The Coming Age of Enophthalmos
The Coming Age of Enophthalmos
Among the age-related factors contributing to the impending epidemic of enophthalmos is prostaglandin-associated periorbitopathy (PAP), a recently recognized adverse reaction from topical prostaglandin analogue (PGA) glaucoma medications that can lead to periorbital fat atrophy and enophthalmos. This clinical entity was independently observed and described in a handful of recently published case series. Various descriptors have been used to name this entity, though the term 'prostaglandin-associated periorbitopathy' was recently coined to encompass the spectrum of changes observed in the eyelids, periorbital fat, and other periorbital and orbital tissues.
Prostaglandin analogues have been used as effective therapy in glaucoma for greater than 15 years. Their exact mechanism of action is not fully understood but ultimately leads to an increase in uveoscleral outflow and a reduction of intraocular pressure (IOP). This class of medications includes bimatoprost, latanoprost, travoprost, unoprostone, and the recently approved tafluprost. Because of their potent IOP lowering effect, and relatively favorable side-effect profile, this class of medication is currently the most used first-line therapy among glaucoma patients. Open-angle glaucoma affected an estimated 2.22 million US citizens in the year 2000, and is projected to affect 3.36 million by 2020. With the current and forthcoming expansion in the elderly population and resultant increase in the prevalence of glaucoma, PGAs are being prescribed more than ever and these trends are likely to increase.
Side-effects associated with the PGAs are well documented and commonly include conjunctival hyperemia, hypertrichosis, increased pigmentation of the periocular skin and iris, dry eye, ocular pruritis, and cystoid macular edema. In 2004, Peplinski and Albiani Smith first reported deepening of the upper eyelid sulcus and dermatochalasis in 3 glaucoma patients treated unilaterally with bimatoprost 0.03%. In 2008, Filippopoulos et al. reported deepening of the lid sulcus but further described the extensive periorbital changes seen in this clinical entity. In their series, five patients were described with significant periorbital changes after 2–4 years of unilateral treatment with bimatoprost 0.03%. Clinical findings included deepening of the upper eyelid sulcus, relative enophthalmos, loss of lower eyelid fullness, and dermatochalasis. Bimatoprost was discontinued in two of the patients and a partial or complete resolution of the periorbital findings was observed. Other case series have since been published describing similar findings in patients using PGAs occurring as early as 3 months after initiation of therapy.
Like many of the previously described side-effects from PGAs, PAP is partially to completely reversible most of the time after cessation of therapy, and resolution typically occurs within 9 months. Some patients have been reported to show resolution after switching from either bimatoprost or travoprost to latanoprost.
The complete spectrum of findings reported with PAP includes deepening of the upper eyelid sulcus, dermatochalasis, periorbital and orbital fat atrophy, enophthalmos, upper eyelid ptosis, inferior scleral show, and tight eyelids (Fig. 2). The mechanisms by which the PGAs cause these changes are not fully understood. Prostaglandins are biological mediators present throughout the entire body and their roles are numerous. The PGAs used in glaucoma are all prostaglandin F2[alpha] (PGF2[alpha]) analogues. PGF2[alpha] binds a prostaglandin receptor and has been shown to block adipogenesis. This inhibitory effect on fat metabolism may lead to the fat atrophy seen in PAP. Fat atrophy is unlikely the only mechanism involved in PAP, but it does account for some of the findings as described by Park et al.. Patients included in their series were treated with bimatoprost, latanoprost, or travoprost and developed a deepened superior eyelid sulcus. Preaponeurotic fat biopsies were collected and compared with untreated fellow eyes Histologically, treated eyes were shown to have an increased adipocyte cell density, a reduction in cell volume, and thus a reduction in periorbital fat volume.
(Enlarge Image)
Figure 2.
Patient with prostaglandin-associated periorbitopathy (original image). This 88-year-old woman with primary open-angle glaucoma in the left eye was treated with travoprost for greater than 1 year. Note deepening of the upper eyelid sulcus, involution of dermatochalasis, periorbital fat atrophy, and upper eyelid ptosis.
Fat atrophy appears to be a major cause of the deep superior lid sulcus and enophthalmos seen in PAP, though not all of the findings in PAP can be explained by fat atrophy alone. Recent studies have reported upper eyelid retraction as opposed to ptosis. The ptosis sometimes seen in PAP may be a pseudoptosis secondary to fat atrophy and enophthalmos. Though some patients with PAP appear to develop lid retraction with fat atrophy, suggesting that fat atrophy is likely not the only mechanism affecting lid position and palpebral aperture. Thus, it has been proposed that prostaglandins may stimulate Müller's muscle and increase lid height. The tightening of the eyelids and periorbital tissues is further evidence suggesting that the mechanisms behind the changes seen in PAP are many and diverse. More studies need to be done to further elucidate these mechanisms.
The periorbital tissue changes in PAP make glaucoma patients particularly difficult to manage and treat. Merely checking IOP can be a challenge because of ptosis and tight eyelids. With a deep upper eyelid sulcus and absence of preseptal fat, lifting a tight lid without applying pressure to the globe becomes very difficult. Providing surgery for these patients presents a unique challenge as well, beginning with placement of the lid speculum and the less-than-optimal exposure as a result of the enophthalmos and tight eyelids. It helps to be aware of these factors when planning surgical treatment in glaucoma patients with PAP to prevent complications.
PAP is now a recognized adverse reaction from the PGAs. It is currently included in the product labeling of nearly all PGAs including Latisse (bimatoprost 0.03%) (Allergan, Irvine, CA, USA), used for eyelash growth in hypotrichosis. Ophthalmologists should be aware of the clinical findings in PAP while following patients on PGAs and inform their patients of the potential periorbital changes before initiating treatment. Prostaglandin analogue use should be in the differential diagnosis for any patient presenting with eyelid ptosis or retraction, enophthalmos, dermatochalasis, or any other findings associated with PAP. With the ever-increasing prevalence of glaucoma and increase in prescribing trends of PGAs, ophthalmologists are likely to encounter PAP. An awareness of PAP when evaluating patients with periorbital findings could lead to a proper diagnosis and potentially prevent a costly workup and unnecessary corrective surgery.
Prostaglandin-associated Periorbitopathy
Among the age-related factors contributing to the impending epidemic of enophthalmos is prostaglandin-associated periorbitopathy (PAP), a recently recognized adverse reaction from topical prostaglandin analogue (PGA) glaucoma medications that can lead to periorbital fat atrophy and enophthalmos. This clinical entity was independently observed and described in a handful of recently published case series. Various descriptors have been used to name this entity, though the term 'prostaglandin-associated periorbitopathy' was recently coined to encompass the spectrum of changes observed in the eyelids, periorbital fat, and other periorbital and orbital tissues.
Prostaglandin analogues have been used as effective therapy in glaucoma for greater than 15 years. Their exact mechanism of action is not fully understood but ultimately leads to an increase in uveoscleral outflow and a reduction of intraocular pressure (IOP). This class of medications includes bimatoprost, latanoprost, travoprost, unoprostone, and the recently approved tafluprost. Because of their potent IOP lowering effect, and relatively favorable side-effect profile, this class of medication is currently the most used first-line therapy among glaucoma patients. Open-angle glaucoma affected an estimated 2.22 million US citizens in the year 2000, and is projected to affect 3.36 million by 2020. With the current and forthcoming expansion in the elderly population and resultant increase in the prevalence of glaucoma, PGAs are being prescribed more than ever and these trends are likely to increase.
Clinical Findings in Prostaglandin-associated Periorbitopathy
Side-effects associated with the PGAs are well documented and commonly include conjunctival hyperemia, hypertrichosis, increased pigmentation of the periocular skin and iris, dry eye, ocular pruritis, and cystoid macular edema. In 2004, Peplinski and Albiani Smith first reported deepening of the upper eyelid sulcus and dermatochalasis in 3 glaucoma patients treated unilaterally with bimatoprost 0.03%. In 2008, Filippopoulos et al. reported deepening of the lid sulcus but further described the extensive periorbital changes seen in this clinical entity. In their series, five patients were described with significant periorbital changes after 2–4 years of unilateral treatment with bimatoprost 0.03%. Clinical findings included deepening of the upper eyelid sulcus, relative enophthalmos, loss of lower eyelid fullness, and dermatochalasis. Bimatoprost was discontinued in two of the patients and a partial or complete resolution of the periorbital findings was observed. Other case series have since been published describing similar findings in patients using PGAs occurring as early as 3 months after initiation of therapy.
Like many of the previously described side-effects from PGAs, PAP is partially to completely reversible most of the time after cessation of therapy, and resolution typically occurs within 9 months. Some patients have been reported to show resolution after switching from either bimatoprost or travoprost to latanoprost.
Mechanisms of Prostaglandin-associated Periorbitopathy
The complete spectrum of findings reported with PAP includes deepening of the upper eyelid sulcus, dermatochalasis, periorbital and orbital fat atrophy, enophthalmos, upper eyelid ptosis, inferior scleral show, and tight eyelids (Fig. 2). The mechanisms by which the PGAs cause these changes are not fully understood. Prostaglandins are biological mediators present throughout the entire body and their roles are numerous. The PGAs used in glaucoma are all prostaglandin F2[alpha] (PGF2[alpha]) analogues. PGF2[alpha] binds a prostaglandin receptor and has been shown to block adipogenesis. This inhibitory effect on fat metabolism may lead to the fat atrophy seen in PAP. Fat atrophy is unlikely the only mechanism involved in PAP, but it does account for some of the findings as described by Park et al.. Patients included in their series were treated with bimatoprost, latanoprost, or travoprost and developed a deepened superior eyelid sulcus. Preaponeurotic fat biopsies were collected and compared with untreated fellow eyes Histologically, treated eyes were shown to have an increased adipocyte cell density, a reduction in cell volume, and thus a reduction in periorbital fat volume.
(Enlarge Image)
Figure 2.
Patient with prostaglandin-associated periorbitopathy (original image). This 88-year-old woman with primary open-angle glaucoma in the left eye was treated with travoprost for greater than 1 year. Note deepening of the upper eyelid sulcus, involution of dermatochalasis, periorbital fat atrophy, and upper eyelid ptosis.
Fat atrophy appears to be a major cause of the deep superior lid sulcus and enophthalmos seen in PAP, though not all of the findings in PAP can be explained by fat atrophy alone. Recent studies have reported upper eyelid retraction as opposed to ptosis. The ptosis sometimes seen in PAP may be a pseudoptosis secondary to fat atrophy and enophthalmos. Though some patients with PAP appear to develop lid retraction with fat atrophy, suggesting that fat atrophy is likely not the only mechanism affecting lid position and palpebral aperture. Thus, it has been proposed that prostaglandins may stimulate Müller's muscle and increase lid height. The tightening of the eyelids and periorbital tissues is further evidence suggesting that the mechanisms behind the changes seen in PAP are many and diverse. More studies need to be done to further elucidate these mechanisms.
The periorbital tissue changes in PAP make glaucoma patients particularly difficult to manage and treat. Merely checking IOP can be a challenge because of ptosis and tight eyelids. With a deep upper eyelid sulcus and absence of preseptal fat, lifting a tight lid without applying pressure to the globe becomes very difficult. Providing surgery for these patients presents a unique challenge as well, beginning with placement of the lid speculum and the less-than-optimal exposure as a result of the enophthalmos and tight eyelids. It helps to be aware of these factors when planning surgical treatment in glaucoma patients with PAP to prevent complications.
Awareness is the Key
PAP is now a recognized adverse reaction from the PGAs. It is currently included in the product labeling of nearly all PGAs including Latisse (bimatoprost 0.03%) (Allergan, Irvine, CA, USA), used for eyelash growth in hypotrichosis. Ophthalmologists should be aware of the clinical findings in PAP while following patients on PGAs and inform their patients of the potential periorbital changes before initiating treatment. Prostaglandin analogue use should be in the differential diagnosis for any patient presenting with eyelid ptosis or retraction, enophthalmos, dermatochalasis, or any other findings associated with PAP. With the ever-increasing prevalence of glaucoma and increase in prescribing trends of PGAs, ophthalmologists are likely to encounter PAP. An awareness of PAP when evaluating patients with periorbital findings could lead to a proper diagnosis and potentially prevent a costly workup and unnecessary corrective surgery.
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