Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 ISSN: 2226-4485 (Print) Original Research ISSN: 2218-6050 (Online) DOI: 10.5455/OVJ.2023.v13.i9.12 Submitted: 02/05/2023 Accepted: 25/08/2023 Published: 30/09/2023 Topical 1% cyclosporine eyedrops for the treatment of crystalline corneal dystrophy in dogs Manuela Crasta1† , Kevin Arteaga1*† , Teresa Peña2,3 and Marta Leiva2,3 AniCura Visionvet, Eye Clinic, San Giovanni in Persiceto, Bologna, Italy 1 Departament de Medicina i Cirurgia Animals, Facultat de Veterinària, Universitat Autònoma de Barcelona, 2 Bellaterra, Spain 3 Servei d’Oftalmologia, Fundació Hospital Clínic Veterinari, Universitat Autònoma de Barcelona, Bellaterra, Spain †Both authors contributed equally to this work. Abstract Background: Crystalline corneal dystrophy (CCD) is the most common type of corneal lipidic deposition in dogs. CCD is a primary metabolic disorder of the corneal fibroblast featuring an accumulation of extracellular and intracellular lipid deposits. Corneal lipid deposits create a corneal opacity and modify the interfibrillar collagen distance, inducing light scattering. Corneal vascularization is not usually associated with the disease, but, in case of chronicity, cell death may produce inflammation, and new corneal vessels are developed. To the best of the authors’ knowledge, this is the first report of a medical approach for CCD treatment in veterinary medicine. Aim: To evaluate the efficacy of topical 1% cyclosporine eyedrops (1% CsA) for the treatment of CCD in dogs. Methods: Medical records of dogs with CCD were retrospectively reviewed (2009–2020). Corneal opacification description (COD) [size (mm), depth, and opacification degree (0–3)] was evaluated at 0, 3, 6, 9, 12, and 15 months postinitial diagnosis. Dogs were classified into three groups: the control group (G0), the group receiving topical 1% CsA once per day (G1), and the group receiving topical 1% CsA twice daily (G2). Results: Ninety-two client-owned dogs (163 eyes) of different breeds, ages, and gender fulfilled the inclusion criteria. When compared to G0, where the eyes significantly increased COD (p < 0.001), G1 and G2 significantly decreased COD (p < 0.001). In fact, the probability of reducing COD was about three times higher in G2 than in G1, being nearly the same for the right [odds ratio (OR) = 2.94; 95% confidence interval (95% CI) = 0.55–15.78] and left eye (OR = 2.92; 95% CI = 0.49–17.26). In addition, for each additional month of treatment in G2, the probability of reducing COD increased significantly (OR = 1.12; 95%CI = 1.00–1.26 for the right eye and OR = 1.16; 95%CI = 1.02–1.32 for the left eye). Conclusion: Long-term treatment with topical 1% CsA eyedrops significantly improved CCD in dogs, being the probability of reducing COD higher when applying the treatment twice daily. Keywords: Cornea, Cyclosporine, Deposits, Dog, Dystrophy. Introduction Ralph, 2021). Corneal lipid deposits create a corneal Crystalline corneal dystrophy (CCD) is the most common opacity and modify the interfibrillar collagen distance, type of corneal lipidic deposition in dogs (Barsotti inducing light scattering. Corneal vascularization is et al., 2008). CCD is a primary metabolic disorder of not usually associated with the disease, but, in case of the corneal fibroblast featuring an accumulation of chronicity, cell death may produce inflammation, and extracellular and intracellular lipid deposits (Barsotti new corneal vessels are developed (Crispin, 2002). et al., 2008). Some purebreds (e.g., Beagle, Siberian Schnyder’s crystalline stromal dystrophy is a very Husky, and Cavalier King Charles Spaniel) are prone similar condition described in humans. Histochemical to suffer from CCD, which tends to affect young and ultrastructural studies in both species have pointed dogs and both eyes more frequently (Spangler et al., to the presence of cholesterol, cholesterol ester, and 1982; Cooley and Dice, 1990; Crispin, 2002). CCD is phospholipids in the affected cornea as responsible characterized by metallic and refracting opacities in the for the structural disorganization of corneal collagen central or paracentral cornea, with different shapes (i.e., fibers. However, a definitive relationship between oval, round, discoid, or ringlike lesion) (Whitley and dyslipoproteinemia has not been found in dogs’ or *Corresponding Author: Kevin Arteaga. AniCura Visionvet, Eye Clinic, San Giovanni in Persiceto, Bologna, Italy. Email: kevinof91@hotmail.com Articles published in Open Veterinary Journal are licensed under a Creative Commons Attribution-NonCommercial 4.0 International License 1167 http://www.openveterinaryjournal.com M. Crasta et al. Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 humans’ disease (Winder, 1994; Crispin, 2002). In (SD-OCT) (Optovue, Inc; Freemont, CA) of the corneal dogs with CCD, subtle defects in vision are difficult dystrophic area was recorded, when available. to assess and confirm. Nonetheless, scientific reports in Dogs were classified into three groups: G0, the control humans have asserted that photopic vision impairment group with no treatment, G1 receiving topical 1% CsA is caused by the glare from corneal crystalline deposits, eyedrops once daily, and G2 receiving topical 1% CsA with some patients requiring lamellar or penetrating twice daily. In all the cases, 1% CsA eyedrops were keratoplasty (Jayne, 2009). Lamellar keratectomy in compounded in sterile conditions as a solution in 80% dogs with CCD is recommended only as a last-resort pure vitamin E (DL-α-tocopherol acetate, racemic option if the opacity significantly obstructs vision since mixture) and 20% medium-chain fatty acids (from the corneal deposit is likely to recur with time. To date, coconut oil). no medical treatment has been shown to decrease or In all the dogs, a comparative assessment of corneal eliminate the opacity in CCD (Whitley and Ralph, opacification description (COD) by double-masked 2021). evaluation of the digital photographic records (Nikon Cyclosporine A (CsA) is a cyclic peptide commonly used D3500® and AF-S Micro Nikkor 60 mmf/2.8 G ED to treat immune-mediated keratoconjunctivitis sicca in macro lens) was performed at the first visit and follow- dogs due to its lacrimostimulant and lacrimomimetic ups. For all dogs, grade 2 was considered as the properties, improving corneal transparency by reducing baseline grading detected at the first visit. At follow- corneal vascularization and pigmentation. CsA also up evaluations, grades 0, 1, and 3 were considered disrupts immune-mediated processes by preventing depending if the corneal deposit was no longer T-cell production. Besides its lipophilic nature, CsA detectable, diminished, or increased, respectively enhances epithelium absorption into the corneal (Fig. 1). For those dogs in which no changes in terms and conjunctival areas (Whitley and Ralph, 2021). of opacification were observed, grade 2 was assigned. In addition, CsA has been shown to stimulate mucin Statistical analysis production, secreted by conjunctival goblet cells, on The statistical analysis was carried out using STATA the ocular surface (Phillips et al., 2000; Moore et al., Statistical Software (Release 14.2. College Station, 2001). Importantly, the safety of topical CsA, in a TX: StataCorp LP) with no adjustment for multiplicity solution of 80% pure vitamin E (DL-α-tocopherol and a statistical significance set at <0.05. Categorical acetate, racemic mixture) and 20% medium-chain fatty variables were described as absolute frequencies acids, has been established previously in dogs and cats and percentages, continuous variables as mean and (Arteaga et al., 2021). standard deviation (SD), when normally distributed, The purpose of the present study was to evaluate the and media and ranges, when non-normally. Categorical efficacy of topical 1% cyclosporine eyedrops (1% CsA) variables were compared using Pearson chi-square and for the treatment of CCD in dogs. continuous variables using the Kruskal–Wallis test. Materials and Methods Logistic regression analyses to estimate association [odds ratio (OR) and 95% confidence interval (95%CI)] Medical records of dogs diagnosed with CCD at two referral veterinary ophthalmology centers, Eye Clinic between efficacy (considering dogs as healed/improved Anicura Visionvet (San Giovanni in Persiceto, Italy) vs. stable/worsened, depending on the difference and Veterinary Teaching Hospital of the Autonomous between the COD grade at baseline and at the last University of Barcelona (Bellaterra, Spain), from 2009 to 2020, were retrospectively reviewed. Full approval from the hospitals to use the medical record information was obtained. Only dogs diagnosed with CCD after a complete ophthalmic examination, with Schirmer tear test 1 (STT-1) values >15 mm/minute, no sign of ocular discomfort, a minimum follow-up of 3 months, and with digital photographic records, were included in the study. Exclusion criteria included concomitant systemic metabolic diseases (e.g., hyperadrenocorticism, diabetes mellitus, or hypothyroidism), hypertriglyceridemia, hypercholesterolemia, disruption of topical treatment before 3 months, and concomitant ocular surface diseases other than those related to breed’s anatomical conformation (e.g., brachycephalic dogs). Recorded medical data included date of presentation, Fig. 1. Cavalier King Charles Spaniel with (a) CCD OD breed, age, gender, the affected eye, main complaint, and (b) OS classified as grade 2 at first presentation, and topical treatment, complications, and follow-up time. In subsequently classified as grade 1 after 12 months of topical addition, spectral domain-optical coherence tomography 1% CsA treatment (c) OD and (d) OS. 1168 http://www.openveterinaryjournal.com M. Crasta et al. Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 follow-up) and treatment group (G0 vs. G1 and G0 vs. Results G2), adjusting for gender, age, breed, and treatment Ninety-two dogs (163 eyes) of 23 different breeds follow-up. Analyses were run separately for each eye, fulfilled the inclusion criteria (Table 1). Brachycephalic considering the right eye [oculus dexter (OD)] and left eye [oculus sinister (OS)]. breeds were overrepresented (38/92; 42%). There were Ethical approval 50 females and 42 males of a median age of 6 years at Not needed as this was a retrospective study. presentation (range: 1–16 years) (Table 2). Seventy-one Table 1. Breed distribution according to their treatment group. G0 G1 G2 Breeds (n = 45) (n = 16) (n = 31) Mix 10 0 1 French Bulldog 9 0 0 Golden Retriever 5 1 0 Cavalier King Charles Spaniel 2 9 9 English Cocker Spaniel 2 0 0 Poodle 2 0 5 Yorkshire Terrier 2 0 1 Maltese 2 0 1 Pug 2 0 0 English Bulldog 1 0 0 West Highland White Terrier 1 0 0 American Bully 1 0 0 Beagle 1 0 1 Boxer 1 0 3 Great Dane 1 0 0 Greyhound 1 0 0 Labrador Retriever 1 2 5 Spaniel Breton 1 0 0 Australian Shepherd 0 2 1 Doberman Pinscher 0 1 2 Boston Terrier 0 0 1 Weimaraner 0 1 0 Siberian Husky 0 0 1 G0: dogs without treatment, control group; G1: dogs receiving topical 1% CsA once daily; G2: dogs receiving topical 1%CsA twice daily. Table 2. Baseline characteristics of dogs according to their treatment group. G0 G1 G2 Total p-value (n = 45) (n = 16) (n = 31) (n = 92) Sex, n (%) 0.070 Female 12 (27) 4 (25) 16 (52) 32 (35) Spayed female 10 (22) 5 (31) 3 (10) 18 (19) Male 14 (31) 6 (38) 11 (35) 31 (34) Castrated male 9 (20) 1 (6) 1 (3) 11 (12) Age (years), median (range) 6.18 (1–16) 4.09 (2.0–10) 4.18 (1.0–11) 6.00 (1–16) 0.023 Follow-up time (months), median (range) 16.2 (3–84) 13.0 (3–30) 13.5 (3–49) 14.9 (3–84) G0: dogs without treatment, control group; G1: dogs receiving topical 1% CsA once daily; G2: dogs receiving topical 1%CsA twice daily. 1169 http://www.openveterinaryjournal.com M. Crasta et al. Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 Table 3. Topical 1%CsA efficacy in oculus dexter and oculus sinister from first to last visit. The figure represents absolute numbers of eyes (and %) unless otherwise stated. G0 G1 G2 Corneal opacification degree OD OS OD OS OD OS (n = 42) (n = 38) (n = 15) (n = 16) (n = 25) (n = 27) Grade 2 to grade 0 (“healed”) 0 (0) 0 (0) 4 (27) 4 (25) 10 (40) 8 (30) Grade 2 to grade 1 (“Improved”) 0 (0) 1 (3) 4 (27) 5 (31) 10 (40) 13 (48) Grade 2 to grade 2 (“stable”) 16 (38) 16 (42) 7 (46) 6 (38) 5 (20) 6 (22) Grade 2 to grade 3 (“worsened”) 26 (62) 21 (55) 0 (0) 1 (6) 0 (0) 0 (0) G0: dogs without treatment, control group; G1: dogs receiving topical 1% CsA once daily; G2: dogs receiving topical 1% CsA twice daily. dogs (71/92; 77%) were bilaterally affected (142 eyes), and 21 unilaterally (21/92; 23%), being 12 ODs and 9 OSs affected. The main complaints reported were the presence of a white spot on the cornea (63/92 dogs; 69%), dull eyes (13/92 dogs; 14%), and increased ocular discharge (11/92 dogs; 12%). When classified among groups, there were 45 dogs (80 eyes) in G0, 16 dogs (31 eyes) in G1, and 31 (52 eyes) in G2 (Table 2). Gender (p = 0.070) and bilaterality (p = 0.087) were not statistically different among the three groups, age (p = 0.023) was not (p = 0.023). The median follow-up for the three groups was 14.9 months, ranging from 3–84 months. At the last follow-up, G1 and G2 had a statistically significant decrease in COD (p < 0.001) while G0 had a significant increase (p < 0.001) (Table 3). Only one eye from G0 went from grade 2 to grade 1. No statistically significant difference in COD between OD and OS at the last follow-up was found in any group (G0, p = 0.513; G1, p = 0.763; G2, p = 0.730). Similarly, no significant difference was observed between brachycephalic and nonbrachycephalic breeds in any group (G0, p = 0.636; G1, p = 0.132; G2, p = 0.248). When compared, the probability of reducing COD was Fig. 2. Longitudinal analysis of efficacy in treated groups about three times higher in G2 than in G1, being nearly (G1 and G2) showing a COD reduction as the treatment time the same for OD (OR = 2.94; 95% CI = 0.55–15.78) increased in (A) OD and (B) OS. COD: Corneal opacification and OS (OR = 2.92; 95% CI = 0.49–17.26) (Fig. 2). degree; G1: Group of dogs treated with 1%CsA once daily; Logistic regression analysis indicated that for each G2: Group of dogs treated with 1%CsA twice daily. additional month of follow-up in G2, and therefore, treatment with 1% CsA eyedrops twice daily, the probability of reducing COD increased significantly Apart from 2 G2-dogs (3/163 eyes; 2%) which had (p = 0.044 for OD and p = 0.019 for OS) (OR = 1.12; excessive tears, no other side effects were noticed. 95% CI = 1.00–1.26 for OD and OR = 1.16; 95% CI = The first dog (1 eye) presented with epiphora during 1.02–1.32 for OS) (Fig. 3). the last examination at 6 months. The second one (2 SD-OCT was performed in 2 and 3 eyes (5/163; 3%) eyes), with epiphora at 9 months of therapy, had no from 1 G1 and 2 G2 dogs, respectively. A hyperreflective longer corneal deposits, and the tearing resolved after area located in the anterior part of the axial stroma reducing frequency to once daily. was found at the site where deposits were clinically detected in all eyes. Focal thickening of the epithelium Discussion was evident after 9 months of treatment with topical CCD is a common ophthalmic disease in dogs that, 1% CsA twice daily in the region where deposits were if left untreated, can cause amblyopia, discomfort, previously located (Fig. 4). corneal erosion, and ulceration (Cooley et al., 1990). 1170 http://www.openveterinaryjournal.com M. Crasta et al. Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 Fig. 3. Longitudinal analysis of G2 showing the percentages of total eyes classified by COD grade during the follow-up (months). Results are presented for (A) the right and (B) the left eye. The three COD grades were: grade 0 (deposit no longer detectable with slit-lamp biomicroscopy, “healed,” shown in dark green), grade 1 (reduction of opacity, “improved,” shown in light green), and grade 2 (baseline, “stable,” shown in yellow). Grade 3 (increased opacity, “worsened”) is not shown since no dogs presented this COD grade in G2. COD: Corneal opacification degree; G2: dogs receiving topical 1% CsA twice daily. This study analyzes the clinical efficacy of topical 1% to areas of chronic drying, especially the central part of CsA eyedrops on the treatment of CCD in dogs. To the the cornea (Carrington et al., 1989; Packer et al., 2015). best of the authors’ knowledge, this is the first report Interestingly, DES has been associated with abnormal of a medical approach for CCD treatment in veterinary tear lipid deposition in mice (Chen et al., 2020). medicine. In general, CCD does not respond to medical treatment, Although CCD has been described in many and topical anti-inflammatory medications may different canine breeds, brachycephalic dogs were exacerbate the lesion. Low-fat diets are anecdotally overrepresented in the present study, which is not suggested to prevent the progression of the disease surprising based on their anatomical conformation (Whitley and Ralph, 2021). The corneal lesions can be features such as short noses, shallow orbits, and removed by keratectomy if the opacity is obstructing projected eyeballs, predisposing these individuals to vision significantly. However, the opacities may recur suffer from tear film instability and dry eye syndrome after keratectomy; therefore, surgery is recommended (DES) (Dinesh and Pookode, 2019). In addition, they for corneal dystrophy only as a last-resort measure may have low corneal sensitivity, incomplete and less in dogs with significant visual deficits. Due to the frequent blinking, and a thin lipid layer tear film, leading ophthalmic complications that could be derived from 1171 http://www.openveterinaryjournal.com M. Crasta et al. Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 corneal temperature right after their application, but the temperature will increase with eyelid closure during normal blinking (Fujishima et al., 1996; Fujishima et al., 1997). Further investigation is required to assess whether topical CsA use modifies corneal temperature in dogs with CCD and its association with lipid deposition. In the present study, COD reduction seems to be faster and more marked with two daily medications than with one, indicating a frequency-dependent response to topical 1%CsA. If CsA is used for this purpose, monitoring STT values is strongly recommended, as overproduction of tears could be seen. Topical CsA has been used in human ophthalmology Fig. 4. Representative digital photographs and SD-OCT of a for more than 40 years and evidence supports its safety Cavalier King Charles Spaniel dog from group G2. (a) Before and efficacy in treating various ocular surface disorders treatment, a digital photograph of the right eye showed a white (McCarthy et al., 1992; Reinhard and Sundmache, and oval refracting opacity in the paracentral cornea and (b) 1999; Sundmacher et al., 2001; Bonfioli et al., 2005; an SD-OCT of the same eye revealed a hyperreflective area Spadavecchia et al., 2006; Duszak 2007). Ophthalmic located in the anterior part of the axial stroma. (c) After 9 emulsions of CsA are prepared in several different oil- months of treatment with 1% CsA twice daily, no deposits based vehicles with concentrations ranging from 0.05% were detected and (d) focal thickening of the epithelium was to 2% (Acheampong et al., 1998). In previous studies, evident in the region where deposits were previously located. our research group has shown that a combination of SD-OCT: Spectral Domain-Optical Coherence Tomography. CsA and vitamin E was a safe and effective treatment for keratoconjunctivitis sicca and chronic superficial a nontreated CCD, finding a topical medication that keratitis in dogs (Arteaga et al., 2021). Ophthalmic reduces corneal opacity is mandatory. α-tocopherol (TOC) is the most effective antioxidant of Topical CsA has been shown to have a stimulatory the vitamin E family and is receiving special attention effect on both the number of conjunctival goblet cells to prevent and treat retinopathies, cataracts, and DES, and the amount of mucin production (Phillips et al., among other ocular pathologies (Xin et al., 2016). In 2000; Moore et al., 2001). Increasing mucin production our study, 100% TOC was used as a new solvent of would likely increase the time of permanence of the CsA. TOC has been reported to substantially reduce lacrimal film, improving the tear film stability and thus the concentration of free radicals in the tear film and to protecting the central part of the cornea. Although the improve the protection of corneal and conjunctival cells, present study shows that the use of topical 1%CsA thus, reducing the risk of inflammation and restoring the eyedrops decreases the deposition of lipids in the ocular surface from damage exposure (Aydemir et al., central cornea, the mechanism of action is not fully 2004; Zapata et al., 2008; Ribeiro et al., 2013; Olchawa understood. Increasing mucin production may extend et al., 2015; Tredici et al., 2020). Furthermore, TOC the durability of the lacrimal tear film and, hence, decreases the rate of corneal autolysis and keratocyte avoid the deposition of lipids in the central cornea. apoptosis (Bilgihan et al., 2001). Therefore, as the Unfortunately, break-up times were not evaluated in stromal cell cycle is reduced, there is less deposition of this study, thus, this theory could not be demonstrated material rich in cholesterol and phospholipids. yet; however, we are currently investigating the possible Even if the use of topical CsA has been associated correlation between CCD and the qualitative alteration with some adverse effects in dogs, in our study, only of the precorneal tear film interferometry. two dogs showed excessive tear production that was In CCD, crystal deposits tend to be distributed in the reversed after reducing the treatment frequency from central and coolest part of the cornea, and a temperature- twice to once daily (Gregory et al., 1989; Kaswan dependent enzyme defect has been hypothesized et al., 1989; Radziejewski and Balicki, 2016). to be the cause (Fielder et al., 1981). It has been The limitations of this study are mostly due to its demonstrated that local temperature changes can affect design. Dogs and treatment were not randomized and the melting point and thermal transition phases of lipids the ophthalmologist performing the examination and (Crispin, 2002; Tkáčová et al., 2011). Previous studies follow-up evaluation was not masked. Another group have evaluated the temperature of the cornea in patients only treated with ophthalmic TOC could have increased with DES and have revealed that the temperature of the power of the study. In the author’s experience, most the central cornea was significantly lower (Mori et al., patients with CCD also have a lipid tear film deficiency 1997; Craig et al., 2000; Kamao et al., 2011; Versura when evaluated by ocular surface interferometry et al., 2015). However, except for those kept in warmed (unpublished results), therefore, only TOC is unlikely to conditions, all types of tear substitutes decrease the reduce CCD. Cristal corneal deposits were not classified 1172 http://www.openveterinaryjournal.com M. Crasta et al. Open Veterinary Journal, (2023), Vol. 13(9): 1167–1174 by size thus, we could not objectively evaluate whether Aydemir, O., Celebi, S. and Yilmaz, T. 2004. Protective the dimension of the deposit could affect its dissolution. effects of vitamin E forms (alpha-tocopherol, Our clinical observation indicated that smaller deposits gamma-tocopherol and d-alpha-tocopherol were more likely to disappear than larger ones. In polyethylene glycol 1,000 succinate) on retinal addition, the age of the participants was not evenly edema during ischemia-reperfusion injury in the distributed among groups, and this could have added guinea pig retina. Int. Ophthalmol. 25(5–6), 283– some bias since the temperature of the central cornea 289. has been shown to decrease, while corneal opacities Barsotti, G., Pasquini, A., Busillo, L., Senese, M., increase with age (Versura et al., 2015; Evans et al., Cardini, G. and Guidi, G. 2008. Corneal crystalline 2018). Since the exact mechanism of action behind our stromal dystrophy and lipidic metabolism in the findings remains unknown, more extensive research on dog. Vet. Res. Commun. 32(Suppl. 1), S227–S229. the subject is needed that could use the present study Bilgihan, K., Adiguzel, U., Sezer, C., Akyol, G. as a guide in designing and implementing larger-scale and Hasanreisoglu, B. 2001. Effects of topical efficacy studies for CCD in dogs. vitamin E on keratocyte apoptosis after traditional photorefractive keratectomy. Ophthalmologica Conclusion 215(3), 192–196. Topical treatment with 1%CsA eyedrops is beneficial in Bonfioli, A.A., Damico, F.M., Curi, A.L. and Orefice, reducing CCD in dogs, significantly improving COD in F. 2005. Intermediate uveitis. Semin. Ophthalmol. the majority of cases. The probability of reducing COD 20, 147–154. with 1%CsA applied twice daily seems to be higher Carrington, S.D., Bedford, P.G., Guillon, J.P. and than once daily. Woodward, E.G. 1989. Biomicroscopy of the tear Acknowledgments film: the tear film of the pekingese dog. Vet. Rec. 124(13), 323–328. None. Chen, Q., Ji, C., Zheng, R., Yang, L., Ren, J., Li, Conflict of interest Y., Han, Y., Zhou, P., Liu, Z. and Qiu, Y. 2020. The authors declare that there is no conflict of interest. N-Palmitoylethanolamine maintains local lipid Funding homeostasis to relieve sleep deprivation-induced There was no funding source for this study. dry eye syndrome. Front. Pharmacol. 10, 1622. Data availability Cooley, P.L. and Dice, P.F. 1990. 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