Engaging Stakeholders to Develop a Roadmap for Dry Eye and MGD PCORI-Funded Research.

Introduction: Although affecting an estimated 35% of the population, Dry Eye is not well understood by patients and the medical community. As a result, both in research and clinical settings, diagnostic and treatment protocols tend to be non-specific, ad hoc, and inadequate, with a narrow industry-driven focus. The purpose of this convening was to propose a research roadmap that orients Dry Eye researchers toward a comprehensive patient-centered approach to diagnosing and treating Dry Eye, Meibomian gland dysfunction (MGD), and related comorbidities with a goal of improving clinical outcomes for Dry Eye/MGD patients. Methods: Sixteen participants, including Dry Eye/MGD patients, caregivers, and patient advocates together with a group of experts in Dry Eye, MGD and other fields identified gaps in research on Dry Eye and MGD diagnostic and treatment approaches (age range 20-80; male to female ratio of 7:11; patients: 7). During a 2-day virtual convening, participants were assigned to topic-specific focus-group sessions to discuss and develop research questions pertaining to Dry Eye and MGD. The research questions were compiled into a proposed patient-centered roadmap for Dry Eye and MGD research. Two additional participants contributed to the proposed roadmap following the convening. Results: The focus groups identified over 80 patient-centered research questions important to patients and other stakeholders and compiled these into a proposed research roadmap. Conclusion: The convened stakeholders aim to establish a cohesive and comprehensive patient-centered approach to treating Dry Eye, Meibomian Gland Dysfunction, and comorbidities. The research roadmap will serve as a reference for researchers, educational institutions, clinicians, and others evaluating diagnostic and treatment protocols in Dry Eye and MGD.

Meibomian Gland Probing Stimulates a Proliferative Epithelial Response Resulting in Duct Regeneration.

Purpose: To demonstrate that the meibomian gland ductal basement membrane and basal epithelial cell layer are in continuity with and may derive from lid margin orifice-associated rete ridge epithelial/basement membrane structures (OARREBS) and to characterize changes in the distal duct microanatomy after meibomian gland probing (MGP) using in vivo confocal microscopy (IVCM). Patients and Methods: Pre/post-MGP IVCM examinations were performed on upper lids. Thirty-six identical glands from 20 lids of 16 patients (49.24 ±17.11 y/o with 13:3 F:M) were identified, analyzed, and compared to control cases. Statistical analyses were performed using ImageJ software and IBM SPSS version 27. All MGPs were performed within 12 weeks of the initial examination. Post-MGP follow-up exams occurred at 5.03 ±4.48 months. Results: Post-MGP images showed more superficially organized OARREBS with accelerated and more superficial basement membrane formation, and an average increase of 32.2%, 25.4%, 32.04%, 77.7%, and 81.3% in duct wall epithelial cell layers (DWECL) (p < 0.001, compared to control (CTC) p < 0.001), distal duct wall thickness (DWT) (p < 0.001, CTC p < 0.001), proximal DWT (p < 0.001, CTC p < 0.001), distal lumen area (p < 0.001, CTC p = 0.037), and proximal lumen area (p < 0.001, CTC p = 0.007), respectively. The increase in the distal DWT and lumen area correlated with the months of follow-up (p = 0.004 and p = 0.010, respectively). Immediate post-MGP imaging revealed the probe track confined to the ductal epithelial compartment. Conclusion: MGP appears to stimulate a proliferative epithelial response characterized by an accelerated more superficial formation of ductal basement membrane with increased DWECL as well as DWT and lumen area at two separate duct foci. These findings suggest activation of lid margin meibomian gland precursor cells and confirm that MGP stimulates an epithelial regenerative phenomenon, not a fibrotic one.

Review of Literature on Intraductal Meibomian Gland Probing with Insights from the Inventor and Developer: Fundamental Concepts and Misconceptions.

Obstructive Meibomian gland dysfunction (MGD) affects millions of patients around the world. Its effective treatment with intraductal meibomian gland probing (MGP), was first reported in 2010. Since then, MGP has provided relief to thousands of patients globally suffering with refractory MGD. The purpose of Meibomian gland probing is restoring the integrity of the gland's central duct by entering the gland through the natural orifice, releasing fixed obstruction thought to be periductal fibrosis, thereby establishing and/or confirming the patency of the duct, and concurrently equilibrating intraductal pressure as well as promoting gland functionality with meibum production. There may or may not be immediate secretion of meibum upon successful restoration of ductal integrity depending on the gland's state of function and degree of atrophy. One double-blind placebo-controlled study has been conducted and, with the accumulated evidence of over 12 other peer reviewed articles in the scientific literature, overwhelmingly indicates that MGP is a safe and effective treatment for the MGD patient refractory to prior standard care and as a first-line treatment. This paper describes relevant fundamental concepts, dispels commonly held misconceptions, and provides an objective review of the current understanding and effectiveness of MGP for the treatment of obstructive MGD. Our analysis will better equip clinicians to draw informed conclusions about both subjective and objective findings reported in MGP studies and researchers to design future robust studies that provide meaningful results.

Successful reversal of neuropathic eye pain by treatment of occult ocular surface disease: Case series and implications.

Purpose: To report the successful approach to managing neuropathic dry eye-like pain (NP) in three consecutive patients described as severe: 1) "burning fire," "burning acid," and "horrible burning pain" with hyperalgesia and allodynia, 2) refractory to topical anesthetic (TA), and 3) without surface hyperemia nor vital staining. Observations: Two of three patients' pain was reversed with significant symptom relief within 48 hours by identification of occult obstructive Meibomian gland dysfunction (o-MGD) and treatment using Meibomian gland probing (MGP) with intraductal steroid lavage (MGP(s)) and aqueous tear deficiency (ATD) treated with punctal thermocautery (PO). The third patient's pain was reversed within one week after treatment of superior conjunctivochalasis (CCh) using amniotic membrane surface reconstruction and ATD using PO with subsequent MGP and MGP(s) for o-MGD. Conclusions and importance: It has been generally thought that central (NP) is strongly suggested by triad of 1) severe chronic burning pain with hyperalgesia and allodynia, 2) refractory to TA with 3) minimal signs. In this three-case series, treatment of occult surface disease consistently led to symptom reversal. Results may represent salutary effect of successful treatment to suppress nociceptive inflammation leading to reversal of central NP. Alternatively, the current triad of diagnostic criteria may be unable to differentiate centralized NP from peripheral sensitization alone, thereby requiring rigorous examination to uncover occult, yet treatable, surface disease to restore eye comfort and reverse psychosocial sequelae when possible. Furthermore, rigorous targeting of surface disease in patients with this pain triad may obviate unnecessary systemic treatments with associated risks of serious side effects.

Meibography guided intraductal meibomian gland probing using real-time infrared video feed.

PURPOSE: To evaluate use of infrared meibography video to visualise meibomian gland probing and correlate probe findings of intraductal space with meibography images. METHODS: Videos were reviewed and probe findings recorded of 996 probed gland orifices from 38 lower lids. RESULTS: 996/997 (99.9%) of gland orifices were successfully probed with 91.8% revealing probe location. There were no false passages. 14% (140/997) of all gland orifices showed whole gland atrophy (WGA) with 99.3% (139/140) probed to 1 mm. Cumulative probe findings for all WGA (not differ significantly from non-WGA) showed 106 (76%), 21 (15%) and 12 (9%) glands with fixed, non-fixed and no resistance (NR), respectively. Lids without WGA showed increased NR/total glands probed while lids with WGAs (≥5) showed increased NR/WGA compared with lids with only 1-4 WGAs (p=0.011, p=0.005, respectively, Mann-Whitney U test) suggesting bimodal NR profile. Visualisation of microtube placement was successfully obtained for therapeutic injections and retrieval of meibum specimens. CONCLUSION: Video confirmed intraductal location and safety of devices. For 73% of non-WGA and 76% of WGAs as well as proximal ducts of glands with proximal atrophy, probing released fixed resistance restoring ductal integrity. A bimodal profile of NR suggests it is found with less diseased gland ducts as well as more advanced atrophic gland disease. Gland and ducts appeared flexible but not distendable while periglandular tissue appeared spongy. Visualisation of devices enables whole or localised gland therapy and meibum specimen retrieval, elegantly raising future research, therapeutic and regenerative opportunities.

Intraductal meibomian gland probing: background, patient selection, procedure, and perspectives.

Obstructive meibomian gland dysfunction is the most common cause of dry eye. Its conventional treatment has focused on using heat and pressure with anti-inflammatory and antimicrobial therapies but has often been a frequent, frustrating experience for patient and physician. New evidence from Meibomian gland intraductal probing suggests fixed intraductal strictures and obstruction correlating to periductal fibrosis first described in 1997. The use of intraductal probing has been reported, by this author and in at least ten independent peer-reviewed academic papers from around the world, to consistently lead to statistically significant improvement in signs and symptoms of gland dysfunction including cases refractory to other extensive treatments. This review will focus on the background of meibomian gland intraductal probing as well as patient selection, procedure, and perspectives.

Expressible Meibomian Glands Have Occult Fixed Obstructions: Findings From Meibomian Gland Probing to Restore Intraductal Integrity.

PURPOSE: To describe and quantify findings of intraductal obstruction during probing expressible and nonexpressible meibomian glands (MGs) in patients with obstructive meibomian gland dysfunction using a 1-mm intraductal MG probe. METHODS: A retrospective study of probe findings from 108 consecutive patients. Nonparametric tests using SPSS software 25.0 to explore relationships between expressibility and probe findings. RESULTS: Of 11,776 probed glands of 404 lids, 84% showed mechanical resistance (MR) and 16% showed no resistance (NR). Fixed, firm, focal unyielding resistance (FFFUR) occurred in 79.5% of obstructed glands, and nonfixed, nonfocal easily yielding soft resistance (SFT) in 20.4%. FFFUR was characterized by an audible and tactile "firm pop" (FP) or "firm gritty" (FG) sensation. No significant difference in MR and FFFUR for lids between 0% and >90% gland expressibility was observed. FP correlated with increased expressibility (P = 0.011), lid tenderness (P = 0.045), and complete proximal obstruction (P = 0.037), whereas SFT correlated with reduced expressibility (P = 0.016). Upper lids showed greater incidence of MR (P < 0.001), FFFUR (P < 0.001), and FG (P < 0.001), whereas lower lids showed greater expressibility (P < 0.001) and NR (P < 0.001). CONCLUSIONS: FFFUR was the most common probe finding in a large series of consecutively probed MGs, with an incidence of 67% of glands and 80% of obstructed glands. FFFUR was independent of gland expressibility, demonstrating expressible glands harbor FFFUR deep to at least one acinus. FP was associated with expressible gland occult obstruction and lid tenderness. SFT correlated with reduced expressibility, perhaps related to altered duct/duct contents. Upper lids correlated with increased MR, FFFUR, and FG and lower lids with increased expressibility and NR, possibly reflecting contrasting anatomy and blink-related microtrauma.

Infrared Video Meibography of Lower Lid Meibomian Glands Shows Easily Distorted Glands: Implications for Longitudinal Assessment of Atrophy or Growth Using Lower Lid Meibography.

PURPOSE: To evaluate measurement reliability of the meibomian gland (MG) tissue area during infrared video meibography (IR-VM) of the lower lid. METHODS: This is a retrospective analysis, using ImageJ, of IR-VM of 17 lids of 11 consecutive patients (age 56.6 ± 15.9 years; 9 females and 2 males) focusing on the presence of a statistically significant variation of the MG tissue area and the MG tissue area relative to the total measurement field (TMF) secondary to inadvertent lid distortion and/or an altered vertical gaze direction during a single-image acquisition video sequence. RESULTS: For lids with distortions, 10 of 10 lids with distortion showed a statistically significant difference (P < 0.0001-0.0136) in the mean individual gland area (MIGA, % change: 16.2%-114.1%) and/or the ratio of MIGA to TMF (% change: 19.8%-108.5%) during its video sequence. For the altered vertical gaze direction, 7 of 9 lids individually showed a statistically significantly increased MIGA/TMF with the globe in primary gaze compared with upgaze (P = 0.001-0.0156), whereas collectively as a group, all 9 lids showed a significant increase in MIGA/TMF (P < 0.0001, % change: 1.1%-38.9%). Two lids from the same patient were evaluated for both types of distortion. CONCLUSIONS: IR-VM of lower lids revealed statistically significant unreliability of measuring the MG tissue area from inadvertent lid distortion or an altered vertical globe gaze direction during meibography. These data suggest that, lacking context seen when using the video, still-shot nonvideo infrared meibography images of the lower lid, and related data, may be specious and should be used with caution in drawing conclusions of the change in the MG area over time, to avoid misguided clinical decision making.

Growth of meibomian gland tissue after intraductal meibomian gland probing in patients with obstructive meibomian gland dysfunction.

PURPOSE: To investigate the impact of meibomian gland probing (MGP) on meibomian gland (MG) area from the upper lids of patients with obstructive meibomian gland dysfunction (o-MGD). METHODS: Retrospective study comparing pre-MGP/post-MGP non-contact infrared meibography results in patients with o-MGD, viewing signs of MG growth within total measurement field. RESULTS: Post-MGP meibography of 34 lids (19 patients, ≥4.5 to ≤12 months' follow-up) showed 41.2% with MG growth. Ten lids had meibographies suitable for analysis, showing significant collective (116 glands) increase in mean individual glandular area (MIGA) of 4.87% (p=0.0145). Four of 10 lids independently showed significant increase in MIGA, ranging from 10.70% to 21.13% (p<0.0001, p=0.0277, p=0.0292, p=0.0345), while six did not.At >12 and <25 months' follow-up, 16 lids (9 additional patients) had follow-up showing 25% with signs of MG growth. Analysis of three lids showed a significant collective (33 glands) increase in MIGA of 11.19% (p=0.0004). Two of three lids independently showed significant increase in MIGA of 13.73% and 20.00% (p=0.0097, p=0.0001). Collectively, for all 13 analysed lids (149 glands), there was a significant increase of 6.38% in total glandular area (p=0.0447) and a significant increase of 6.23% in MIGA (p=0.0003). CONCLUSION: MGP was associated with increased MG tissue area and growth of atrophied MGs as viewed on meibography. MGP provides unequivocal physical proof of a patent meibum outflow tract through the natural orifice, and may promote glandular growth in part by direct mechanical establishment of a patent duct/orifice system.

Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland dysfunction.

PURPOSE: To perform a retrospective evaluation of a new treatment for obstructive meibomian gland dysfunction (O-MGD) using invasive orifice penetration and intraductal probing. SETTING: Office-based ophthalmology private practice. METHODS: Medical charts of 25 consecutive patients with O-MGD (based on presence of lid margin or tarsal hyperemia, lid margin telangiectasia, thickening or irregularity, and meiboman gland orifice metaplasia) plus lid tenderness or symptoms of lid margin congestion were reviewed to evaluate the effect of probing on tenderness and congestion. RESULTS: Twenty-four of 25 patients (96%) had immediate postprobing relief, whereas all 25 patients (100%) had relief of symptoms by 4 weeks after procedure. Twenty patients (80%) only required 1 reatment and had an average of 11.5-month follow-up. Five patients (20%) had retreatment at an average of 4.6 months. All patients had symptom relief at time of last follow-up. Of 56 symptomatic and treated lids, 42 (75%) were upper lids. Patients frequently reported improvement in newly recognized but previously subclinical symptoms. CONCLUSIONS: Invasive orifice penetration and intraductal probing seems to provide lasting rapid symptom relief for patients with O-MGD. Probing findings in this study frequently included (1) mild resistance upon orifice penetration, (2) proximal duct gritty tactile and aural sensation suggestive of keratinized cellular debris, and (3) focal variable resistance deeper within the duct, which may be relieved with the probe, suggestive of fibrovascular tissue. Taken together, these findings may offer probing characteristics that may allow for a grading system for duct obstruction. The postprobing improvement of symptoms not previously appreciated supports the notion that meibomian gland disease exists subclinically.

Effect of ocular surface reconstruction by using amniotic membrane transplant for symptomatic conjunctivochalasis on fluorescein clearance test results.

PURPOSE: To evaluate the hypothesis that the therapeutic effect of amniotic membrane transplantation (AMT) ocular surface reconstruction in the setting of symptomatic temporal conjunctivochalasis is through improved tear clearance. METHODS: Twelve eyes with delayed tear clearance by the fluorescein clearance test in the setting of symptomatic temporal conjunctivochalasis were subjected to surface reconstruction by using AMT and evaluated for the effect on delayed tear clearance, symptoms, surface erosions, artificial tear use, visual acuity, and tear strip wetness. RESULTS: AMT of temporal symptomatic conjunctivochalasis did not improve tear clearance; however, it significantly improved symptoms (Fisher exact test, P = 0.001), surface erosions (Fisher exact test, P = 0.008), and log minimal angle resolution visual acuity (Fisher exact test, P = 0.007) and reduced artificial tear use (Fisher exact test, P = 0.015). There was also an improvement in tear strip wetting, but this did not reach statistical significance. CONCLUSIONS: Relief of symptoms and improvement in clinical signs after AMT for symptomatic temporal conjunctivochalasis was not caused by improved tear clearance.

A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance.

PURPOSE: To evaluate loteprednol etabonate ophthalmic 0.5% suspension, versus placebo for treatment of the inflammatory component of keratoconjunctivitis sicca in patients with delayed tear clearance. DESIGN: Randomized, double-masked, placebo-controlled clinical trial. METHODS: Sixty-four patients with keratoconjunctivitis sicca and delayed tear clearance were randomly assigned to receive either loteprednol or vehicle 4 times a day for 4 weeks. Patients were evaluated at weeks 2 and 4 of treatment and 2 weeks after treatment was discontinued. Symptoms were scored using a visual analog scale (VAS) of 1 to 100. Corneal fluorescein staining was scored 0 to 4 in five areas. Conjunctival injection was graded 0 to 3 in the inferior bulbar, nasal bulbar, and inferior tarsal areas. Lid margin injection was graded 0 to 3. Safety was assessed by funduscopy, lens examination, biomicroscopy, visual acuity, and Goldmann tonometry, and by monitoring adverse events and changes in symptoms. RESULTS: In subsets of patients with at least moderate clinical inflammation, there was a significant difference between the loteprednol-treated group and vehicle-treated group after 2 weeks of therapy. The differences did not reach statistical significance at 4 weeks, although the loteprednol-treated patients retained their improvement compared with the vehicle-treated group. Safety evaluations showed both treatments to be well tolerated and similar in the frequency and type of adverse event reported. CONCLUSION: The use of topical loteprednol etabonate 0.5% 4 times a day may be beneficial in patients who have keratoconjunctivitis sicca with at least a moderate inflammatory component.