Topical anaesthesia plus intracameral lidocaine versus topical anaesthesia alone for phacoemulsification cataract surgery in adults

Background: Phacoemulsification cataract surgery is usually performed in adults under local anaesthesia. Topical anaesthesia, which involves instilling anaesthetic drops to the ocular surface prior to and during surgery, has found large acceptance internationally. It is safe and allows for rapid patient turnover and visual recovery. Some surgeons have supplemented topical anaesthesia with intracameral lidocaine, reasoning that this may further reduce intraoperative pain, particularly during surgical stages involving manipulation of intraocular structures and rapid changes in fluid dynamics. This review, originally published in 2006 and updated in 2020, explores the efficacy and safety of using supplementary intracameral lidocaine in phacoemulsification cataract surgery. Objectives: To assess whether supplementing topical anaesthesia with intracameral lidocaine for phacoemulsification cataract surgery in adults reduces intraoperative and postoperative pain, and to assess differences in participant satisfaction, need for additional intraoperative anaesthesia, surgeon satisfaction, measures of intraocular toxicity, and adverse effects attributable to choice of anaesthesia. Search methods: We searched CENTRAL, MEDLINE, Embase, LILACS BIREME iAH, and six trial registries on 4 February 2020. We also searched the reference lists of identified studies. There were no language restrictions. Selection criteria: We included only randomized controlled trials (RCTs) where participants underwent phacoemulsification for age-related cataract under topical anaesthesia with or without intracameral lidocaine either in two eyes of the same participant, or in different participants. We also included studies that used oral or intravenous sedation in addition to local anaesthesia. Data collection and analysis: Two review authors independently extracted data and assessed trial methodological quality using standard Cochrane procedures. Main results: We identified five new RCTs in this updated review. We included a total of 13 trials in the review, conducted in the UK, the USA, Australia, Italy, Canada, Taiwan, Singapore, India, and Pakistan, and comprising 2388 eyes of 2355 participants (one study was a paired-eye study with each participant acting as their own control). The age range of participants was 34 to 95 years. We excluded studies that only included low-risk participants and excluded more difficult operative cases, for example hard lens nuclei or small pupils. We excluded studies assessing only participants with Fuchs' endothelial dystrophy. We judged one study as at high risk for selection bias. We assessed five studies as having an unclear risk of bias for random sequence generation and seven studies an unclear risk of bias for allocation concealment. We judged three studies as at high risk of performance bias, as the surgeon was not blinded, and two studies as at unclear risk of bias for this domain. No studies were judged as at high risk for detection bias, but five studies were judged to have an unclear risk of bias for this domain. We judged all 13 included studies to have a low risk of attrition bias and an unclear risk of reporting bias. Data from eight RCTs favoured topical anaesthesia plus intracameral lidocaine 0.5% to 1% over topical anaesthesia alone for reducing intraoperative pain when measured using a 10-point visual analogue scale, analysed as a continuous outcome. Mean pain score was 0.26 lower in the supplemental intracameral lidocaine group (95% confidence interval (CI) −0.39 to −0.13, 1692 eyes, moderate-quality evidence). Data from seven RCTs favoured supplemental intracameral lidocaine for reducing intraoperative pain when measured as a dichotomous outcome. The odds ratio of experiencing any pain was 0.40 versus the topical anaesthesia-only group (95% CI 0.29 to 0.57, 1268 eyes, moderate-quality evidence). Data from four RCTs did not show any additional benefit on postoperative pain when measured using a 10-point visual analogue scale (mean difference 0.12 points, 95% CI −0.29 to 0.05, 751 eyes, moderate-quality evidence). The impact on participant satisfaction was uncertain as only one small study investigated this outcome. The study suggested no difference between groups (mean difference 0.1 points, 95% CI −0.47 to 0.27, 60 eyes, low-quality evidence). Data from seven RCTs did not demonstrate a difference between groups in the need for additional intraoperative anaesthesia (odds ratio 0.88, 95% CI 0.56 to 1.39, 1194 eyes of 1161 participants; low-quality evidence), although this result is uncertain. A variety of measures were reported relating to possible intraocular toxicity. Data from four RCTs did not demonstrate a difference between groups in mean percentage corneal endothelial cell count change from pre- to postoperatively (mean difference 0.89%, 95% CI −1.12% to 2.9%, 254 eyes of 221 participants, moderate-quality evidence). Synthesis of the evidence from eight RCTs identified no difference in intraoperative adverse events between groups (odds ratio 1.00, 95% CI 0.32 to 3.16, 1726 eyes, low-quality evidence). This result should be interpreted with caution, mainly due to a lack of clear definitions of adverse events, low numbers of events, heterogeneity between studies, and large confidence intervals. Large observational studies may have been more appropriate for looking at this outcome. Authors' conclusions: There is moderate-quality evidence that supplementation of topical anaesthesia with intracameral lidocaine 0.5% to 1% for phacoemulsification cataract surgery in adults reduces participant perception of intraoperative pain. The odds of experiencing any pain (as opposed to no pain) were 60% less for the topical anaesthesia plus intracameral lidocaine group versus the topical anaesthesia-only group. However, the numerical amplitude of the effect may not be of great clinical significance on the continuous pain score scale. Generally, the pain scores were consistently low for both techniques. We found moderate-quality evidence that there is no additional benefit of intracameral lidocaine on postoperative pain. There is insufficient evidence to determine the impact on participant satisfaction and need for additional intraoperative anaesthesia due to low-quality evidence. There is moderate-quality evidence that intracameral lidocaine supplementation does not increase measures of intraocular toxicity, specifically loss of corneal endothelial cells. There is low-quality evidence that the incidence of intraoperative adverse events is unchanged with intracameral lidocaine supplementation, but as RCTs are not the optimum medium for looking at this, this result should be interpreted with caution. Further research specifically investigating the adverse effects of intracameral anaesthesia might help to better determine its safety profile. Economic evaluations would also be useful for detailing cost implications

Fibroblasts profiling in scarring trachoma identifies IL-6 as a functional component of a fibroblast-macrophage pro-fibrotic and pro-inflammatory feedback loop

Trachoma is a conjunctiva scarring disease, which is the leading infectious cause of blindness worldwide. Yet, the molecular mechanisms underlying progressive fibrosis in trachoma are unknown. To investigate the contribution of local resident fibroblasts to disease progression, we isolated conjunctival fibroblasts from patients with scarring trachoma and matching control individuals, and compared their gene expression profiles and functional properties in vitro. We show that scarring trachoma fibroblasts substantially differ from control counterparts, displaying pro-fibrotic and pro-inflammatory features matched by an altered gene expression profile. This pro-inflammatory signature was exemplified by increased IL-6 expression and secretion, and a stronger response to macrophage-mediated stimulation of contraction. We further demonstrate that scarring trachoma fibroblasts can promote Akt phosphorylation in macrophages in an IL-6 –dependent manner. Overall this work has uncovered a distinctive molecular fingerprint for scarring trachoma fibroblasts, and identified IL-6- as a potential contributor to the chronic conjunctival fibrosis, mediating reciprocal pro-fibrotic/pro-inflammatory interactions between macrophages and fibroblasts

The Application of Infrared Imaging and Optical Coherence Tomography of the Lacrimal Punctum in Patients Undergoing Punctoplasty for Epiphora

Purpose To determine the application of imaging the stenotic lacrimal punctum with infrared photographs and optical coherence tomography (OCT) and to identify characteristics of the lacrimal punctum in patients who benefit from punctoplasty. Design Case-control study. Participants Twenty patients with epiphora who were listed for punctoplasty and 20 healthy controls. Methods Prospectively, 20 patients listed for punctoplasty were asked to rate their epiphora, using the Munk score, before and after punctoplasty. They also underwent preoperative OCT and infrared imaging of the affected punctum. They were divided into 2 groups, depending on whether the epiphora improved, and were compared with 20 healthy controls. Main Outcome Measures Measurements of puncta from infrared and OCT images were obtained along with Munk scores of patient epiphora. Results The infrared image measurements were significantly smaller in those patients whose epiphora improved compared with those whose did not in both the area of the punctal aperture and in the maximum punctal diameter. Additionally, those patients with improvement in epiphora had a significantly smaller preoperative punctal diameter at 100 μm depth on OCT compared with healthy controls; this was not observed in patients whose epiphora failed to improve. There was no significant difference in the punctum diameter among the 3 groups at the punctum surface entrance or at 500 μm depth. Patients with epiphora had a higher tear meniscus within the punctum compared with healthy controls. Conclusions Lacrimal punctum infrared and OCT imaging may be helpful in predicting patients more likely to benefit symptomatically from punctoplasty, with patients with smaller puncta having greater symptomatic improvement. However, the results suggest that inner punctum diameter (not readily measurable by slit-lamp examination), rather than the surface diameter, is correlated with outcome. Additionally, OCT measurements of the tear meniscus height within the punctum may be related to the degree of epiphora

Characterizing the Occluded Lacrimal Punctum Using Anterior Segment Optical Coherence Tomography.

PURPOSE: Epiphora is sometimes associated with an absent or occluded lacrimal drainage punctum (or puncta). This study uses noninvasive "enhanced depth" anterior segment optical coherence tomography (OCT) to give improved characterization and understanding of absent or fully occluded puncta and the underlying canaliculus. METHODS: Anterior segment spectral domain OCT images were collected prospectively from 9 lower puncta of 6 patients with epiphora and absent or fully occluded puncta, not amenable to dilation in clinic, to see if a canaliculus was visible on OCT imaging below the occluded punctum. RESULTS: An epithelial lined canalicular lumen was visible on OCT in 4 lower eyelid puncta from 2 patients and OCT identified 80% (4/5) of the canaliculi that were located on microscope-assisted punctal exploration. These lumens were seen within 580 μm depth from the eyelid margin surface. A half of the eyes in which a canaliculus was identified on OCT (the 2 eyes in a single patient) had resolution of epiphora following punctoplasty, and the other patient was found to have coexisting nasolacrimal duct stenosis and required later dacryocystorhinostomy. The positive predictive value for identifying a canaliculus on lower eyelid punctal exploration in acquired complete punctal occlusion (excluding the congenital case) was 1, with a negative predictive value of 1. CONCLUSIONS: This study demonstrates that canaliculi can be imaged with OCT where formal access is precluded by an occluded punctum. This noninvasive investigation might help predict the likelihood of successful retrieval of a canaliculus at surgical exploration

Eyelid and Sternum Fibroblasts Differ in Their Contraction Potential and Responses to Inflammatory Cytokines

BACKGROUND: Adverse skin scarring varies by anatomical site with, for example, presternal skin showing a greater hypertrophic response when compared with eyelid; such differences have traditionally been attributed to regional variations in skin tension, thickness, and Langer's lines. Fibroblasts are the main cell implicated in fibrosis, and they too are known to show anatomical variation in their expression, differentiation, and intercellular interactions. We, therefore, investigated whether intrinsic differences in skin fibroblasts derived from separate locations might contribute to the observed discrepancies in clinical scarring. METHODS: Primary in vitro cultures were established using matched eyelid and presternal skin from 3 healthy donors undergoing blepharoplasty surgery. We used an in vitro collagen gel model of fibroblast-mediated tissue contraction to compare the properties of the dermal fibroblasts from each site. Cell contractile force and matrix stiffness were assessed in 3-dimensional tissue constructs using an automated high-throughput device. RESULTS: Dermal fibroblasts isolated from eyelid and sternum differ both in their ability to contract a gel matrix and in their response to cytokine stimulation; despite having lower intrinsic contractile force (P < 0.01) and resting stiffness (P < 0.02), the presternal cells were more contractile (P < 0.001) following stimulation with serum, or inflammatory cytokines transforming growth factor-β (P < 0.01) and interleukin-1β (P < 0.05). CONCLUSIONS: The propensity to cutaneous scarring may, at least in part, result from intrinsic differences in the local fibroblasts' ability to contract and their sensitivity to inflammatory cytokines. Improved understanding of the underlying molecular pathways should prove useful in identifying new therapeutic targets for altering surgical and other scarring

Mesenchymal Stem Cell–Like Properties of Orbital Fibroblasts in Graves’ Orbitopathy

PURPOSE. Graves’ orbitopathy (GO) is a sight-threatening autoimmune disorder causing extraocular muscle fibrosis, upper lid retraction and eye bulging due to orbital fat expansion. These clinical features are mediated by aspects of orbital fibroblasts differentiation, including adipogenesis and fibrosis. Our previous work suggested that this dual phenotype might be a manifestation of mixed cell populations, partially linked to the expression of mesenchymal stem cell (MSC) marker CD90. Thus, we set out to determine whether GO orbital fibroblasts displayed MSC properties. METHODS. Control and GO orbital fibroblasts previously characterized for CD90 and CD45 expression were analyzed by flow cytometry for classical MSC positive (CD73, CD105) and negative (CD14, CD19, HLA-DR, and CD34) markers. Graves’ orbitopathy fibroblasts were tested further for their ability to undergo lineage specific differentiation following standard protocols. RESULTS. Control and GO fibroblasts strongly expressed CD73 and CD105, with a higher percentage of positive cells and stronger expression levels in GO. Neither cell type expresses CD14, CD19, and HLA-DR. Protein CD34 was expressed at low levels by 45% to 70% of the cells, with its expression significantly lower in GO cells. Graves’ orbitopathy fibroblasts displayed features of osteogenesis (calcium deposits, and osteocalcin [BGLAP] and osteonectin [SPARC] expression), chondrogenesis (glycosaminoglycan production; SOX9 and aggrecan [ACAN] expression), myogenesis (α-smooth muscle actin expression), and neurogenesis (β-III tubulin expression) upon differentiation. CONCLUSIONS. Our findings suggest that orbital fibroblasts contain a population of cells that fulfil the criteria defining MSC. This subpopulation may be increased in GO, possibly underlying the complex differentiation phenotype of the diseas

A Tenon's capsule/bulbar conjunctiva interface biomimetic to model fibrosis and local drug delivery

Glaucoma filtration surgery is one of the most effective methods for lowering intraocular pressure in glaucoma. The surgery efficiently reduces intra-ocular pressure but the most common cause of failure is scarring at the incision site. This occurs in the conjunctiva/Tenon's capsule layer overlying the scleral coat of the eye. Currently used antimetabolite treatments to prevent post-surgical scarring are non-selective and are associated with potentially blinding side effects. Developing new treatments to target scarring requires both a better understanding of wound healing and scarring in the conjunctiva, and new means of delivering anti-scarring drugs locally and sustainably. By combining plastic compression of collagen gels with a soft collagen-based layer, we have developed a physiologically relevant model of the sub-epithelial bulbar conjunctiva/Tenon's capsule interface, which allows a more holistic approach to the understanding of subconjunctival tissue behaviour and local drug delivery. The biomimetic tissue hosts both primary human conjunctival fibroblasts and an immune component in the form of macrophages, morphologically and structurally mimicking the mechanical proprieties and contraction kinetics of ex vivo porcine conjunctiva. We show that our model is suitable for the screening of drugs targeting scarring and/or inflammation, and amenable to the study of local drug delivery devices that can be inserted in between the two layers of the biomimetic. We propose that this multicellular-bilayer engineered tissue will be useful to study complex biological aspects of scarring and fibrosis, including the role of inflammation, with potentially significant implications for the management of scarring following glaucoma filtration surgery and other anterior ocular segment scarring conditions. Crucially, it uniquely allows the evaluation of new means of local drug delivery within a physiologically relevant tissue mimetic, mimicking intraoperative drug delivery in vivo

Analysis of blink dynamics in patients with blepharoptosis

Owing to the rapid movements of the human upper eyelid, a high-speed camera was used to record and characterize voluntary blinking and the blink dynamics of blepharoptosis patients were compared to a control group. Twenty-six blepharoptosis patients prior to surgery and 45 control subjects were studied and the vertical height of the palpebral aperture (PA) was measured manually at 2 ms intervals during each blink cycle. The PA and blinking speed were plotted with respect to time and a predictive model was generated. The blink dynamic was analysed in closing and opening phases, and revealed a reduced speed of the initial opening phase in ptotic patients, suggesting intrinsic muscle function change in ptosis pathogenesis. The PA versus time curve for each subject was reconstructed using custom-built parameters; however, there were significant differences between the two groups. Those parameters used included the rate of closure, the delay between opening and closing, rate of initial opening, rate of slow opening (nonlinear function) and the 'switch point' between those two rates of opening. The model was tested against a new group of subjects and was able to discriminate ptosis patients from controls with 80% accuracy

Videographic Analysis of Blink Dynamics following Upper Eyelid Blepharoplasty and Its Association with Dry Eye

Background: This study was undertaken to characterize the effects of upper eyelid blepharoplasty on blink dynamics and to evaluate the hypothesis that changes in blink dynamics following blepharoplasty are associated with postoperative dry eye. // Methods: The voluntary blink of 14 eyes of 7 patients with dermatochalasis undergoing upper eyelid blepharoplasty was recorded with a high-speed camera preoperatively and 6–8 months postoperatively, alongside a group of 11 controls. The images were analyzed for palpebral aperture, blink duration, and maximum velocity during opening and closing phases. Patients undergoing blepharoplasty were assessed for dry eye symptoms pre- and postoperatively at 6–8 months using the ocular surface disease index score. // Results: Despite intraoperative orbicularis oculi resection, there was no significant compromise of blink duration or maximum velocity of eyelid opening or closure post-blepharoplasty. Postoperatively, patients had an increase in palpebral aperture compared with both preoperatively (8.71 versus 7.85mm; P = 0.013) and control groups (8.71 versus 7.87mm; P = 0.04). Postoperatively at 6–8 months, there was an increase in dry eye symptoms in 6 of 7 patients compared with preoperatively (ocular surface disease index, 16.6 versus 12.5; P < 0.05). There was no positive correlation between the increase in palpebral aperture and the increase in dry eye symptoms (r = –0.4; P = 0.30). // Conclusions: Using modern videographic technology, this study demonstrates that upper eyelid blepharoplasty results in an increase in resting palpebral aperture but has no effect on dynamic blink parameters. Changes in palpebral aperture or blink dynamics are unlikely to be the cause of dry eye syndrome following blepharoplasty

Macrophages promote a profibrotic phenotype in orbital fibroblasts through increased hyaluronic acid production and cell contractility

Graves’ orbitopathy (GO) is an autoimmune inflammatory disease affecting the orbit. Orbital fibroblasts are a key component in GO pathogenesis, which includes inflammation, adipogenesis, hyaluronic acid (HA) secretion, and fibrosis. Macrophages are thought to participate in the immunological stage of GO, but whether they can directly affect the fibroblasts phenotype and modulate disease progression is unknown. We previously showed that GO adipogenic and fibrotic phenotypes could be modelled in a pseudo-physiological 3D environment in vitro. Here, we introduced macrophages in this 3D culture model to investigate role for macrophages in modulating adipogenesis, HA production, and contractility in orbital fibroblasts. Macrophages had a minimal effect on lipid droplet formation in fibroblasts, but significantly increased HA production and cell contractility, suggesting that they may promote the fibrotic phenotype. This effect was found to be mediated at least in part through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation and linked to an increase in actin polymerization and protrusive activity in fibroblasts. Overall our work shows for the first time a direct role for macrophages in modulating the fibroblasts’ phenotype in GO, supporting a role for macrophages in the progression of the fibrotic phenotype through induction of HA production and stimulation of the contractile phenotype in orbital fibroblasts