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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 1  |  Page : 36-40

Prostaglandin-associated periorbitopathy: A prospective study in Indian eyes


Department of Orbit and Oculoplasty, Giridhar Eye Institute, Kochi, Kerala, India

Date of Submission17-Dec-2019
Date of Acceptance11-Jan-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
Dr. M Manju
D 501, Purva Eternity, Athani, Kakkanad, Ernakulam - 682 030, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_90_19

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  Abstract 


Context: Prostaglandin analogs (PGAs) are commonly used antiglaucoma medications in the current era. The purpose of this study is to monitor the periorbital changes in patients started on topical PGA. Aim: The aim of this study is to study the periorbital changes in patients on PGA eye drops. Settings and Design: It is a prospective, uncontrolled, nonrandomized study. Subjects and Methods: During the initial visit, periorbital area was assessed by ptosis, proptosis, and lash length measurement. Color photography of periocular area was taken using a well-illuminated background for documentation and comparison. All the clinical assessments and color photography were repeated after 6 months. Statistical Analysis Used: Data were analyzed using the SPSS software version 16.0 and Microsoft Excel 2007. Results: Six eyes (9.5%) in the initial evaluation and 22 eyes (34.9%) in the follow-up visit showed periocular hyperpigmentation. There was a statistically significant increase in periocular hyperpigmentation with a P < 0.001. Two eyes in the initial evaluation and 23 eyes in the follow-up visit had deepening of the upper eyelid sulcus (DUES). There was a statistically significant increase in DUES with a P < 0.001. Of 63 eyes, 41 eyes (65%) developed prostaglandin-associated periorbitopathy (PAP) at the end of 6 months, and there is a statistically significant increase in the development of PAP after 6 months' P < 0.001. Conclusions: This study demonstrated a statistically significant increase in periorbital changes within 6 months of PGA use. Patients should be informed about the periorbital changes that could happen, and their cosmetic concerns should be addressed properly.

Keywords: Deepening of upper eyelid sulcus, periorbital hyperpigmentation, prostaglandin-associated periorbitopathy


How to cite this article:
Manju M, Pauly M. Prostaglandin-associated periorbitopathy: A prospective study in Indian eyes. Kerala J Ophthalmol 2020;32:36-40

How to cite this URL:
Manju M, Pauly M. Prostaglandin-associated periorbitopathy: A prospective study in Indian eyes. Kerala J Ophthalmol [serial online] 2020 [cited 2020 Aug 12];32:36-40. Available from: http://www.kjophthal.com/text.asp?2020/32/1/36/282666




  Introduction Top


Glaucoma is a progressive optic neuropathy with loss of retinal ganglion cells and their axons, resulting in the loss of visual acuity and constriction of visual fields. The medical treatment of glaucoma has recently experienced a significant increase in the number of agents available.[1] Prostaglandin analogs (PGAs) are now the preferred agents as the first-line treatment of glaucoma and ocular hypertension, due to its sustained intraocular pressure (IOP) lowering effects and good compliance due to once a day dosage.[2] The agents used include LATANOPROST (0.005%), TRAVOPROST (0.004%), BIMATOPROST (0.03%), and TRAFLUPROST (0.0015%).

Adverse effects

PGA act on prostaglandin F receptor (FP prostanoid receptor). Prostaglandin F2-alpha receptor when combined with cell surface FP receptor activated mitogen-activated protein kinase and phosphorylates and the peroxisome proliferator-activated receptor gamma receptor, resulting in the prevention of orbital fibroblasts to differentiate into adipocytes.[3],[4] Adipocyte atrophy can lead to changes such as involution of dermatochalasis, resolution of inferior orbital fat pads, enophthalmos, tight orbit syndrome, and Deepening of Upper Eyelid Sulcus (DUES). All these changes lead to Prostaglandin Associated Periorbitopathy (PAP).[5]

Need for this research

Indian eyes have a number of melanocytes in the periocular area, and there can be a difference in the periocular hyperpigmentation compared to Western eyes. The low body mass index of the Indian population compared to the Western population can affect the periocular fat atrophy. Hence, it is important to have research on the periocular changes in the Indian population for better patient counseling as well as the selection of Anti glaucoma medication (AGM).

Aim

The study aimed to study the periorbital changes in patients on PGA eye drops.


  Subjects and Methods Top


Study population

The study population includes patients who are diagnosed with glaucoma and are started on PGA within a period of 6 months attending the outpatient department/emergency department.

Study design

It is a prospective, uncontrolled, nonrandomized study which included patients taking treatment for glaucoma in the outpatient clinic.

Sample size

The sample size was calculated using the following formula:



Where Z1−α/2 = 1.96

p = Expected proportion

d = Absolute precision.

Inclusion criteria

All patients who are started on PGA for <6 months irrespective of type of glaucoma or combination of drugs used were included in the study.

Exclusion criteria

  1. Patients who had underwent any surgery other than cataract surgery
  2. Patients already having lid diseases such as ptosis, thyroid-related orbitopathy, or lid tumors were excluded from the study.


Methodology

Data regarding name, age, and occupation of the patient are collected. Detailed history regarding presenting complaints and systemic illness was taken. The visual acuity was recorded using Snellen acuity chart, and color vision was recorded using ishiharas psuedoisochromatic charts. IOP was recorded using applanation tonometry. Gonioscopy as well as field analysis using Humphrey visual field analyzer was also done.

Ptosis measurement

Margin to reflex distance (MRD) 1, MRD 2, and palpebral fissure height were calculated. Grading of ptosis was done by measuring the difference of the two values: mild – up to 2 mm, moderate – 2 mm to 3 mm, and severe – 4 mm or more.[6] Ptosis measurement was done in the initial and follow-up visits, and any change in grade of ptosis in the follow-up visit was considered statistically significant.

Measurement of enophthalmos

The analysis of periorbital fat loss following PGA use and the development of enophthalmos was done with the Hertel's exophthalmometer. The measurements were taken on the first visit and the follow-up visit. A difference of 2 mm between the first visit and the follow-up visit was considered statistically significant.

Periocular hyperpigmentation

The pigmentation of the periocular area, including the upper and lower lids, was analyzed and graded. The examination was repeated in the follow-up visit, and a change of grade was regarded as prostaglandin-associated hyperpigmentation. Grading of periocular hyperpigmentation was done in comparison to the surrounding skin based on the following parameters: skin color comparable to other facial skin areas, faint pigmentation of infraorbital fold, pigmentation more pronounced, deep dark color all four lids involved, Grade 3+ pigmentation, and spreading beyond infraorbital fold.[7]

Lash length

The length of the eyelash was measured by asking the patient to close the eye and measuring the longest lash. Measurements were taken in the first visit and follow-up visit, and a difference of more than 2 mm was taken as drug-induced eyelash lengthening.[8] The presence of lash abnormalities such as trichiasis and distichiasis was also considered.

Color photograph

Color photography of periocular area was taken using the well-illuminated background. Both eyes and the periocular area were included in the study. The photograph was taken again during the follow-up visit, and a comparative study was done to analyze the presence of any periocular hyperpigmentation. All the photographs were analyzed and compared.

Prostaglandin-associated periorbitopathy

The patient was considered to have PAP if he or she has a significant change in any one of the seven factors given below: upper eyelid ptosis (A change equal to or more than 2 mm), DUES, involution of dermatochalasis, orbital fat atrophy, enophthalmos (change equal to or more than 2 mm in Hertel's exophthalmometer), flattening of lower eyelid bags, and inferior scleral show.[9]

Statistical methods

Data were analyzed using the IBM SPSS Software-version 16.0, Chicago, USA and Microsoft Excel 2007.


  Results Top


A total of 63 eyes were analyzed in the study. Among the 32 patients analyzed, there were 19 males and 13 females. The mean age group was 63.94 years [Table 1]. Out of 32 patients who were included in the study, 19 (40.6%) were male and 13 (59.4%) were female. When the association of gender with the development of PAP was analyzed, there was no statistically significant association with a P = 0.722. There is no statistically significant association between different age groups and development of PAP.
Table 1: Assessment of the deepening of the upper eyelid sulcus in the initial and follow-up visit

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In the initial visit, 9.5% of patients had Grade 1 pigmentation. In the follow-up visit, 18 eyes (28.6%) had Grade 1 pigmentation, and 2 eyes had Grade 2 and Grade 3 pigmentations each [Figure 1]. The length of the eyelash was measured by asking the patient to close the eye and measuring the longest lash. Measurements were taken in the first visit and in the follow-up visit, and a value more than 2 mm was taken as drug-induced eyelash lengthening. The presence of lash abnormalities such as trichiasis and distichiasis was also considered [Figure 2].
Figure 1: Bar diagram showing the distribution of periorbital hyperpigmentation at two different periods across the study population

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Figure 2: Line diagram showing an increase in the lash length in the study population over the study period

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In the initial visit, only four patients had DUES, and in the follow-up visit, 22 patients had DUES. There was a significant increase in the incidence of DUES in the follow-up visit in patients on PGA with a P < 0.001% [Table 1].

There was no statistically significant change in MRD values in the initial and follow-up visit [Figure 3].
Figure 3: Bar diagram showing the distribution of margin to reflex distance 1 at 2 different periods across the study population

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There is a statistically significant decrease in the proptometry values in the initial and follow-up visit with a P < 0.001. There was significant periocular fat atrophy with 6 months of PGA use. In the initial visit, 6 eyes (9.6%) had dermatochalasis, and in the follow-up visit, 5 eyes (7.5%) had dermatochalasis. There was no statistically significant change in the dermatochalasis in the initial and follow-up visit [Figure 4].
Figure 4: Proptometry values in the study population over the study period

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Comparative analysis of proptometry values with the three PGAs used was done, and there was no statistically significant difference between the three drugs used with a P = 1.00. When the comparative analysis was done between differences in MRD values with the drugs used, there was no statistically significant change in MRD values with the type of drug used [Table 2].
Table 2: Comparison of type of drug used with the difference in proptometry values

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  Discussion Top


Periocular hyperpigmentation and prostaglandin analogs

In this study, during the initial evaluation, only 6 eyes (9.5%) showed periocular hyperpigmentation, and for 57 eyes, there was no pigmentation. However, in the follow-up visit, 18 eyes (28.6%) had Grade 1, and 2 eyes each had Grade 2 and Grade 3 pigmentations each. In the follow-up visit, 22 eyes (34.9) had periocular hyperpigmentation [Figure 5]. There is a significant increase in the eyes showing periocular hyperpigmentation after PGA use for 6 months with a P < 0.001 [Figure 1]. When three types of PGA were compared regarding the occurrence of PGA, there was no statistically significant difference between the three. Inoue et al. in their study showed that there were no significant differences in the frequency of eyelid pigmentation among the four types of PGA[10] Their study also showed that owing to the differences in the administration period, the frequency of eyelid pigmentation was 0%–25.9% in patients with >3 months of medication use.
Figure 5: Patient with Grade 1 periocular hyperpigmentation, developed Grade 3 periocular hyperpigmentation in the follow-up visit patient with no deepening of the upper eyelid sulcus, developed Grade 1 deepening of the upper eyelid sulcus in the follow-up visit

Click here to view


Lash length and prostaglandin analogs

The lengthening of eyelashes caused by PGA is due to the stimulation of keratinocytes. In this study, at the initial evaluation, the average lash length was 8.24 mm and in the follow-up visit after 6 months was 10.38 mm. This study showed a statistically significant increase in lash length after PGA use for 6 months with a P < 0.001. This study also compared the increase in lash length between latanoprost, bimatoprost, and travoprost. In this study, we could not demonstrate any statistically significant differences between the three types of PGA and the eyelash lengthening.

Deepening of the upper eyelid sulcus and prostaglandin analogs

In the initial evaluation, only two eyes had DUES Grade 1. In the 6 months follow-up visit, 20 eyes had Grade 1 DUES and 1 eye each had Grade 2 and 3 DUES. In the follow-up visit, 24 (38.1%) showed DUES [Figure 5]. There is a statistically significant increase in the occurrence DUES after 6 months of PGA use with a P < 0.001. Kucukevcilioglu et al. reported DUES in 80% of patients using bimatoprost, 45% of patients using travoprost, and 15.7% of patients using latanoprost.[9] Inoue et al. analyzed the frequency of DUES with respect to the type of PGA, and they reported that DUES observed in 24% of the latanoprost group, 50% of the travoprost group, and 60% of the bimatoprost group.[11]

Ptosis and prostaglandin analogs

The ptosis evaluation was done before and after PGA use for 6 months, and a change of ≥2 mm was considered PGA-induced ptosis. In our study, there was no change in the ptosis measurement values after 6 months of PGA use. None of the patients had a difference of 2 mm in ptosis measurement after PGA use for 6 months. Pasquale et al. in their study mentioned the occurrence of ptosis in patients with PAP by its action on the myocytes in the Muller's muscle.[11] W Kim et al. in their article on PAP changes in Korean patients showed the incidence of PGA-induced ptosis in 3.4% of the patients on PGA. However, the average duration of their study was 26.1 months.[12]

Orbital fat atrophy and prostaglandin analogs

The average initial proptometry values of 63 eyes were 15.17, and average value after 6 months was 14.43. There is a statistically significant correlation between two values. This study could demonstrate significant orbital fat atrophy induced by PGA after 6 months of drug use with a P < 0.001. Seibold et al., in their study, reported that bimatoprost, travoprost, and latanoprost can suppress the proliferation of preadipocytes.[13]

Involution of dermatochalasis and prostaglandin analogs

In the initial visit, 6 eyes had dermatochalasis, and in the follow-up visit after 6 months, 5 eyes had dermatochalasis. There was no statistically significant involution of dermatochalasis after 6 months. Sarnoffet al. reported significant changes in the periorbital area induced by the topical application of bimatoprost ophthalmic solution (0.03%). They proposed that when used bilaterally, in selected candidates and titrated appropriately, bimatoprost can be used for the involution of dermatochalasis and for resolution of periorbital fat pads as an agent for chemical blepharoplasty.[14]

Comparison between bimatoprost, latanoprost, and travoprost and development of prostaglandin-associated periorbitopathy

When the lengthening of eyelashes was analyzed and different drugs are compared, there was no statistically significant correlation between different groups with a P = 0.462. This is contradictory to the previous studies in which the bimatoprost was showing more effect on the lengthening of eyelashes than the other two drugs. When the DUES was compared between three drugs, there was no statistically significant difference between the three types of PGA. Inoue et al. showed that 24% of Japanese glaucoma patients undergoing LAT treatment developed DUES.[10]


  Conclusions and Recommendations Top


  1. PGA can induce significant periocular changes with regard to periocular hyperpigmentation, DUES, and lengthening of eyelashes even within a period of 6 months
  2. The difference between the three types of PGA with regard to PAP is not significant with after the completion of 6 months of use
  3. The patients should be informed about the possible periocular changes that can occur, and the cosmetic concerns of the patient should be properly addressed
  4. It is better to avoid PGA in unilateral glaucoma to avoid visible facial asymmetry.


Financial support and sponsorship

This study was financially supported by PubMed and Google Scholar.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Patradul C, Tantisevi V, Manassakorn A. Factors Related to Prostaglandin-Associated Periorbitopathy in Glaucoma Patients. Asia-Pacific journal of ophthalmology (Philadelphia, Pa.) 2017;6:238-42.  Back to cited text no. 1
    
2.
Casimir DA, Miller CW, Ntambi JM. Preadipocyte differentiation blocked by prostaglandin stimulation of prostanoid FP2 receptor in murine 3T3-L1 cells. Differentiation 1996;60:203-10.  Back to cited text no. 2
    
3.
Prum BE, Rosenberg LF, Gedde SJ, Mansberger SL, Stein JD, Moroi SE, Herndon LW, Lim MC, Williams RD. Primary open-angle glaucoma preferred practice pattern® guidelines. Ophthalmology 2016;123:P41-111.  Back to cited text no. 3
    
4.
Noecker RS, Dirks MS, Choplin NT, Bernstein P, Batoosingh AL, Whitcup SM, Bimatoprost/Latanoprost Study Group. A six-month randomized clinical trial comparing the intraocular pressure-lowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma. American journal of ophthalmology 2003;135:55-63.  Back to cited text no. 4
    
5.
Shrirao N, Khurana M, Mukherjee B. Prostaglandin-associated periorbitopathy. Indian journal of ophthalmology 2016;64.  Back to cited text no. 5
    
6.
Nakakura S, Tabuchi H, Kiuchi Y. Latanoprost therapy after sunken eyes caused by travoprost or bimatoprost. Optometry and Vision Science. 2011;88:1140-4.  Back to cited text no. 6
    
7.
Sheth PB, Shah HA, Dave JN. Periorbital hyperpigmentation: A study of its prevalence, common causative factors and its association with personal habits and other disorders. Indian journal of dermatology. 2014;59:151.  Back to cited text no. 7
    
8.
Holló G, Kóthy P. Prostaglandin analogue–induced pigmentation of the skin of the nasal septum and nasal alae in a glaucoma patient. European journal of ophthalmology 2015;25:38-9.  Back to cited text no. 8
    
9.
Kucukevcilioglu M, Bayer A, Uysal Y, Altinsoy HI. Prostaglandin associated periorbitopathy in patients using bimatoprost, latanoprost and travoprost. Clin Exp Ophthalmol 2014;42:126-31.  Back to cited text no. 9
    
10.
Inoue K, Shiokawa M, Higa R, Sugahara M, Soga T, Wakakura M, et al. Adverse periocular reactions to five types of prostaglandin analogs. Eye (Lond) 2012;26:1465-72.  Back to cited text no. 10
    
11.
Pasquale LR. Prostaglandin-associated periorbitopathy. Advanced Ocular Care. 2011:21-5.  Back to cited text no. 11
    
12.
Kim HW, Choi YJ, Lee KW, Lee MJ. Periorbital changes associated with prostaglandin analogs in Korean patients. BMC ophthalmology. 2017;17:126.  Back to cited text no. 12
    
13.
Seibold SA, Cerda JF, Mulichak AM, Song I, Garavito RM, Arakawa T, Smith WL, Babcock GT. Peroxidase activity in prostaglandin endoperoxide H synthase-1 occurs with a neutral histidine proximal heme ligand. Biochemistry. 2000;39:6616-24  Back to cited text no. 13
    
14.
Sarnoff DS, Gotkin RH. Bimatoprost-induced chemical blepharoplasty. Journal of drugs in dermatology: JDD 2015;14:472-7.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

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