Δ = -77.8 ± 104.7 µm, p < 0.001), with CST SD across 24 months of 42.0 ± 32.8 µm. Baseline and 24-month VA were 58.8 ± 19.2 and 62.4 ± 20.6 Early Treatment of Diabetic Retinopathy Study letters (Δ = +3.7 ± 20.8 letters, p = 0.008). CST SD over 24 months was a statistically significant negative predictor of 24-month change in VA (-15.41 [-20.98, -9.83] letters per 100 µm, p < 0.001). Quartile analysis of 24-month VA by CST SD showed a +11.2-letter difference between the first and last quartiles (p < 0.001). Baseline CST was a predictor of 24-month CST SD (24.88 [22.69, 27.06] µm per 100 µm, p < 0.001). CONCLUSIONS: Higher macular thickness fluctuations are related to poorer visual outcomes at 24 months in patients with nAMD treated with anti-vascular endothelial growth factor injections. Macular thickness variability may be an important prognostic factor of visual outcomes in nAMD eyes.

Visual outcomes following cataract surgery in age-related macular degeneration patients.

OBJECTIVE: To evaluate visual acuity (VA) outcomes, prognostic factors, and changes in disease severity in patients with age-related macular degeneration (AMD) undergoing cataract surgery. DESIGN: Retrospective cohort study PARTICIPANTS: Patients with AMD or healthy control patients who underwent cataract surgery between 2012 and 2017. METHODS: Eyes were categorized into 3 AMD groups-intermediate AMD (iAMD), fovea-involving geographic atrophy (GA), neovascular AMD (nAMD)-and 3 preoperative VA-matched control groups (iAMDc), fovea-involving geographic atrophy control (GAc), neovaascular AMD control (nAMDc). RESULTS: We compared 216 iAMD, 35 GA, and 184 nAMD eyes with 130, 31, and 129 controls. At postoperative month 12 (POM12), VA increased significantly in iAMD and nAMD (+10.1 ± 14.5 and +9.7 ± 18.9 letters, p < 0.001), but not in GA (p = 0.68). All control groups showed significant VA gains (iAMDc: +17.1 ± 9.7, GAc: +30 ± 12.9, and nAMDc: +26.4 ± 15.6 letters, p < 0.001). For AMD groups, POM12 VA and gain in VA were significantly lower than that of controls (p < 0.01), and better preoperative VA predicted smaller VA gains (p ≤ 0.007). Longer duration of AMD in iAMD, ellipsoid zone disruption in nAMD, and lower central subfield thickness in GA were associated with poorer VA outcomes (p < 0.05). Development of nAMD occurred in 8 iAMD eyes and was associated with longer duration of disease (p = 0.001). For nAMD eyes, injection frequency did not vary between the 12-month pre- and postoperative periods (p = 0.051). CONCLUSIONS: Cataract surgery improves VA for patients with iAMD and nAMD, albeit not to the level of those without retinal pathology. Preoperative VA, AMD duration, and optical coherence tomography parameters may be important prognostic factors for cataract surgery in patients with AMD.

Functional imaging of mitochondria in retinal diseases using flavoprotein fluorescence.

Mitochondria are critical for cellular energy production and homeostasis. Oxidative stress and associated mitochondrial dysfunction are integral components of the pathophysiology of retinal diseases, including diabetic retinopathy (DR), age-related macular degeneration, and glaucoma. Within mitochondria, flavoproteins are oxidized and reduced and emit a green autofluorescence when oxidized following blue light excitation. Recently, a noninvasive imaging device was developed to measure retinal flavoprotein fluorescence (FPF). Thus, oxidized FPF can act as a biomarker of mitochondrial dysfunction. This review article describes the literature surrounding mitochondrial FPF imaging in retinal disease. The authors describe the role of mitochondrial dysfunction in retinal diseases, experiments using FPF as a marker of mitochondrial dysfunction in vitro, the three generations of retinal FPF imaging devices, and the peer-reviewed publications that have examined FPF imaging in patients. Finally, the authors report their own study findings. Goals were to establish normative reference levels for FPF intensity and heterogeneity in healthy eyes, to compare between healthy eyes and eyes with diabetes and DR, and to compare across stages of DR. The authors present methods to calculate a patient's expected FPF values using baseline characteristics. FPF intensity and heterogeneity were elevated in diabetic eyes compared to age-matched control eyes, and in proliferative DR compared to diabetic eyes without retinopathy. In diabetic eyes, higher FPF heterogeneity was associated with poorer visual acuity. In conclusion, while current retinal imaging modalities frequently focus on structural features, functional mitochondrial imaging shows promise as a metabolically targeted tool to evaluate retinal disease.

Risk factors and timing of subsequent cutaneous squamous cell carcinoma in patients with cutaneous squamous cell carcinoma: A retrospective cohort study.

BACKGROUND: Information about the frequency and timing of subsequent cutaneous squamous cell carcinoma (cSCC), along with associated risk factors, is limited. However, this information is crucial to guide follow-up care for these patients. OBJECTIVE: To evaluate the risk and timing of subsequent cSCC in patients who presented with an initial diagnosis of cSCC. METHODS: Retrospective review of an institutional review board-approved, single-institution registry of invasive cSCC. All patients had at least 2 primary cSCCs diagnosed on 2 separate dates 2 months apart. RESULTS: A total of 299 primary cSCCs were included. At 6 months from initial cSCC diagnosis, 18.06% (n = 54) of patients developed subsequent cSCC; at 1 year, 31.77% (n = 94); at 3 years, 67.56% (n = 202); and at 5 years, 87.96% (n = 263) developed subsequent cSCC. Risk factors associated with subsequent cSCC include age at initial diagnosis (hazard ratio [HR], 1.02; 95% confidence interval, 1.004-1.027; P = .008), T2 stage (HR, 1.66; 95% CI, 1.07-2.57; P = .025), and poor tumor grade. Tumor grades well, moderate, and unknown have HRs of 0.21 (P < .001), 0.16 (P .001), and 0.25 (P = .001), respectively. CONCLUSIONS: Of patients who develop subsequent cSCC, 18.06% do so within 6 months, and 31.77% do so within 1 year of initial cSCC diagnosis. Patients with advanced age, poor histologic differentiation, and American Joint Committee on Cancer T2 stage are at highest risk. Close clinical follow-up after the initial diagnosis is recommended.

The Short-term Effect of a Single Lapse in Anti-Vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema Within Routine Clinical Practice.

PURPOSE: Diabetic macular edema (DME) is a leading cause of vision loss in diabetics. Anti-vascular endothelial growth factor (VEGF) therapy has been shown to be an effective treatment option for DME, although the injections are costly and require frequent visits, which increases the risk for unintended treatment lapses. The aim of this study is to characterize the effects of an unintended treatment lapse in patients with DME undergoing anti-VEGF therapy. DESIGN: Retrospective, comparative case series. METHODS: This retrospective chart review compared patients seen in a multicenter institutional practice with DME exhibiting an unintended minimum 3-month lapse in anti-VEGF treatment, with a control group of DME patients receiving regular anti-VEGF treatment without lapses. The primary outcome was difference in central subfield thickness (CST) between the control group and the treatment lapse group at 6 months following treatment lapse. RESULTS: A total of 164 patients were evaluated, 82 patients in the treatment lapse group and 82 patients in the control group. The average age was 65 years, and the average lapse in treatment was 6.2 ± 3.5 months (range 3-24 months). Comparison of data between the lapse and control groups revealed no significant differences in CST (359.9 ± 108.3 µm and 335.4±94.6 µm, respectively, P = .066) or in visual acuity (66.5 ± 14.3 and 68.9 ± 14.5, respectively, P = .136). Limitations included a relatively small sample size, retrospective nature, and only a single lapse being evaluated. CONCLUSIONS: An unintended, single, relatively short-term lapse in anti-VEGF treatment in patients with DME did not appear to result in significant anatomic or visual compromise upon resumption of regular follow-up and treatment.

Fluctuations in Macular Thickness in Patients with Retinal Vein Occlusion Treated with Anti-Vascular Endothelial Growth Factor Agents.

PURPOSE: To evaluate macular thickness fluctuations in patients with retinal vein occlusions (RVOs) treated with anti-vascular endothelial growth factor (VEGF) agents and to assess whether patients with larger fluctuations have poorer visual outcomes. DESIGN: Retrospective cohort study. PARTICIPANTS: Treatment-naive patients with RVO. METHODS: Central subfield thickness (CST), cube volume (CV), and cube average thickness (CAT) were collected from OCT images obtained at baseline and 3, 6, 9, and 12 months, and standard deviations (SDs) across 12 months were calculated. Mixed-effects regression was performed to examine the relationship between macular thickness SD and 12-month visual acuity (VA). Standard multiple regression was performed to identify predictors of macular thickness SD. MAIN OUTCOME MEASURES: Standard deviations across 12 months for CST, CV, and CAT and VA at 12 months. RESULTS: One hundred thirty-four eyes, including 71 with branch RVO (BRVO) and 63 with central RVO (CRVO), were evaluated. Mean baseline and 12-month CST were 488.6 ± 165.0 µm and 334.3 ± 131.9 µm (change, -154.3 ± 210.2 µm; P < 0.001), with CST SD of 114.1 ± 77.0 µm. Baseline and 12-month VA were 52.8 ± 20.9 letters and 65.9 ± 17.3 letters (change, +13.1 ± 20.3 letters; P < 0.001). Central subfield thickness SD was a significant negative predictor of 12-month VA (-5.21 letters/100 µm; 95% confidence interval [CI], -10.21 to -0.22 letters/100 µm; P = 0.041) when adjusting for baseline factors and injections. Baseline CST and number of injections were not predictive (P ≥ 0.101). Stratification by CST SD demonstrated a 10-letter difference in 12-month VA between the first and fourth quartiles. Baseline CST and RVO diagnosis were the only significant predictors of CST SD (CRVO vs. BRVO: +34.64 µm/100 µm [95% CI, 29.33-39.94 µm/100 µm; P < 0.001] and +22.13 µm/100 µm [95% CI, 4.81-39.44 µm/100 µm; P = 0.013]). Associations using CV and CAT were similar. CONCLUSIONS: Larger macular thickness fluctuations are associated with poorer visual outcomes in patients with RVO treated with anti-VEGF agents. Macular thickness fluctuations, in addition to absolute macular thickness, may be an important prognostic biomarker in these patients.

Visual Acuity Outcomes after Cataract Extraction with Intraocular Lens Implantation in Eyes with Diabetic Retinopathy.

PURPOSE: To evaluate change in best-corrected visual acuity (BCVA) in patients with diabetes and diabetic retinopathy (DR) after cataract extraction (CE). DESIGN: Retrospective cohort study. PARTICIPANTS: Diabetic eyes of patients 18 years of age or older that underwent CE at the Cleveland Clinic from 2012 through 2018. METHODS: Chart review examining visual acuities from patient visits before and after surgery, as well as OCT images. Statistical analysis was carried out using multiple linear regression models. MAIN OUTCOME MEASURES: The primary end point was change in BCVA during the first postoperative year. The secondary end point was the association of central subfield thickness at baseline with change in BCVA. Additional preoperative factors examined were age, race, gender, laterality, insulin use, hemoglobin A1c, creatinine, blood urea nitrogen, and estimated glomerular filtration rate. RESULTS: Diabetic eyes without DR (n = 138) and eyes with mild/moderate nonproliferative DR (NPDR; n = 125), severe NPDR (n = 20), and proliferative DR (PDR; n = 72) were included. A year after surgery, eyes without DR gained a median of 11.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (interquartile range [IQR], 5.0-20.0) from 65.0 (IQR, 58.0-70.0) before surgery, eyes with mild or moderate DR gained 10.0 letters (IQR, 5.0-22.0) from 65.0 (IQR, 58.0-76.0), eyes with severe NPDR gained 20.5 letters (IQR, 8.0-28.5) from 55.0 (IQR, 26.0-65.0), and eyes with PDR gained 15.0 letters (IQR, 6.0-29.5) from 55.0 (IQR, 35.0-61.0). Eyes without DR or mild or moderate NPDR showed significantly greater improvements in VA 1 year after surgery compared with eyes with severe NPDR or PDR when controlling for baseline visual acuity (VA), with eyes with more severe DR showing less expected VA gain (P < 0.001). Length of disease most strongly related to baseline DR severity (ρ = 0.431; P < 0.001). CONCLUSIONS: Cataract surgery is beneficial in most patients with DR without severe concurrent macular pathologic features. However, preoperative VA and the severity of DR can limit visual outcomes.

Development of a novel in vitro cadaveric model for analysis of biomechanics and surgical treatment of Bertolotti syndrome.

BACKGROUND CONTEXT: Bertolotti syndrome (BS) is caused by pseudoarticulation between an aberrant L5 transverse process and the sacral ala, termed a lumbosacral transitional vertebra (LSTV). BS is thought to cause low back pain and is treated with resection or fusion, both of which have shown success. Acquiring cadavers with BS is challenging. Thus, we combined 3D printing, based on BS patient CT scans, with normal cadaveric spines to create a BS model. We then performed biomechanical testing to determine altered kinematics from LSTV with surgical interventions. Force sensing within the pseudojoint modeled nociception for different trajectories of motion and surgical conditions. PURPOSE: This study examines alterations in spinal biomechanics with LSTVs and with various surgical treatments for BS in order to learn more about pain and degeneration in this condition, in order to help optimize surgical decision-making. In addition, this study evaluates BS histology in order to better understand the pathology and to help define pain generators-if, indeed, they actually exist. STUDY DESIGN/SETTING: Model Development: A retrospective patient review of 25 patients was performed to determine the imaging criteria that defines the classical BS patient. Surgical tissue was extracted from four BS patients for 3D-printing material selection. Biomechanical Analysis. This was a prospective cadaveric biomechanical study of seven spines evaluating spinal motions, and loads, over various surgical conditions (intact, LSTV, and LSTV with various fusions). Additionally, forces at the LSTV joint were measured for the LSTV and LSTV with fusion condition. Histological Analysis: Histologic analysis was performed prospectively on the four surgical specimens from patients undergoing pseudoarthrectomy for BS at our institution to learn more about potential pain generators. PATIENT SAMPLE: The cadaveric portion of the study involved seven cadaveric spines. Four patients were prospectively recruited to have their surgical specimens assessed histologically and biomechanically for this study. Patients under the age of 18 were excluded. OUTCOME MEASURES: Physiological measures recorded in this study were broken down into histologic analysis, tissue biomechanical analysis, and joint biomechanical analysis. Histologic analysis included pathologist interpretation of Hematoxylin and Eosin staining, as well as S-100 staining. Tissue biomechanical analysis included stiffness measurements. Joint biomechanical analysis included range of motion, resultant torques, relative axis angles, and LSTV joint forces. METHODS: This study received funding from the American Academy of Neurology Medical Student Research Scholarship. Three authors hold intellectual property rights in the simVITRO robotic testing system. No other authors had relevant conflicts of interest for this study. CT images were segmented for a representative BS patient and cadaver spines. Customized cutting and drilling guides for LSTV attachment were created for individual cadavers. 3D-printed bone and cartilage structural properties were based on surgical specimen stiffness, and specimens underwent histologic analysis via Hematoxylin and Eosin, as well as S-100 staining. Joint biomechanical testing was performed on the robotic testing system for seven specimens. Force sensors detected forces in the LSTV joint. Kruskal-Wallis tests and Dunnett's tests were used for statistical analysis with significance bounded to p<.05. RESULTS: LSTV significantly reduces motion at the L5-S1 level, particularly in lateral bending and axial rotation. Meanwhile, the LSTV increases adjacent segment motion significantly at the L2-L3 level, whereas other levels have nonsignificant trends toward increased motion with LSTV alone. Fusion involving L4-S1 (L4-L5 and L5-S1) to treat adjacent level degeneration associated with an LSTV is associated with a significant increase in adjacent segment motion at all levels other than L5-S1 compared to LSTV alone. Fusion of L5-S1 alone with LSTV significantly increases L3-L4 adjacent segment motion compared to LSTV alone. Last, ipsilateral lateral bending with or without ipsilateral axial rotation produces the greatest force on the LSTV, and these forces are significantly reduced with L5-S1 fusion. CONCLUSIONS: BS significantly decreases L5-S1 mobility, and increases some adjacent segment motion, potentially causing patient activity restriction and discomfort. Ipsilateral lateral bending with or without ipsilateral axial rotation may cause the greatest discomfort overall in these patients, and fusion of the L5-S1 or L4-S1 levels may reduce pain associated with these motions. However, due to increased adjacent segment motion with fusions compared to LSTV alone, resection of the joint may be the better treatment option if the superior levels are not unstable preoperatively. CLINICAL SIGNIFICANCE: This study's results indicate that patients with BS have significantly altered spinal biomechanics and may develop pain due to increased loading forces at the LSTV joint with ipsilateral lateral bending and axial rotation. In addition, increased motion at superior levels when an LSTV is present may lead to degeneration over time. Based upon results of LSTV joint force testing, these patients' pain may be effectively treated surgically with LSTV resection or fusion involving the LSTV level if conservative management fails. Further studies are being pursued to evaluate the relationship between in vivo motion of BS patients, spinal and LSTV positioning, and pain generation to gain a better understanding of the exact source of pain in these patients. The methodologies utilized in this study can be extrapolated to recreate other spinal conditions that are poorly understood, and for which few native cadaveric specimens exist.

What Are the Predictors of Poor Patient-Reported Outcomes After Shoulder Instability Surgery?

BACKGROUND: Prospectively collected responses to Patient Acceptable Symptom State (PASS) questions after shoulder instability surgery are limited. Responses to these outcome measures are imperative to understanding their clinical utility. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate which factors predict unfavorable patient-reported outcomes after shoulder instability surgery, including "no" to the PASS question. We hypothesized that poor outcomes would be associated with male adolescents, bone loss, combined labral tears, and articular cartilage injuries. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients aged ≥13 years undergoing shoulder instability surgery were included in point-of-care data collection at a single institution across 12 surgeons between 2015 and 2017. Patients with anterior-inferior labral tears were included, and those with previous ipsilateral shoulder surgery were excluded. Demographics, American Shoulder and Elbow Surgeons (ASES) and Single Assessment Numeric Evaluation (SANE) scores, and surgical findings were obtained at baseline. ASES and SANE scores, PASS responses, and early revision surgery rates were obtained at a minimum of 1 year after the surgical intervention. Regression analyses were performed. RESULTS: A total of 234 patients met inclusion criteria, of which 176 completed follow-up responses (75.2%). Nonresponders had a younger age, greater frequency of glenoid bone loss, fewer combined tears, and more articular cartilage injuries (P < .05). Responders' mean age was 25.1 years, and 22.2% were female. Early revision surgery occurred in 3.4% of these patients, and 76.1% responded yes to the PASS question. A yes response correlated with a mean 25-point improvement in the ASES score and a 40-point improvement in the SANE score. On multivariate analysis, combined labral tears (anterior-inferior plus superior or posterior tears) were associated with greater odds of responding no to the PASS question, while both combined tears and injured capsules were associated with lower ASES and SANE scores (P < .05). Sex, bone loss, and grade 3 to 4 articular cartilage injuries were not associated with variations on any patient-reported outcome measure. CONCLUSION: Patients largely approved of their symptom state at ≥1 year after shoulder instability surgery. A response of yes to the PASS question was given by 76.1% of patients and was correlated with clinically and statistically significant improvements in ASES and SANE scores. Combined labral tears and injured capsules were negative prognosticators across patient-reported outcome measures, whereas sex, bone loss, and cartilage injuries were not.