Prostaglandin analogues are now the preferred agents as first line treatmentfor glaucoma and OHTN (Ocular Hypertension Treatment) due to its sustained intra-ocular pressure (IOP) lowering effects. They act on tissue matrix   relaxation of ciliary body muscle thus increases uveoscleraloutflow.¹ Drugs like Bimatoprost works by increasing 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 agents are used chronically used in glaucoma patients side effects of these drugs should be given due importance. Prostaglandin analogues can act on 4 types of cell line namely adipocytes, myocytes,melanocytes and keratinocytes.

Prostaglandin analogues act on Prostaglandin F Receptor (FP prostanoid receptor). By activating this receptor pre-adipocyte differentiation is inhibited which as a result prevents cells from expressing adipocyte-specific genes and accumulating fat droplets.³ Prostaglandin F2alpha receptor when combined with cell surface FP receptor activated mitogen-activated protein kinase, and phosphorylates and the Peroxisome proliferator-activated receptor gamma (PPAR-gamma receptor)resulting in the prevention of orbital fibroblasts to differentiate into adipocytes⁴.

Adipocyte atrophy can lead to changes like:

Involution of dermatochalasis

Decreased in inferior orbital fat pads,

Enophthalmos

Tight orbit syndrome

Deepening of the upper eyelid sulcus (DUES)

All these changes lead to Prostaglandin Associated Periorbitopathy (PAP).

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

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

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

Prostaglandin analogues contain preservatives like Benzalkonium chloride (BAK) and SofZia system. Chronic use of drugs containing BAK leads todry eye and punctate epitheliopathy.⁵ Dry eye occurs due to direct toxic effect on epi -cells, indirect effect on lacrimal gland, cytotoxicity and allergic reaction. Sof-Zia system can also induce Epitheliopathy.⁶

Review of Literature

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

Chanikarn Patradul: Studied various factors related to prostaglandin associated periorbitopathy. They concluded that Compared with 0.005% latanoprost:  0.004% travoprost and 0.03% bimatoprost, are more likely to cause PAP.The duration of prostaglandin use and the gender will not affect development of PAP.Old age is a risk factor for the development of PAP1.Incidence of deepening of the upper eyelid sulcus in prostaglandin associated periorbitopathy with a latanoprost.

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

YukakoTaketani: He studied the mechanism of development of PAP by applying various prostaglandin analogues over the adipocytes during development. They concluded that prostaglandin analogues can affect adipogenesis by acting on FP-Prostanoid receptor.

Michael P. Rabinowitz; L. Jay Katz: Unilateral Prostaglandin-Associated Periorbitopathy: A Syndrome Involving Upper Eyelid Retraction distinguishable from the aging sunken eyelid.They have concluded that 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 6 months in patients attending Giridhar Eye Institute, a tertiary care centre in South India.

Objectives

·         To study the periorbital changes in patients on prostaglandin analogues by photographic documentation of current status and after 6 month.

·         To study the ocular surface changes in patients on prostaglandin analogues by clinical examination pre and post 6 months

·         Extended study to whether the type of glaucoma and combination of drugs affect the periocular changes

Material & Methods

·         Study area: Giridhar Eye Institute, Kochi

·         Study population: Patients on PGA for less than 6 months attending the OPD/ED (Emergency Department).

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

·         Exclusion criteria: Patients who has undergone any surgery other than cat surgery

·         Patients having already detected ocular surface diseases

·         Patients already having lid diseases like ptosis, 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 was calculated 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 normal curve at a considered level of significance. p is the probability of success in each trial. Precision is the closeness of repeated measurements to each other.

Statistical Methods

Results relating to continuous 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 analyzed using Wilcoxon signed rank test or Paired t test. The differences between qualitative variables will be analysed using McNemar’s test. The results 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. Clinical assessment of ocular surface including dry eye work up will be done. Ptosis measurement and proptometry will be done to assess periorbital area.

Colour photography of periocular area will be taken using well-illuminated background. All the clinical assessments and colour photography will be repeated after 6 months. A comparative study will be done to assess the changes in various parameters and statistical analysis will be done.

References

1.      Patradul C, Tantisevi V, Manassakorn A. Factors Related 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-associated periorbitopathy with a latanoprost ophthalmic solution. Eye. 2014 Dec 1;28(12):1446-51.

3.      Taketani Y, Yamagishi R, Fujishiro T, Igarashi M, Sakata R, Aihara M. Activation of the Prostanoid FP Receptor Inhibits Adipogenesis Leading to Deepening of the Upper Eyelid Sulcus in Prostaglandin-Associated PeriorbitopathyFP Agonist-Induced Inhibition of Adipogenesis. Investigative ophthalmology & visual science. 2014 Mar 1;55(3):1269-76.

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

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

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

7.      Peplinski LS, Smith KA. Deepening of lid sulcus from topical bimatoprost therapy. Optometry & Vision Science. 2004 Aug 1;81(8):574-7.

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

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

10.  Inoue K, Shiokawa M, Wakakura M, Tomita G. Deepening of the upper eyelid sulcus caused by 5 types of prostaglandin analogs. Journal of glaucoma. 2013 Oct 1;22(8):626-31.

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

12.  Tappeiner C, Perren B, Iliev ME, Frueh BE, Goldblum D. Orbital fat atrophy in glaucoma patients treated with topical bimatoprost--can bimatoprost cause enophthalmos?.KlinischeMonatsblatter fur Augenheilkunde. 2008 May;225(5):443-5.

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