Fishman comment: Blink analysis is a simple yet under appreciated technique that helps dry eye diagnosis and treatment. This paper illustrates the utility of blink analysis.

Authors: Kunihiko Hirosawa1,2, Takenori Inomata1,2,3,4,5*, Jaemyoung Sung1, Masahiro Nakamura2,6, Yuichi Okumura1,2,4, Akie Midorikawa‐Inomata5, Maria Miura1,2, Kenta Fujio1,2,

Yasutsugu Akasaki1,2, Keiichi Fujimoto1,2, Jun Zhu1,7, Atsuko Eguchi5, Ken Nagino5,

Mizu Kuwahara1,2, Hurramhon Shokirova1, Ai Yanagawa2 & Akira Murakami1,2,3

Abstract: Various symptoms of the dry eye disease (DED) interfere with the quality of life and reduce work productivity. Therefore, screening, prevention, and treatment of DED are important. We aimed

to investigate the potential diagnostic ability of the maximum blink interval (MBI)(the length of time participants could keep their eyes open) with disease‐specific questionnaire for DED. This cross‐sectional study included 365 patients (252 with DED and 113 without DED) recruited between September 2017 and December 2019. Discriminant validity was assessed by comparing the non‐DED and DED groups based on the MBI with a Japanese version of the Ocular Surface Disease Index (J‐OSDI) and tear film breakup time (TFBUT) with J‐OSDI classifications. The MBI with J‐OSDI showed good discriminant validity by known‐group comparisons. The positive and predictive values of MBI with J‐OSDI were 96.0% (190/198 individuals) and 37.1% (62/167 individuals), respectively. The area under the receiver operating characteristic curve (AUC) of MBI with J‐OSDI was 0.938 (95% confidence interval 0.904–0.971), the sensitivity was 75.4% (190/252 individuals), and the specificity was 92.9% (105/113 individuals), which are similar to the diagnostic ability of TFBUT with J‐OSDI (AUC 0.954). In conclusion, MBI with J‐OSDI may be a simple, non‐invasive screening test for DED.

What is Known:
• The intestinal microbiome plays a crucial role in several inflammatory diseases of the eye and is considered a therapeutic target.
• Probiotics play a role in the prevention and treatment of different conditions in children.

What is New:
• In children probiotic supplementation is safe and effective.
• Probiotic supplementation reduced the time required for complete resolution of the chalazion.

Intestinal microbiome: a new target for chalaziosis treatment in children?

Published: 23 November 2020

Mariaelena Filippelli, Roberto dell’Omo, […]Ciro Costagliola
European Journal of Pediatrics (2020)

Intestinal dysbiosis (changes in the gut commensal microbiome) is related to several ophthalmic diseases. The aim of this study was to verify whether oral specific probiotics can alter the clinical course of chalaziosis and its recurrence.

A prospective comparative pilot study involving 26 children suffering from chalaziosis was conducted. Children were randomly divided into two groups. The first group received medical treatment (lid hygiene, warm compression and dexamethasone/tobramycin ointment for at least 20 days), and the second group received medical treatment plus a daily supplementation of oral probiotics (≥ 1 × 10^9 live cells of Streptococcus thermophilus ST10 (DSM 25246), ≥ 1 × 10^9 live cells of Lactococcus lactis LCC02 (DSM 29536) and ≥ 1 × 10^9 live cells of Lactobacillus delbrueckii subsp. bulgaricus (DSM 16606) with maltodextrin as the bulking agent (Probiotical S.p.A., Novara, Italy).

All patients were evaluated at 2-week intervals for 3 months. If the lesion had not disappeared or decreased in size to 1 mm or less in diameter at the time of subsequent visits, the same procedure was repeated for another 3-month cycle. There was a significant difference in the time taken for complete resolution of the chalazion between the two groups in favour of the children receiving the probiotics. The treatment was not associated with any significant complications in either group. Trial registration: The trial was registered at clinical trials.gov under NCT04322500 on 25/03/2020 (“retrospectively registered”).

Conclusions: Modification of the intestinal microbiome with specific probiotics can alter the clinical course of chalaziosis in children by re-establishing intestinal and immune homeostasis. Probiotic supplementation can increase the effectiveness of traditional therapies by prompting the complete resolution of chalaziosis in a shorter amount of time, in an easy and feasible way.

— Read on link.springer.com/article/10.1007/s00431-020-03880-5

Fishman Comments: Recurrent cornea erosions (RCE) can be a tough condition to treat. One particularly frustrating cause is LASIK or PRK. I see a number of patients who have been diagnosed with “dry eye” and/or neuropathic pain syndrome after refractive surgery. However, a careful examination of the cornea in many cases reveals recurrent epithelial erosions. Often RCE can be difficult to detect because by the time the patient is seen in the office, the epithelium can heal.  It is therefore extremely important to see the patient as soon as they report symptoms in hope that the corneal erosion can be detected at the slit lamp. While RCE can be a “1 second diagnosis,” and often diagnosed by history alone, it can take persistence to definitively make this diagnosis in some patients.

There are numerous other causes of RCE and as this article reports, “Recurrent corneal erosion (RCE) typically occurs in eyes that have had previous abrading injuries (even years prior), eyes with epithelial basement membrane dystrophy (EBMD), corneal dystrophies such as lattice degeneration, corneal degenerations such as band keratopathy, or prior ocular surgery for refractive errors, cataracts, or corneal transplantation. ”

“Recurrent corneal erosion: a comprehensive review.” Darby D Miller 1, Syed A Hasan 1, Nathaniel L Simmons 2, Michael W Stewart. Clin Ophthalmol . 2019 Feb 11;13:325-335.

Purpose: To comprehensively review the literature regarding recurrent corneal erosion (RCE) and to present treatment options and recommendations for management.

Overview: RCE usually presents with sharp, unilateral pain upon awakening, in an eye with an underlying basement membrane dystrophy, prior ocular trauma, stromal dystrophy or degen- eration, or prior surgery for refractive errors, cataracts, or corneal transplantation. Making the correct diagnosis requires a careful slit-lamp examination of both eyes coupled with a high degree of suspicion. Several treatments are commonly used for RCE but new therapies have been introduced recently. Conservative treatment consists of antibiotic and preservative-free lubricating drops, with topical cycloplegics and oral analgesics to control pain. Patients who are unresponsive to these therapies may benefit from therapeutic bandage contact lenses (BCL). Newer therapies include oral matrix metalloproteinase (MMP) inhibitors, blood-derived eye drops, amniotic membrane graft application, and judicious application of topical corticosteroids. Once the epithelium is healed, a course of hypertonic saline solution and/or ointment can be used. Surgical procedures may be performed in patients who fail conservative therapy. Punctal occlusion with plugs increases the tear film volume. Epithelial debridement with diamond burr polishing (DBP), anterior stromal puncture (ASP), or alcohol delamination should be considered in selected patients. DBP can be used for patients with basement membrane dystrophies and is the preferred treatment overall due to a low recurrence rate. ASP can be used for erosions outside the central visual axis. Excimer laser phototherapeutic keratectomy is an attractive option in eyes with central RCE since it precisely removes tissue while preserving corneal transparency. In patients with RCE who are also candidates for refractive surgery, photorefractive keratectomy can be considered.

Fishman Comments (continued): Another possibly treatment option is to use autologous serum eye drops (ASED) combined with a bandage contact lens. The below article describes some success with this treatment.  At FishmanVision, we can provide our patients with a subset of ASED called PRGF.

“Therapeutic outcomes of combined topical autologous serum eye drops with silicone–hydrogel soft contact lenses in the treatment of corneal persistent epithelial defects: A preliminary study.” By Yu-Kuei Lee et al.

Abstract
Purpose
To evaluate the efficacy of the combination of topical 20% autologous serum eye drops (ASEs) and silicone–hydrogel soft contact lenses (SCLs) for the treatment of corneal persistent epithelial defects (PEDs), and to compare the recurrence of epithelial breakdown with or without continuous use of ASEs after silicone–hydrogel SCLs removal.
Methods
We conducted a prospective interventional study of 21 eyes of 21 patients with PEDs treated with combined ASEs and silicone–hydrogel SCLs from September 2014 to August 2015. SCLs were removed after total re-epithelialization and patients were subsequently randomized divided into two groups: (1) with and (2) without continuous use of ASEs for an additional 2 weeks. PEDs healing rate and epithelial defect recurrence were evaluated.
Results
PEDs healed in all eyes within 3 weeks. Recurrence was noted in five eyes (50%) in patients without continued use of ASEs for 2 weeks after total re-epithelialization and SCLs removal during a 3-month follow-up (odds ratio: 23.0; P < 0.05). Recurrent epithelial defects were successfully treated with secondary SCLs application combined with autologous serum use. No adverse events were noted during the entire treatment period.
Conclusions
The combined use of ASEs and silicone–hydrogel SCLs can successfully treat recalcitrant PEDs. Prolonged use of ASEs after total re-epithelialization can decrease recurrence rates.

Summary: Newly introduced therapies for RCE enable therapy to be individualized and lower the recurrence rate.
Keywords: recurrent corneal erosion, anterior basement membrane dystrophy, map-dot- fingerprint dystrophy, epithelial basement membrane dystrophy, corneal abrasion

Fishman comments: The effect of Botox on ocular surface disease is seriously under appreciated. While the cosmetic benefit of Botox is widely known, Botox use was actually “invented” by an Ophthalmologist (Dr. Alan Scott) to treat strabismus (eye muscle misalignment) in kids.

BoTox does have some other less well known off-label uses including reducing eyelid friction in cases of SLK (Botox the muscle of Riolan), reducing epiphora in cases of obstructive outflow (both functional and mechanical), and pain control in neuropathic pain syndrome. These are just a few examples, but this paper provides a nice summary of other effects on the ocular surface.

Ren-Wen Ho et al. Toxins 2019, 11, 66; doi:10.3390/toxins11020066

Abstract
Clinical usage of botulinum neurotoxin (BoNT) in ophthalmology has dramatically increased since the 1980s and has become one of the most widely used agents for treating facial movement disorders, autonomic dysfunction and aesthetic wrinkles. Despite its high efficacy, there are some complications with periocular BoNT injections due to its chemodenervation effect. Among these, there is still controversy over the BoNT effect on tear film homeostasis and the ocular surface. A periocular BoNT injection could dry the eye by reducing tear production of the lacrimal gland and increase tear evaporation due to potential eyelid malposition and abnormal blinks. On the contrary, the injection of BoNT in the medial eyelids could treat dry eye disease by impairing lacrimal drainage. Regarding the ocular surface change, corneal astigmatism and high-order aberrations may decrease due to less eyelid tension. In conclusion, the entire awareness of the effect of BoNT and the patients’ ocular condition is crucial for successful and safe results.

A few comments on mechanism (if you are interested..)
The below figure (from Emerg Infect Dis. 2005;11(10):1578-1583) nicely illustrates the mechanism of how BoTox inhibits vesicular docking at the pre-synaptic neuron. “BoNTs are zinc metalloproteases that cleave and inactivate specific cellular proteins essential for the release of the neurotransmitter acetylcholine.” More specifically, Botox cleaves SNARE proteins (https://doi.org/10.1016/S0092-8674(00)80727-8) and SNARE proteins mediate vesicle fusion.  As an aside, I did my PhD in Prof. Richard Scheller’s lab (and ZareLab) at Stanford where many of these mechanisms of synaptic neurotransmission were discovered.

Above figure from the paper – Barr JR, Moura H, Boyer AE, Woolfitt AR, Kalb SR, Pavlopoulos A, et al. Botulinum Neurotoxin Detection and Differentiation by Mass Spectrometry. Emerg Infect Dis. 2005;11(10):1578-1583. https://dx.doi.org/10.3201/eid1110.041279

The below video snippet is an example of dead Demodex mites on a lash. We see no leg movement on video microscopy and presume mite death.  Demodex mites are parasites with a length ranging from 200-400 microns (1) . One study suggests that six or more Demodex mites per 16 lashes is clinically significant (2). 4 mites on a single lash is likely a pathologic level as is the case here. There are many treatment options including but not limited to oral or topical Ivermectin, IPL, and tree tea oil. Dr. Fishman recently published a paper showing for the first time Demodex death by IPL.  

This patient used tea tree oil lid scrubs to kill the parasites which is a nice first-line option. While the active ingredient in tree tea oil is Terpinen-4-ol, the mechanism of death is not fully established. The mites still need removal from lashes with effective lid scrubbing. Often this requires in-office lid debridement. 

References: 

(1) “Human Demodex Mite: The Versatile Mite of Dermatological Importance. Parvaiz Anwar Rather, Iffat Hassan.” Indian J Dermatol. 2014 Jan-Feb; 59(1): 60–66.

(2)  “Demodex blepharitis: clinical perspectives.” Stephanie R Fromstein, Jennifer S Harthan, Jaymeni Patel, and Dominick L Opitz. Clin Optom (Auckl). 2018; 10: 57–63.

Prevalence of ocular surface disease symptoms in peri- and postmenopausal women

Garcia-Alfaro, Pascual MD; Bergamaschi, Luciana MD; Marcos, Celia MD, PhD; Garcia, Sandra BSc; Rodríguez, Ignacio MScAuthor Information Menopause: September 2020 – Volume 27 – Issue 9 – p 993-998

Conclusions:

Sixty-four percent of the pre- and postmenopausal women studied had OSD symptoms. There was a correlation between OSD symptoms and age, postmenopause, and earlier age at menopause, which was associated with an increased prevalence.

Fishman comments: Dr. Galor continues to be one the TOP academic physician/ researchers in the area of dry eye and neuropathic pain. This article from 2017 by Dr. Galor et al. does a terrific job of summarizing the mechanisms, treatments and challenges of neuropathic pain and dry eye and how they are inextricably related. The take home message for me is that eye pain can originate from local ocular surface findings – so called nociceptive pain  (like inflamed corneal nerves, recurrent erosions, superior limbic keratoconjunctivitis, etc.) and then switch over to neuropathic pain which is an abnormal signaling of the nervous system. The key is for the physician to determine if the pain is nociceptive, neuropathic, or both.

Authors:  Anat Galor, MD, MSPH, Hamid-Reza Moein, MD, Charity Lee, BS, Adriana Rodriguez, MD, Elizabeth R. Felix, PhD, Konstantinos D. Sarantopoulos, MD, PhD, and Roy C. Levitt, MD

Abstract: Dry eye is a common, multifactorial disease currently diagnosed by a combination of symptoms and signs. Its epidemiology and clinical presentation have many similarities with neuropathic pain outside the eye. This review highlights the similarities between dry eye and neuropathic pain, focusing on clinical features, somatosensory function, and underlying pathophysiology. Implications of these similarities on the diagnosis and treatment of dry eye are discussed.

Fishman comment:  Post-concussion syndrome (PCS) is a very debilitating condition in which individuals suffer from symptoms including “headaches, dizziness, fatigue, irritability, reduced concentration, sleep disturbance, memory loss, sensitivity to noise or light, double or blurred vision, nausea, anxiety and depression.” Electrovestibulography (EVestG) is an objective diagnostic tool for PCS. It is an important development because it provides objective parameters to allow patients gauge their progression to recovery.

However, one of the challenges in treating PCS is co-morbid depression that may interfere with gauging whether clinical improvement is occurring. This brilliant and heady Nature paper “showed that when depression and PCS are co-morbid in a PCS group, the EVestG features could be used to detect both conditions with two different and relatively independent neurophysiological mechanisms that can be applied simultaneously.”

Title: “Investigating the validity and reliability of Electrovestibulography (EVestG) for detecting post- concussion syndrome (PCS) with and without comorbid depression. Sci Rep 8, 14495 (2018). https://doi.org/10.1038/s41598-018-32808-1.

Authors: Suleiman, A., Lithgow, B., Mansouri, B. et al. Investigating the validity and reliability of Electrovestibulography (EVestG) for detecting post-concussion syndrome (PCS) with and without comorbid depression.

Abstract: Features from Electrovestibulography (EVestG) recordings have been used to classify and measure the severity of both persistent post-concussion syndrome (PCS) and major depressive disorder. Herein, we examined the effect of comorbid depression on the detection of persistent PCS using EVestG. To validate our previously developed EVestG classifier for PCS detection, the classifier was tested with a new blind dataset (N = 21). The unbiased accuracy for identifying the new PCS from controls was found to be >90%. Next, the PCS group (N = 59) was divided into three subgroups: PCS with no-depression (n = 18), PCS with mild-depression (n = 27) and PCS with moderate/severe-depression (n = 14). When moderate/severe depression was present, PCS classification accuracy dropped to 83%. By adding an EVestG depression feature from a previous study, separation accuracy of each PCS subgroup from controls was >90%. A four and three-group (excluding mild-depression subgroup) classification, achieved an accuracy of 74% and 81%, respectively. Correlation analysis indicated a significantcorrelation (R = 0.67) between the depression feature and the MADRS depression score as well as between the PCS-specific feature and Rivermead Post-Concussion Questionnaire (RPQ) (R = −0.48). No significant correlation was found between the PCS-specific feature and the MADRS score (R = 0.20) or between RPQ and the depression feature (R = 0.12). The (PCS-specific and depression-specific) EVestG features used herein have the potential to robustly detect and monitor changes, relatively independently, in both persistent PCS and its depression comorbidity. Clinically, this can be particularly advantageous.

Fishman Comment: I have been very impressed with the use of serum tears in the treatment of neuropathic corneal pain. At FishmanVision, we use a subset of serum tears called Plasma Rich in Growth Factors (PRGF). PRGF is itself a subset of PRP. Compared to other modalities, patients appear to find a relief in pain from PRGF.   In this paper, the authors suggest that the Endocannabinoid system may be involved. As a quick refresher, The endocannabinoid system is a complex biological regulatory system, conserved among vertebrates, which regulates both systemic and CNS functions that include immune response, pain, neuronal activity, in addition to metabolic and cardiovascular functions

“Platelet-rich Plasma Exerts Antinociceptive Activity by a Peripheral Endocannabinoid-Related Mechanism.” Tissue Eng Part A. 2013 Oct;19(19-20):2120-9.

Authors: Fiorella Descalzi 1, Valentina Ulivi, Ranieri Cancedda, Fabiana Piscitelli, Livio Luongo, Francesca Guida, Luisa Gatta, Sabatino Maione, Vincenzo Di Marzo

Abstract
In regenerative medicine, platelet by-products containing factors physiologically involved in wound healing, have been successfully used in the form of platelet-rich plasma (PRP) for the topical therapy of various clinical conditions since it produces an improvement in tissue repair as well as analgesic effects. Measurement of endocannabinoids and related compounds in PRP revealed the presence of a significant amount of anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide. Investigation of the activity of PRP on the keratinocyte cell line NCTC2544 in physiological and inflammatory conditions showed that, under inflammatory conditions, PRP induced in a statistically significant manner the production of these compounds by the cells suggesting that PRP might induce the production of these analgesic mediators particularly in the physiologically inflamed wounded tissue. Studies in a mouse model of acute inflammatory pain induced by formalin injection demonstrated a potent antinociceptive effect against both early and late nocifensive responses. This effect was observed following intrapaw injection of (1) total PRP; (2) lipids extracted from PRP; and (3) an endocannabinoid-enriched lipid fraction of PRP. In all conditions, antagonists of endocannabinoid CB1 and CB2 receptors, injected in the paw, abrogated the antinociceptive effects strongly suggesting for this preparation a peripheral mechanism of action. In conclusion, we showed that PRP and PRP lipid extract exert a potent antinociceptive activity linked, at least in part, to their endocannabinoids and related compound content, and to their capability of elevating the levels of these lipid mediators in cells.

Fishman comment: This is our recent work on a new method for measuring the mRNA on the ocular surface. The implications for this research range from microbiome analysis to point of care testing for infectious diseases.

Abstract:

Harvey Fishman MD PHD, Jonathan Mansbridge, Vera Morhenn; Tape Stripping: A Novel Noninvasive Method Using RNA Sequences for Diagnosing Ocular Surface Diseases of the Eye and Eyelid. Invest. Ophthalmol. Vis. Sci. 2020;61(7):392.
Purpose : Currently, diagnosing ocular surface diseases of the eye or eyelid is complex, often requiring a biopsy and analysis with biological markers for a definitive answer. We propose tape-stripping biopsy, a rapid, minimally invasive method of diagnosing ocular surface pathology extending to the ocular microbiome and malignant tumors.

Methods : After topical anesthesia, the conjunctiva, cornea, or eyelid margin was touched with 4 separate Sebutapes disks (6 mm diameter) 5 times each and placed into an Eppendorf tube. RNA was isolated and sequenced using the Illumina system. Sequence frequency was determined and evaluated as transcribed RNA abundance using the Tuxedo suite of programs. This was an IRB approved clinical study using human subjects.

Results : Using this non-invasive method, we were able to isolate ~10,000 RNA sequences from microenvironments on the ocular surface that were human and included both coding and non-coding RNA. Samples showed individual variability but also differences that could be related to disease such as a reduction in mucin (MUC 1, 4, 5AC, 13, 15, 16, 20 and 21) gene expression in dry eye. A marked increase in the proportion of non-coding RNA was seen in a sample from a conjunctival nevus.

Conclusions : We can identify an RNA transcription profile from the eye, by tape stripping, a simple non-invasive method, that can, using hybridization-based rapid RNA identification, be applied to many eye diseases including malignancies, inflammation and infectious agents and extended to the ocular microbiome of the eye.

This is a 2020 ARVO Annual Meeting abstract.

Ye Elaine Wang, MD1; Victoria L. Tseng, MD, PhD1; Fei Yu, PhD1,2; et al. Joseph Caprioli, MD1; Anne L. Coleman, MD, PhD1,3

JAMA Ophthalmol. 2018;136(2):141-147. doi:10.1001/jamaophthalmol.2017.5702

Key PointsQuestion  Does an association exist between daily dietary intake of polyunsaturated fatty acids, especially ω-3 fatty acids, and the risk of glaucoma in the US population?

Findings  In a cross-sectional population study of 3865 participants, increased daily levels of eicosapentaenoic acid and docosahexaenoic acid intake were associated with significantly lower risks of glaucoma. Daily levels of total polyunsaturated fatty acid intake in the higher quartiles, however, were associated with significantly increased odds of having glaucoma.

Meaning  These findings indicate that longitudinal studies or randomized clinical trials assessing potential ω-3 fatty acid (eicosapentaenoic acid and docosahexaenoic acid) protection against glaucoma are warranted.

Abstract
Importance  Identifying whether an association exists between daily dietary polyunsaturated fatty acid (PUFA) consumption and the prevalence of glaucoma in the United States may provide modifiable dietary risk factors for the development of glaucoma.

Objective  To analyze the association between glaucoma and daily dietary intake of PUFAs, including ω-3 fatty acids, in the US population.

Design, Setting, and Participants  Data from 3865 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2008 database who were 40 years or older, had participated in the vision health and dietary intake questionnaires, and had available results from laboratory tests and eye examinations that included frequency-doubling technology visual field loss detection tests and optic disc photographs were included. Data collection was performed by NHANES from 2005 to 2006. Data for the present study were downloaded from their database May 1 to 30, 2017. Data analyses were performed from June 1 to October 1, 2017.

Exposures  Daily dietary intake of PUFAs, including ω-3 fatty acids.

Main Outcomes and Measures  Prevalence of glaucoma in the United States as defined using the Rotterdam criteria, which included a combination of optic cupping or asymmetry and visual field defect results.

Results  Of the 83 643 392 weighted survey participants included in this cross-sectional study, 43 660 327 (52.2%) were women and 3 076 410 (3.7%) met our criteria for having glaucoma. Compared with participants without glaucoma, those with glaucoma were older (mean [SE] age, 61.4 [0.8] vs 53.7 [0.4] years; P < .001). Increased levels of daily dietary intake of eicosapentaenoic acid (odds ratio [OR], 0.06; 95% CI, 0.00-0.73) and docosahexaenoic acid (OR, 0.06; 95% CI, 0.01-0.87) were associated with significantly lower odds of having glaucoma. However, participants with daily total dietary PUFA intake levels in the second (OR, 2.84; 95% CI, 1.39-5.79) and third (OR, 2.97; 95% CI, 1.08-8.15) quartiles showed significantly increased odds of meeting our criteria for a diagnosis of glaucoma.

Conclusions and Relevance  Increased daily dietary consumption levels of eicosapentaenoic acid and docosahexaenoic acid were associated with lower likelihood of glaucomatous optic neuropathy. However, consumption levels of total PUFAs in the higher quartiles were associated with a higher risk of glaucoma, which may have resulted from the relative intakes of ω-6 and ω-3 fatty acids and other confounding comorbidities. This study also hypothesizes that increasing the proportion of dietary ω-3 consumption levels while controlling overall daily PUFA intake may be protective against glaucoma. However, longitudinal studies or randomized clinical trials are needed to assess these hypotheses.

Air composition influences Dry Eye (DE) symptoms as demonstrated by studies that have linked the outdoor environment to DE. However, there is insufficient data on the effect of short-term exposure to indoor environments on DE symptoms. We conducted a prospective experimental research, in which an older building served as an experimental site, and a newer building served as the control site. Indoor air quality was monitored in both buildings. One-hundred-and-ninety-four randomly selected individuals were interviewed in the afternoon exiting the buildings and de-identified responses were recorded. Self-reported DE symptoms were modeled with respect to experimental and control buildings, adjusting for potential confounders. The experimental site had 2-fold higher concentration of airborne particulate matter (24,436 vs. 12,213 ≥ 0.5 µm/ft3) and microbial colonies (1066 vs. 400/m3), as compared to the control building. DE symptoms were reported by 37.5% of individuals exiting the experimental and 28.4% exiting the control building. In the univariate analysis, subjects exiting the experimental building were 2.21× more likely to report worsening of DE symptoms since morning compared to the control building (p < 0.05). When adjusting for confounders, including a history of eye allergy, subjects from the experimental building were 13.3× more likely to report worsening of their DE symptoms (p < 0.05). Our findings suggest that short-term exposure to adverse indoor environmental conditions, specifically air pollution and bioaerosols, has an acutely negative impact on DE symptoms.
— Read on www.mdpi.com/2077-0383/9/5/1316

Purpose
To evaluate facial Demodex densities in participants with varying severities of blepharitis secondary to Demodex folliculorumassessed by the highest number of cylindrical dandruff on one lid.

Methods
This double masked cross-sectional study included 58 participants [19 control, 21 mild/moderate and 18 severe Demodex blepharitis] who underwent a standardized skin-surface biopsy and a lash epilation for each lid to obtain the forehead Demodex densities and the overall lash mite count, respectively. Also, facial photographs were taken to evaluate facial erythema and dermatological conditions. The Ocular Surface Disease Index [OSDI], non-invasive break-up time [NIBUT], tear meniscus height [TMH], bulbar conjunctival redness as well as additional questions on watery eyes, ocular itching and itching along the lids were assessed.

Results
Both mild/moderate and severe Demodex blepharitis groups were over the cut-off value [≥ 5 mites/cm 2] that confirms a facial demodicosis (mild/moderate: 5 ± 1; severe: 6 ± 1) while the control group was below it (2 ± 1). Thereby, group comparisons showed that an increased severity of Demodex blepharitis was associated with higher forehead mite densities (p = 0.002) and increased lash mite count (p < 0.001). The degree of facial erythema was also positively correlated with forehead mite densities (rs = 0.31, p = 0.02). When compared to the controls, the mild/moderate group had more watery eyes (X 2 = 6.54, p = 0.02), a lower TMH (U = 100.5, p = 0.006) and the severe group had more itching along the lids (X 2 = 4.94, p = 0.04). The other ocular signs and symptoms [NIBUT, bulbar conjunctival redness, OSDI] were not affected by the severity of Demodex blepharitis (p > 0.05).

Conclusion
Palpebral and facial Demodex infestation can co-exist, as the presence of blepharitis secondary to Demodex is associated with increased facial mite densities.

Coronavirus disease 2019 (COVID-19) is an important health problem that was defined as a pandemic by the World Health Organization on 11 March 2020. Although great concern has been expressed about COVID-19 infection acquired through ocular transmission, its underlying mechanism has not currently been clarified. In the current work, we analyzed and elucidated the two main elements that should be taken into account to understand the “ocular route”, both from a clinical and molecular point of view. They are represented by the dynamism of the ocular surface system (e.g., the tear film turnover) and the distribution of ACE2 receptors and TMPRSS2 protein. Although it seems, at the moment, that there is a low risk of coronavirus spreading through tears, it may survive for a long time or replicate in the conjunctiva, even in absence of conjunctivitis signs, indicating that eye protection (e.g., protective goggles alone or in association with face shield) is advisable to prevent contamination from external droplets and aerosol.
— Read on www.mdpi.com/2077-0383/9/5/1269/htm

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are currently no SARS-CoV-2-specific treatments or vaccines available due to the novelty of the virus. Hence, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here we developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against SARS-CoV-2 strains. Three immunizations using two different doses (3 μg or 6 μg per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support clinical development of SARS-CoV-2 vaccines for humans.

— Read on science.sciencemag.org/content/early/2020/05/06/science.abc1932

Dr. Fishman’s comments on latest DREAM study publication:

Why is there is a huge disparity between the clinical experience of most well-known dry eye and corneal specialists and the results that are emerging from the DREAM study? To cut to the chase, the study lumped together all of the many different subtypes of dry eye disease, and they failed to consider the impact of the baseline differences in gut microbiome when enrolling the patients. Let’s unpack these ideas here.

Contrary to what the DREAM study investigators report that Omega-3 fatty acids supplementation is essentially ineffective for dry eye patients (including the newest installment), many patients with dry eye disease who start on supplementation with Omega-3 FA as a primary therapy have remarkable improvements in their symptoms. These “real world” clinical experiences have been confirmed by numerous publications that show quantitative improvement in signs of ocular surface disease (for e.g, osmolarity, tear breakup time, OSDI, MMP-9 levels). More importantly, precise analytical chemistry measurements (for e.g., LC / mass spectrometry) show improvements in the meibum and ocular surface conditions in patients with dry eye disease. This has been my overwhelming experience over the past 15 years as well. Just last week, I had three patients who remarked that primary therapy of Omega-3 supplements completely resolved their dry eye symptoms and “changed their life.” Ironically, it was the same day that this latest DREAM study paper was released ahead-of-print.

Much has been written on the short comings of the DREAM study including poor control (olive oil), huge heterogeneity of the causes/etiology of dry eye patients (lumping dry eye patients together), flawed inclusion/exclusion criteria, the type of omega-3 FA used in the study (i.e, GLA based) and the dose amount. Moreover in the NEJM publication, while both groups improved, the study group authors in lectures and interviews argue that Omega-3 FA are ineffective for dry eye patients.

So what is the missing link ? I think that one of the most obvious disconnects is that the investigators lumped together all the subtypes of dry eye disease. It would be equivalent of running a clinical trial on “cancer” and failing to identify the myriad of cancer subtypes and concluding that a single therapy failed because it did not collectively cure lung, colon, skin cancer etc. When you think of the many etiologies of dry eye (similar to the many subtypes of cancer), how could one ever believe that a single intervention would show any statistical significance with such heterogeneity in etiology.

Secondly, just as the DREAM study lumped together all subtypes of dry eye disease, they lumped together the gut microbiome of every patient. Why is this another disconnect? One of my (many) theories as to why Omega-3 FAs help a significant subset of dry eye patients (and not all), is that certain dry eye subtypes have a gut microbiome dysbiosis that is helped with the “pre-biotic” effects of the Omega-3 FAs. This effect could very well have a long lasting impact on the microbial community in the gut and may not be altered simply by withdrawing Omega-3FA for the time period studied in this latest DREAM study report. Failing to take this into account could very much wash out the results.

Interestingly, the dramatic clinical improvement that I often see and the many published works finding the same seem an unlikely effect from just the Omega-3 FAs alone. Instead, I hypothesize that there is an amplification effect via the hundreds of millions of bacterial species that makeup the microbiome of the gut. It goes without saying, that my writing these theories down here are just that… theories. We need to test these hypotheses with well-controlled double-blinded clinical studies. At FishmanVision, we have already published on the gut microbiome and dry eye disease, and this is an active area of clinical and research interest for us. Click here for our ARVO poster.

I enjoy lecturing on the gut -eye connection , and you can click here for short snippet of a lecture on the impact of the microbiome and dry eye disease that I gave at an annual Alldocs meeting.

Associations Between Systemic Omega-3 Fatty Acid Levels With Moderate-to-Severe Dry Eye Disease Signs and Symptoms at Baseline in the Dry Eye Assessment and Management Study”

Authors: Kuklinski, Eric J. BA; Hom, Milton M. O.D., F.A.A.O.; Ying, Gui-Shuang Ph.D.; Lin, Meng C. O.D., Ph.D.; Chapkin, Robert S. Ph.D.; Jones, Richard Ph.D.; Moser, Ann B.A.; Kim, Ka Yeun BS; Maguire, Maureen G. Ph.D.; Asbell, Penny A. M.D., M.B.A., F.A.C.S. the DREAM Study Research Group

Eye & Contact Lens: Science & Clinical Practice: February 24, 2020 – Volume Publish Ahead of Print – Issue – doi: 10.1097/ICL.0000000000000687

Abstract

Purpose: 

Omega-3 (n-3) fatty acid supplementation is used to treat systemic inflammatory diseases, but the role of n-3 in the pathophysiology and therapy of dry eye disease (DED) is not definitive. We evaluated the relationship of systemic n-3 levels with signs and symptoms at baseline in the Dry Eye Assessment and Management (DREAM) Study.

Methods: 

Blood samples from participants at baseline were analyzed for n-3 and n-6, measured as relative percentage by weight among all fatty acids in erythrocytes. Symptoms were evaluated using the Ocular Surface Disease Index. Signs including conjunctival staining, corneal staining, tear breakup time (TBUT), and Schirmer’s test with anesthesia were also evaluated.

Results: 

There was no correlation between the systemic n-3 levels and DED symptoms. When the associations with signs of DED were assessed, lower DHA levels were associated with higher conjunctival staining, with mean scores of 3.31, 2.96, and 2.82 for low, medium, and high levels of DHA, respectively (linear trend P=0.007). None of the other signs were associated with DHA or the other measures of n-3.

Conclusion: 

Previous studies have found varying results on the role of n-3 supplementation with the signs and symptoms of DED. Among patients with DED enrolled in the DREAM Study, lower systemic n-3 levels were not associated with worse symptoms and most signs of DED.

Fishman comments: Another brilliant article by Dr. Pflugfelder and co-workers. Here, they show a correlation between tear MUC5AC concentration and GC area and suggests tear MUC5AC mucin can be used as a disease-relevant biomarker for conjunctiva GC health.

Authors: Khimani, K.S., Go, J.A., De Souza, R.G. et al. Sci Rep 10, 2933 (2020). https://doi.org/10.1038/s41598-020-59956-7

Fishman comments: The article says it best… “Conjunctival melanoma is a rare tumor with an incidence of 0.2 to 0.8 cases per 1 million people, although the incidence is increasing.” “In daily practice, it can be very difficult to distinguish a benign from a malignant melanocytic lesion based on only histologic, immunohistochemical, and the well-known molecular findings.” This paper shows that the use of microRNA can be a powerful way to help differentiate benign vs. malignant tumors.  My research at FishmanVision expands upon this method by using a non-invasive method to measure miRNA from pigmented lesions. We are running an IRB investigator sponsored clinical trial, and if you have a conjunctival nevus, please contact FishmanVision for more details.

Authors: van Ipenburg, Jolique A. et al. Ophthalmology, Volume 127, Issue 3, 432 – 434(DOI: https://doi.org/10.1016/j.ophtha.2019.10.008 )

In this study, the authors focused on discriminating miRNA levels in benign versus malignant conjunctival melanocytic lesions and differences in miRNA levels in the conjunctival melanoma with versus without metastases to determine whether it is possible to predict metastatic potential.

mmc3

Fishman comments: Super interesting article on the effects of female mouse tear fluid on male behavior. The authors found that female tears contain a factor that strongly inhibits inter-male aggression.

Cavaliere, R.M., Silvotti, L., Percudani, R. et al. Female mouse tears contain an anti-aggression pheromone. Sci Rep 10, 2510 (2020). https://doi.org/10.1038/s41598-020-59293-9

Abstract
Tears contain pheromones that trigger specific behavioral responses. In the mouse, male tear fluid is involved in long and short-term effects such as the receptive behavior and pregnancy block in females and the aggression in males. In contrast, pup tears exert an inhibitory effect on male mating behavior, also promoting sexual rejection in females. In the rat, a male lacrimal protein acts as an intraspecific and heterospecific signal enhancing sexual behavior in females and evoking avoidance behavior in mouse. However, behavioral effects of female tears on male behavior have yet to be described. Here, we report that female lacrimal fluid of different mouse strains contains a relatively small and involatile factor that abolishes inter-male aggression switching it into a copulatory behavior. The production of this molecule by the lacrimal glands is not affected by the estrous cycle but it is sensitive to ovariectomy, thus suggesting a control mediated by hormones. Moreover, this lacrimal anti-aggression pheromone modulates the activity of the lateral habenula, a brain area responsible for the valence of the aggressive interactions.

Matrix metalloproteinases (MMPs) are a group of enzymes that in concert are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth and normal tissue turnover. Presence of MMP-9 in the tear film indicates an inflammatory process. The MMP-9 detector shown below is a nice way to track treatment efficacy and in planning future treatments.

Fishman comments: Our paper is the first to show direct evidence of “Demodex Death by IPL” using live video microscopy.   Honored to collaborate on this important work with Dr. Periman (aka @dryeyemaster) and Dr. Shah (@sfgotox).

Photobiomodul Photomed Laser Surg. 2020 Jan 27. doi: 10.1089/photob.2019.4737. [Epub ahead of print]
Real-Time Video Microscopy of In Vitro Demodex Death by Intense Pulsed Light. Fishman HA, Periman, LM, Shah, AA.

Abstract
Objective: To directly observe the in vitro real-time effects of intense pulsed light (IPL) on a Demodex mite extracted from an eyelash of a patient with ocular rosacea. Background: Demodex is a risk factor in the pathogenesis of oculofacial rosacea, meibomian gland dysfunction (MGD), and dry eye disease (DED). Recent studies suggested IPL to control or eradicate Demodex organisms in the periocular area. Despite encouraging reports, the direct effect of IPL on Demodex is not well understood.

Methods: An eyelash infested with Demodex was epilated from a 62-year-old female patient with oculofacial rosacea. Following isolation and adherence of a mite onto a microscope slide, real-time video microscopy was used to capture live images of the organism before, during, and after administration of IPL pulses. IPL pulses were delivered with the M22 IPL (Lumenis), with IPL settings used for treatment of DED due to MGD (the “Toyos protocol”). A noncontact digital laser infrared thermometer was used to measure the temperature of the slide.

Results: Before the IPL pulses, legs of the Demodex mite spontaneously moved in a repetitive and semicircular motion. During administration of IPL, spontaneous movements of the legs continued. Immediately after administration of five IPL pulses, the temperature of the slide increased from room temperature to 49°C. Immediately afterward, the Demodex mite became completely immobilized. The legs appeared retracted, smoother, less corrugated, bulkier, and less well-defined. Movement of the Demodex mite was not observed at the hourly inspections for 5 h and after 24 h following the application of IPL pulses.

Conclusions: Our video directly demonstrates the effect of IPL on a live Demodex mite extracted from a freshly epilated eyelash. The results suggest that IPL application with settings identical to those used for treatment of DED due to MGD causes a complete destruction of the organism.

Fishman comments: Methotrexate is a commonly used drug to treat various ocular autoimmune conditions including  uveitis and scleritis. Unfortunately, GI side effects are a problem. This is a nice paper exploring the possibility of reducing GI toxicity by  increasing the protective intestinal microbiota. Hopefully, we will continue to understand the microbiome better to reduce our dependence on toxic immune modulating drugs

Authors: Duozhuang Tang, Ting Zeng, Yiting Wang, Hui Cui, Jianying Wu, Bing Zou, Zhendong Tao, Liu Zhang, George B. Garside & Si Tao (2020) Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity, Gut Microbes, DOI: 10.1080/19490976.2020.1714401

Methotrexate (MTX) is a typical chemotherapeutic drug that is widely used in the treatment of various malignant diseases as well as autoimmune diseases, with gastrointestinal toxicity being its most prominent complication which could have a significant effect on the prognosis of patients. Yet effective ways to alleviate such complications remains to be explored. Here we show that 30% dietary restriction (DR) for 2 weeks dramatically increased the survival rate of 2-month-old female mice after lethal-dose MTX exposure. DR significantly reduced intestinal inflammation, preserved the number of basal crypt PCNA-positive cells, and protected the function of intestinal stem cells (ISCs) after MTX treatment. Furthermore, ablating intestinal microbiota by broad-spectrum antibiotics completely eliminated the protective effect achieved by DR. 16S rRNA gene deep-sequencing analysis revealed that short-term DR significantly increased the Lactobacillus genus, with Lactobacillus rhamnosus GG gavage partially mimicking the rescue effect of DR on the intestines of ad libitum fed mice exposed to lethal-dose MTX. Together, the current study reveals that DR could be a highly effective way to alleviate the lethal injury in the intestine after high-dose MTX treatment, which is functionally mediated by increasing the protective intestinal microbiota taxa in mice.

This is a very common comment that eye care professionals hear from their patients and thus an excellent opportunity to unpack many important issues in ophthalmology and optometry. I am going to break this into several blog posts and part (I) will start with optics. Future blog posts will focus on ophthalmic disease which, by far, is often the reason for this comment, but as you will find, not always. If you are a real optics nerd, like me, check out the greatest book ever on this topic entitled, “The Fine Art of Prescribing Glasses Without Making a Spectacle of Yourself” by Benjamin Milder and Melvin L. Rubin.

Let’s start with optics and let’s assume that the refraction was perfect. (And please, no jokes about the word “assumption” -as in the line that Walter Matthau delivers in the movie, Bad News Bears).  

Now, what can go wrong from the point at which the ‘assumed’ correct prescription goes into the hands of the optician and then to the lab that make the lens?

1. The famous “minus” vs. “plus” prescription (transcription) error. A really nutty thing in eyecare is the way prescriptions are written. Prescriptions can be written in “plus” cylinder notation or “minus” cylinder notation and they are mathematically identical.  A problem occurs when the lens making lab gets these two confused and the glasses prescription will be very off.  This is very uncommon but can happen. As an interesting historical side note, Ophthalmologists typically use the “plus” notation and Optometrists typically work in the “minus” notation.  There are several possible reasons for this that date back to the 1800’s when cylinders were ground into the front vs. back of lenses and how Ophthalmologists vs. Optometrists then wrote the prescriptions. However, the notation differences have persisted. My theory is that as surgeons, “plus” cylinder notation helps us think about the surgical correction of astigmatism better.  However, the plus (no pun intended) of using “minus” cylinder notation is that it makes it easier to write contact lens prescriptions without having to transpose the prescription.
2. Optical center errors. When you have glasses made, the optician marks the exact spot on the lens that corresponds to the center of the patient’s pupil. This then gets transmitted to the lens lab and they will create a lens that has it’s optical center corresponding to the patient’s pupil. It is remarkable to me how many patients have incorrectly positioned optical centers in their glasses. I see this error made all the time by both opticians (MARKING THE LENS) and by the lens maker (MAKING THE LENS).  The patients will have a variety of problems with these glasses including poor vision, double vision, fatigue, and general unhappiness.  Determining the optical center of the lens is not trivial and often done incorrectly. This error then sends the prescribing doctor and the lens maker in an endless loop of finger pointing and trying to correct the problem.  I have been frustrated by this problem for years until now. We (at FishmanVision) recently obtained the Visionix VX-40, a wavefront device that provides a visual topographic map of the power ranges across the lens of the glasses and determines an immense amount of information on the lens including the optical center, lens aberrations, the size and position of the progressive zone.  The Visionix VX-40 has allowed us to determine whether the lenses were made correctly. It is a game changer for us and for our patients.
3. Aniseikonia (image size difference). In all fairness, this is really not an error by either the doctor or the lens lab, but an iatrogenic issue associated with the magnification that the lens makes on the patient’s retina. This issue is conceptually simple – if each eye has a different prescription (hence magnification), then the image size that gets projected onto the patient’s retina will be different and the patient can experience a huge number of issues that range from dizziness, fatigue (also known as asthenopia), pulling sensation, and overall miserableness.  The error really is in not recognizing the problem and then trying various fixes like prisms, “dumbing down one lens” to better equalize the difference, patching, none of which will be satisfactory in my experience. To add insult to injury, the aniseikonia can be optical or can be retinal. I will write an entire blog post on causes of retina aniseikonia, but for now, let’s stick to optical aniseikonia. If the patient has optical aniseikonia, then the lenses can be made to equalize the image magnification. Aniseikonic lenses are one of several ways to solve this problem. Sometimes, the problem is only in the reading zone and another solution is to use a special lens grinding technique used to neutralize the unwanted prism effect when looking down through the reading area (usually a bifocal) of widely differing lens powers.
4. Reading add errors. The reading add has a whole host of issues from a PAL zone that is too narrow, to a PAL zone or bifocal that is positioned too low, to a PAL design that doesn’t allow an large enough viewing area for the reading task needed.
5. Stress induced optical aberrations. Frames can cause warpage of a plastic lens and the lens will have optical aberrations that can be seen with cross polarizers. This is a simple solution and you have to remake the lens without internal stress.
6. Frame wrap angle. Frame wrap angle describes the horizontal angle of the lens plane in front of the eyes. Check out the excellent article in 20/20mag.com on this subject.
7. Pantoscopic tilt. The Pantoscopic tilt describes the vertical angle between a wearer’s primary gaze and the intersection of the same with the plane of the lenses. Progressive wearers find even minor amounts of frame-front skew will cause significant visual distress and discomfort. Check out the excellent article in 20/20mag.com on this subject.
8. Vertex distance errors – the glasses are made and fitted with a vertex distance that is different from the vertex distance that was in the phoropter when the refraction was performed. Check out the excellent article in 20/20mag.com on this subject.
9. Large angle kappa and PALS. Angle Kappa is the angle between the pupillary axis and the visual axis. It is termed positive when the pupillary axis is nasal to the visual axis, and negative when the pupillary axis is temporal to the visual axis. Please see the excellent article in 20/20mag.com for full details.

The American Academy of Ophthalmology (AAO) publishes guidelines called preferred practice patterns (PPP). In the staged management of dry eye disease as per the PPP, punctal occlusion (plugs) for dry eye disease has been a level II (step 2) option for many years. It has been an excellent solution for treating dry eyes, so much so, that the American Board of Ophthalmology (ABO) would “grade” ophthalmologists on whether plugs were attempted in dry eye disease treatment.

___________________________________________________________________________________

Recently, punctal occlusion has become less popular with the advent of so many new treatment options including thermal eyelid pulsation (iLux, MiboFlow, LipiFLow), Maskin probing, iTear tear stimulation  (and the now defunct, TrueTear lacrimal gland stimulation), serum eye drops, Xiidra, Azasite amongst others and new treatments are coming along in the pipeline every day.

However, like all treatment options, punctal occlusion is not a panacea and has it’s downsides. Punctal plugs can and often fall out; they can rub on the conjunctiva and cause irritation; and plugs can cause nasal lacrimal sac infection and canaliculitis. Similarly, cauterizing the punctum is a “permanent” and invasive procedure. As described in the AAO’s PPP, cautery is a level IV (step 4) option and never a first line option for punctal occlusion. In general, cautery should never be performed before a trial of plugs first.  Moreover, some dry eye specialists argue that occlusion prevents inflammatory mediators (i.e toxic tears) from being flushed away and can exacerbate inflammation. Tears that are overly salty can be similarly irritating.

However, punctal occlusion via plugs or cautery definitely has its place in dry eye disease management and probably needs to be utilized more often than currently occurs in many dry eye practices.  As part of my intensive dry eye workup at FishmanVision, I rely on precise measurements of tear film levels using OCT anterior segment imaging. Anterior OCT allows me to accurately measure the level of tears present and is much more reliable than Schirmer testing. When the patient has a scant tear volume as measured by OCT, I have found the patient benefits greatly from punctal occlusion.  In my experience, while iTear, Cyclosporine, Lifitegrast, fish oils, etc (all of which I utilize) are somewhat helpful for increasing tear film levels, for those patients with a low tear film, these treatment options rarely achieve sufficient relief and occlusion often works best.

Of course, the real question is the etiology of why tear volume is so low in these patients. I will cover etiology in a future blog.

Fishman comments: From an analytical chemistry standpoint, the ocular microbiome is an extremely complex environment to measure. This work is interesting and adds to our understanding of the impact of the ocular microbiome and dry eye disease. We have a long way to go to truly understand these interactions. My own work on the gut microbiome and dry eye disease also just scratches the surface of what I believe will be an incredibly important area in the future.

Authors: ZhenHao Li, Yufang Gong,ShuZe Chen,
SiQi Li,Yu Zhang,HuiMin Zhong,ZhouCheng Wang,YiFan Chen,QiXin Deng,YuTing Jiang,LiYing Li,Min Fu & GuoGuo Yi
Journal of Microbiology volume 57, pages1025–1032(2019).

Abstract
rRNA gene high-throughput sequencing was performed in the conjunctival swab samples to investigate the composition of the OS bacterial community in DE (n=35) and NDE (n=54) and compared the composition of MGD (n=25) and NMGD (n=10) among DE subjects. Deep sequencing of OS 16S rDNA from DE (n=35) and NDE (n=54) demonstrated great a difference in alpha and beta diversity between the OS bacterial flora (P < 0.05). The similar OS microbial structures were shown at the phylum and genus levels by bioinformatics analysis between them, and in LEfSe (linear discriminant analysis effect size) analysis, Bacteroidia and Bacteroidetes were enriched in DE, while Pseudomonaswas plentiful in NDE (linear discriminant analysis [LDA] > 4.0). Among the DE group, there was no significant difference in α and β diversity between MGD and NMGD (P > 0.05). Surprisingly, Bacilli was the dominant microbe in MGD, and Bacteroidetes was the superior bacteria in NMGD among DE subjects (LDA > 4.0). Different diversity of OS bacteria composition between DE and NDE and the altered diversity of OS bacteria may play an important role in DE. Moreover, the lower dominance of OS bacteria in DE may be associated with the occurrence and development of DE. Although there was no significant difference in alpha and beta analysis, the OS dominant microbe between MGD and NMGD among DE was different.

Fishman commentary: Neat finding by Dr. Kuppermann and colleagues.

Role of Resveratrol in Transmitochondrial AMD RPE Cells by Sonali Nashine 1, Anthony B. Nesburn 1,2, Baruch D. Kuppermann 1 and Maria Cristina Kenney 1,3,* Nutrients 2020, 12(1), 159; https://doi.org/10.3390/nu12010159

Abstract
Resveratrol is a phytoalexin, stilbenoid compound with antioxidant properties attributable to its bioactive trans-resveratrol content. This study characterized the effects of over-the-counter (OTC) resveratrol nutritional supplements and a HPLC-purified resveratrol formulation, in human transmitochondrial age-related macular degeneration (AMD) retinal pigment epithelial (RPE) patient cell lines. These cell lines, which were created by fusing blood platelets obtained from dry and wet AMD patients with mitochondria-deficient (Rho0) ARPE-19 cells, had identical nuclei (derived from ARPE-19 cells) but different mitochondria that were derived from AMD patients. After resveratrol treatment, the levels of cell viability and reactive oxygen species production were measured. Results demonstrated that treatment with different resveratrol formulations improved cell viability and decreased reactive oxygen species generation in each AMD patient cell line. Although further studies are required to establish the cytoprotective potential of resveratrol under different physiological conditions, this novel study established the positive effects of OTC resveratrol supplements in macular degeneration patient cybrid cell lines in vitro.

Dr. Periman (a.k.a Dry Eye Master – @dryeyemaster) and colleagues present wonderful work on the use of IPL to treat chalazia. As described, IPL shows incredible promise of a drug-free, incision-free and injection-free method of addressing chalazia.

IPL was offered to these patients to manage their acute or chronic chalazion/chalazia as a drug-free, incision-free and injection-free method of addressing their lesions that fits into their lives. Patient A had a significant job interview in 2 days. Patient B was scheduled for LASIK in 3 weeks and so rapid control of her eyelid disease and inflammatory burden was important. Patient C suffered multiple chalazia over the years and was exceptionally needle phobic. IPL was an acceptable and effective alternative for these patients. High patient satisfaction was reported. Prior peer reviewed publications support the role of IPL for rosacea and MGD.

Fishman commentary. Classic review article by Dr. Pflugfelder. We need to better understand the innate immune system – ” the field is rapidly realizing the complexity of other innate and adaptive immune factors involved in the development and progression of disease”

Authors: Michael E. Stern, Chris S. Schaumburg & Stephen C. Pflugfelder (2013). Dry Eye as a Mucosal Autoimmune Disease, International Reviews of Immunology, 32:1, 19-41, DOI: 10.3109/08830185.2012.748052

Abstract

Fishman Commentary: In many patients, dry eye disease present with a neuropathic component, which I refer to as the “trigeminal ganglion pain continuum.” In this paper, the authors show that changes at the synaptic level in the brainstem occur in dry eye disease.

Highlights

* Patients with dry eye have an abnormal enhancement of excitability in blink reflex circuits.

* The abnormalities were present in both, primary and secondary dry eye syndromes.

* The abnormal sensorimotor integration may be due to sensitization due to excessive sensory input

MeralE. Kızıltan^aCezmiDogan^bSelahattinAyas^aJosepValls-Sole^cAysegulGunduz^a

^aDepartment of Neurology, Cerrahpasa Medical Faculty, I.U.C, Istanbul, Turkey

^bDepartment of Ophtalmology, Cerrahpasa Medical Faculty, I.U.C, Istanbul, Turkey

^cIDIBAPS (Institut d’Investigació August Pi i Sunyer), Barcelona, Spain

Abstract

Background

We hypothesized that there may be changes in sensory integration pathways in patients with dry eye. To confront this issue, we analyzed blink reflex (BR), prepulse modulation (PPM) of BR, and excitability recovery of BR to paired stimuli in 17 experimental subjects with dry eye syndrome.

Method

We included 17 experimental subjects, 8 with primary and 9 with secondary, dry eye syndrome. We also examined a control group of 14 age and gender matched control subjects. After clinical evaluation, we recorded BR, PPM of BR (at 50 and 100 ms intervals) and BR percentage recovery to paired stimulation (at 300 and 500 ms intervals).

Results

None of the patients had any spasm activity. Experimental subjects had significantly larger R2 and R2c AUCs, significantly greater excitability recovery at 300 ms interval and significantly reduced R2 and R2c prepulse inhibition, in comparison to control subjects. Experimental subjects with primary dry eye syndrome had higher number of spontaneous blinks than experimental subjects with secondary dry eye syndrome (54.0 ± 10.3 for primary dry eye and 43.5 ± 13.3 secondary dry eye).

Patient with corneal neuropathy from a refractive surgery 7 years ago.

Fishman Comments:

Incredibly interesting work on stem cell transplantation for restoring the lacrimal gland function. MSC in 2 µl saline were injected into the LG. Important basic science in the field of dry eye disease.

Authors: Jana Dietrich, Lolita Ott, Mathias Roth, Joana Witt,Gerd Geerling, Sonja Mertsch& Stefan Schrader 
Scientific Reports volume 9, Article number: 18299 (2019) Cite this article

Abstract

Fishman commentary: Treatment pearls for dupilumab associated ocular surface disease.

Authors: JodieRaffi^abRaaginiSuresh^aTimothyBerger^aHarveyFishman^cJenny E.Murase^ad
https://doi.org/10.1016/j.ijwd.2019.08.007 International Journal of Women’s Dermatology . Available online 24 August 2019.

Fishman commentary. Excellent article on ocular surface disease and dupilumab.  Significant improvement after patch testing in nearly half of patients suggests that allergic contact dermatitis contributes to some cases of dupilumab-associated eye complications.

Click here for PDF

Authors:  JodieRaffi^abRaaginiSuresh^aHarveyFishman^cNinaBotto^aJenny E.Murase^ad

Abstract

Methods: This cross-sectional study included 42 healthy volunteer women who had no dry eye symptoms (Ocular Surface Disease Index score < 13) and aged between 18 and 40 years. The subjects were classified into 2 groups: an eyeliner-use group (EL: regularly used eyeliner ≥3 d/wk and continuously used ≥6 mo) and a noneyeliner-use group as controls. A questionnaire for ocular surface symptoms using a visual analog scale was administered. Then, a number of eye tests were performed [grading of conjunctival inflammation, fluorescein tear breakup time, ocular surface fluorescein staining, Schirmer I, evaluation of meibomian gland (MG) function, detection of eyelid margin abnormalities, and Demodex detection].

Results: Tear breakup time was significantly lower in the EL group compared with controls (3.0 ± 1.9 vs. 5.8 ± 2.1 s, P < 0.001). MG grading was significantly higher in the EL group than in controls (P = 0.004); higher grade (grades 2–3) was found in 85.7% of EL and 47.6% of controls. Meiboscore was also higher in EL than in controls (P = 0.001). Regarding the morphological changes in lid margin, only telangiectasia was detected significantly more in EL (28.6%) compared with controls (4.8%) (P = 0.041). Conjunctival inflammation was observed 4 times more in EL (66.7%) than in controls (14.3%), P = 0.001. Other outcomes included ocular surface symptoms and fluorescein staining scores, and Schirmer I and Demodex detection were not significantly different between both groups.

Conclusions: The regular use of eyeliner induces tear film instability and MG dysfunction.

Dr. Fishman comment: 2 interesting take aways- the use of MPOD to track diet and how brain Lutein may be important for cognitive achievement . “This is the first study to demonstrate that retinal L and Z, measured as MPOD, is positively related to academic achievement in children”

Published in : Nutr Neurosci. 2018 Nov;21(9):632-640. Authors:  Barnett SM¹, Khan NA^2,3,4, Walk AM², Raine LB⁵, Moulton C⁶, Cohen NJ^7,8,9, Kramer AF^5,8, Hammond BR Jr¹⁰, Renzi-Hammond L¹⁰, Hillman CH^5,11.

Abstract

Purpose : The human microbiome has been studied for centuries and recently has been associated with health issues ranging from metabolic disorders such as obesity and diabetes to inflammatory disorders such as inflammatory bowel disease.⁵ However, only recently have associations of the gut microbiome with ocular diseases been realized.^2,3,4 In this study, we investigated whether there is a connection between the bacterial diversity of the gut microbiome and dry eye disease.

Methods : We performed retrospective chart review of patients presenting to FishmanVision (Palo Alto, CA) that had been prescribed the SmartGut microbiome screening test (uBiome, San Francisco, CA). Using 16S rRNA gene sequencing based stool test, we compared levels (low, normal, high) of 26 bacterial organisms for patients diagnosed with dry eye disease vs. “normals.”¹

Results : The uBiome analysis was carried out on 17 patients (13 diagnosed with dry eye disease and 4 without dry eye). No patient had high level of any bacteria and no patient reported low level for 11 organisms. Bacteroides fragilis, Alistipes, and Collinsella were normal (0/4) in non-dry eye patients, but they were low in 8% (1/13), 8% (1/13), and 46% (6/13) of dry eye patients. Prevotella, Odoribacteria, Bifidobacterium, Barnesellia, and Akkermansia muciniphila were all low in 25% (1/4) of non-dry eye patients, while they were low in 23% (3/13), 31% (4/13), 38% (5/13), 54% (7/13), and 77% (10/13) of dry eye patients. Lactobacillus was low in 75% (3/4) of non-dry eye patients and in only 62% (8/13) of dry eye patients. Anaerotruncus colihominis was low in 50% (2/4) of non-dry eye patients and in 77% (10/13) of dry eye patients. Methanobrevibacter smithii and Oxalobacter formigenes were low in 100% (4/4) of non-dry eye patients and in 85% (11/13) of dry eye patients. Butyrivibrio crossotus, Ruminococcus albus, and Dialister invisus were low in 100% (4/4) of non-dry eye patients and 92% (12/13) of dry eye patients. These observations are illustrated in Figure 1.

Conclusions : Collinsella, Barnesellia, Akkermansia muciniphila were lower in dry eye patients compared to normal patients. Lower gut microbiome diversity in dry eye patients may have important clinical ramifications in the treatment of dry eye disease.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 – May 2, 2019.

https://iovs.arvojournals.org/article.aspx?articleid=2746694&resultClick=1

We report on a novel light intensity device (LuxIQ) that helps clinicians assess the severity of dry eye disease in a quantitative manner. Currently, the inability to quantify and accurately assess the severity of dry eyes is a huge impediment in the field of dry eye disease.  This novel device is a major advancement for both clinicians and researchers for the development of new therapies and for the accurate assessment of current treatments in the field of dry eye disease.

Purpose:

To evaluate the effectiveness of a novel device that quantifies light sensitivity in patients reporting Dry Eye Disease (DED) symptoms, and whether light sensitivity measurement is an effective indicator of DED.

Methods:

15 patients reporting DED symptoms were recruited during their regularly scheduled visit to a Dry Eye clinic. A routine screening exam was conducted, including Non-Invasive Tear Break-up Time (NIBUT), Schirmer strips, and Osmolarity. In addition, each patient was asked to adjust a device (LuxIQ™, Jasper Ridge Inc) to their preferred illuminance and white light color temperature on a 40-cm near vision chart (Colenbrander Mixed Contrast), over an illuminance range of 0-5000 lux and color temperature range of 2,700 to 6,500°K. Measurement was bilateral (both eyes open) Patients were not told the purpose of this measurement. 8 control subjects, who did not report DED symptoms, were also measured for illuminance and color temperature preference.

Results:

The average illuminance and color temperature for the DED patients was 1750±753 lux and 4507±784°K, and for the controls 2643±1435 lux and 5000±852°K (see figure 1). The DED distribution shows a strong peak between 1000 and 2000 lux, and is significantly lower than the control (p=.21). The NIBUT, Schirmer and Osmolarity scores showed no correlation to one another. Interestingly, the sole correlation between methods seen is between illuminance and NIBUT for patients with illuminance <3000 lux and the time in both eyes <5 seconds, with a linear r²correlation of 0.91.

Conclusion:

We observed strong evidence of a measurable relation between preferred illuminance and DED symptoms. Of the four diagnostic methods used in this study, preferred illuminance was the most consistent, a promising result as it is also the quickest, simplest, and least invasive of the methods. The correlation between short NIBUT times and preferred illuminance further supports the conclusion that preferred illuminance is a valid indicator of DED. We are continuing this IRB-approved study, and expect to evaluate significantly more patients.

Authors:

1. Fishman¹, P.G. Borden², M. Klein², ¹Fishman Vision, Palo Alto, CA; ²Jasper Ridge Inc, Menlo Park, CA.