Periorbital and ocular surface changes in patients on Prostaglandin Analogue eye drops.

Prostaglandin analogues are now thepreferred agents as first linetreatmentfor glaucoma and OHTN (Ocular Hypertension Treatment) due toits sustained intra-ocular pressure (IOP) lowering effects. They act on tissuematrix   relaxation of ciliary body muscle thusincreases uveoscleraloutflow.1Drugs like Bimatoprost works byincreasing both trabecular outflow and uveoscleral outflow. The PGA(prostaglandin analogue) can reduce IOP by 25-30%.2

 Agents used are:

 LATANOPROST  .005%

 TRAVOPROST    .004%

 BIMATOPROST   .03%

 TRAFLUPROST   .0015%

 All these agents are used in odd dosages. As agentsare used chronically used in glaucoma patients side effects of these drugsshould be given due importance. Prostaglandin analogues can act on 4 types ofcell line namely adipocytes, myocytes,melanocytes and keratinocytes.

 Prostaglandin analogues act on Prostaglandin F Receptor (FP prostanoidreceptor). By activating this receptor pre-adipocyte differentiation isinhibited which as a result prevents cells from expressing adipocyte-specificgenes and accumulating fat droplets.3 Prostaglandin F2alpha receptorwhen combined with cell surface FP receptor activated mitogen-activated proteinkinase, and phosphorylates and the Peroxisome proliferator-activated receptor gamma (PPAR-gamma receptor)resulting in the prevention oforbital fibroblasts to differentiate into adipocytes4. Adipocyte atrophy can lead tochanges like:

 Involutionof dermatochalasis

Decreasedin inferior orbital fat pads,

Enophthalmos

Tightorbit syndrome

Deepeningof the upper eyelid sulcus (DUES)

 Allthese changes lead to Prostaglandin Associated Periorbitopathy (PAP).

 Levator muscle atrophy, mullersmuscle atrophy and atrophic changes in orbital fascia leads to Upper eye lidptosis and Lower eye lid retraction.

 Increase in melanogenesis by theprostaglandin analogues leads to Peri-ocular hyper pigmentation

 Increase in hair growth duringanagen phase of hair growth cycle leads to increase in length of the lashes,distichiasis and trichiasis.

 Prostaglandin analogues containpreservatives like Benzalkonium chloride (BAK) and SofZia system. Chronic useof drugs containing BAK leads todry eye and punctate epitheliopathy.5Dry eye occurs due to direct toxic effect on epi -cells, indirect effect onlacrimal gland, cytotoxicity and allergic reaction. Sof-Zia system canalso induce Epitheliopathy.6

Reviewof Literature

 Peplinski LS, Albiani Smith: It’s thefirst journal published in 2004.They studied the development of deepening ofupper eyelid sulcus in 3 patients on Bimatoprost unilaterally They have alsodescribed the reversal of the change on discontinuation of the therapy7.

 Chanikarn Patradul: Studiedvarious factors related to prostaglandin associated periorbitopathy. They concludedthat Compared with 0.005% latanoprost:  0.004% travoprost and 0.03% bimatoprost, aremore likely to cause PAP.The duration of prostaglandin use and the gender willnot affect development of PAP.Old age is a risk factor for the development ofPAP1.Incidence of deepening of the upper eyelid sulcus in prostaglandinassociated periorbitopathy with a latanoprost.

 Ophthalmic solution by Sakata SShirato, K Miyata and M Aihara: They studied the incidence of development ofPAP in patients on Latanoprost 0.005% in Japanese population and took facialphotographs and followed up in 2,4and6 months. They have concluded that only 3out of 52 eyes developed PAP. So the incidence of PAP in latanoprost users areless compared to bimatoprost users.

 YukakoTaketani:He studied the mechanism of development of PAP by applying variousprostaglandin analogues over the adipocytes during development. They concludedthat prostaglandin analogues can affect adipogenesis by acting on FP-Prostanoidreceptor.

 Michael P. Rabinowitz; L. JayKatz: UnilateralProstaglandin-Associated Periorbitopathy: A Syndrome Involving Upper EyelidRetraction distinguishable from the aging sunken eyelid.They have concludedthat PGA can induce adenexal changes and orbital far atrophy

 Aims &Objectives

 Aims

 To study the Periorbital &Ocular surface changes in patients on Prostaglandin Analogues more than 6months in patients attending Giridhar Eye Institute, a tertiary care centre inSouth India.

 Objectives

 Â·        To study theperiorbital changes in patients on prostaglandin analogues by photographicdocumentation of current status and after 6 month.

·        To study theocular surface changes in patients on prostaglandin analogues by clinicalexamination pre and post 6 months

·        Extended study towhether the type of glaucoma and combination of drugs affect the periocularchanges

Material &Methods

 Â·        Study area: Giridhar Eye Institute, Kochi

·        Study population: Patients on PGA for less than6 months attending the OPD/ED (Emergency Department).

·        Inclusion criteria:  All patients on PGA for less than 6 monthsirrespective of type of glaucoma or combination of drugs used

·        Exclusion criteria: Patients who has undergoneany surgery other than cat surgery

·        Patients having already detected ocular surfacediseases

·        Patients already having lid diseases likeptosis, thyroid related orbitopathy, or lid tumours

 Study design: Prospective observational study.

 Sample size > 60 eyes

 Study duration: 1 year (September 2017-september 2018)

 The sample size wascalculated using the below formula

 where    Z1- α/2      =    1.96

p            =    Expected Proportion

d            =   Absolute Precision

 Z1- α/2 is the value of area under the normalcurve at a considered level of significance. p is the probability of success ineach trial. Precision is the closeness of repeated measurements to each other.

 Statistical Methods

 Results relating tocontinuous variables will be expressed as mean and standard deviation.The categorical variables will be expressed using counts and percentages.Thedifferences between quantitative variables will be analyzedusing Wilcoxon signed rank test or Paired t test. The differencesbetween qualitative variables will be analysed using McNemar’s test. Theresults will be considered as statistically significant if P-value <0.05.

 Data will beanalysed using SPSS Version 16.0

 Methodology

 Type of glaucoma,duration of PGA use, combination of drugs used will be noted. Clinicalassessment of ocular surface including dry eye work up will be done. Ptosismeasurement and proptometry will be done to assess periorbital area.

 Colour photography ofperiocular area will be taken using well-illuminated background. All theclinical assessments and colour photography will be repeated after 6 months. Acomparative study will be done to assess the changes in various parameters andstatistical analysis will be done.

References

 1.     Patradul C, Tantisevi V, Manassakorn A. FactorsRelated to Prostaglandin-Associated Periorbitopathy in Glaucoma Patients.Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2017;6(3):238.

 2.     Sakata R, Shirato S, Miyata K, Aihara M.Incidence of deepening of the upper eyelid sulcus in prostaglandin-associatedperiorbitopathy with a latanoprost ophthalmic solution. Eye. 2014 Dec1;28(12):1446-51.

 3.     Taketani Y, Yamagishi R, Fujishiro T, IgarashiM, Sakata R, Aihara M. Activation of the Prostanoid FP Receptor InhibitsAdipogenesis Leading to Deepening of the Upper Eyelid Sulcus inProstaglandin-Associated PeriorbitopathyFP Agonist-Induced Inhibition ofAdipogenesis. Investigative ophthalmology & visual science. 2014 Mar1;55(3):1269-76.

 4.     Casimir DA, Miller CW, Ntambi JM. Preadipocytedifferentiation blocked by prostaglandin stimulation of prostanoid FP2 receptorin murine 3T3-L1 cells. Differentiation. 1996 Aug 1;60(4):203-10.

 5.     Horsley MB, Kahook MY. Effects of prostaglandinanalog therapy on the ocular surface of glaucoma patients. Clinicalophthalmology (Auckland, NZ). 2009;3:291.

 6.     Stewart WC, Stewart JA, Nelson LA. Ocularsurface disease in patients with ocular hypertension and glaucoma. Current eyeresearch. 2011 May 1;36(5):391-8.

 7.     Peplinski LS, Smith KA. Deepening of lid sulcusfrom topical bimatoprost therapy. Optometry & Vision Science. 2004 Aug1;81(8):574-7.

 8.     Rabinowitz MP, Katz LJ, Moster MR, Myers JS, ProMJ, Spaeth GL, Sharma P, Stefanyszyn MA. Unilateral prostaglandin-associatedperiorbitopathy: a syndrome involving upper eyelid retraction distinguishablefrom the aging sunken eyelid. Ophthalmic Plastic & Reconstructive Surgery.2015 Sep 1;31(5):373-8.

 9.     Sarkar R, Ranjan R, Garg S, Garg VK, SonthaliaS, Bansal S. Periorbital hyperpigmentation: a comprehensive review. The Journalof clinical and aesthetic dermatology. 2016 Jan;9(1):49

 10.  InoueK, Shiokawa M, Wakakura M, Tomita G. Deepening of the upper eyelid sulcuscaused by 5 types of prostaglandin analogs. Journal of glaucoma. 2013 Oct1;22(8):626-31.

 11.  Park J,Cho HK, Moon JI. Changes to upper eyelid orbital fat from use of topicalbimatoprost, travoprost, and latanoprost. Japanese journal of ophthalmology.2011 Jan 1;55(1):22-7.

 12.  TappeinerC, Perren B, Iliev ME, Frueh BE, Goldblum D. Orbital fat atrophy in glaucomapatients treated with topical bimatoprost--can bimatoprost causeenophthalmos?.KlinischeMonatsblatter fur Augenheilkunde. 2008 May;225(5):443-5.

 13.  SuzukiM, Massingale ML, Ye F, Godbold J, Elfassy T, Vallabhajosyula M, Asbell PA.Tear osmolarity as a biomarker for dry eye disease severity. Investigativeophthalmology & visual science. 2010 Sep 1;51(9):4557-61.