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`Hyperemia in Glaucoma Patients
`Donald Nixon, MD; Reviewer: Arthur Turk, MD
`
`Posted: 7/25/2008
`
`Introduction
`Although the evaluation of a glaucoma patient on medical therapy complaining of red eyes may not have the cachet
`of performing nonpenetrating surgery or laser angle therapy, it is nevertheless an essential component of the
`successful care and management of patients with this disease. Indeed, red eyes can prove particularly troublesome
`if they become persistent and therefore affect the tolerability of the agent -- which in turn affects compliance. Poor
`compliance can result in treatment failure due to a decrease in overall intraocular pressure (IOP) control. Because
`glaucoma is the second leading cause of blindness worldwide[1] and currently pharmacologic IOP lowering is the
`first-line therapeutic option for glaucoma, the advent of red eyes in a patient is not uncommon. It is therefore of the
`utmost importance to be able to identify red eyes, to distinguish the cause of the red eyes -- whether from a true
`allergic reaction, ocular surface disease, or irritation from the medication itself -- and to act to alleviate the problem
`so that adherence and treatment efficacy are not compromised.
`
`Distinguishing Hyperemia From Underlying Disorders
`Hyperemia, or redness alone in clinical terms, is only a sign of a problem, and may be associated with a broad
`group of ocular diseases or, possibly, be part of a response to allergic inflammation or irritation. Within the eyes, the
`redness that we see is caused by the vasodilatation of the conjunctival blood vessels against the white background
`of the sclera.[2] The presentation of red eyes, however, is only a starting point in the diagnostic sleuthing necessary
`to find and treat its underlying cause. Allergists will generally treat obvious atopic conjunctivitis, but they refer to
`ophthalmologists for more extensive differential diagnosis.
`
`To make the diagnosis, there are various grading systems available, including standard photographic charts[3] and
`the Corneal and Contact Lens Research Unit (CCLRU) grading scale.[2] They include verbal descriptions and
`photographs that illustrate increasing levels of conjunctival hyperemia. Although conjunctival hyperemia is an
`important clinical sign of ocular disease or inflammation, it is important to note that even a normal eye has a degree
`of hyperemia; it is more common in males than females; and the area of the nasal bulbar has the highest grading. It
`is thus the degree of hyperemia, not its presence alone, which separates normal from abnormal.
`
`Hyperemia is a symptom; allergy, on the other hand, refers to a specific process that stimulates inflammation. True
`allergic (atopic, type I) reactions stem from hypersensitivity to a substance (allergen). There is an antibody-antigen
`interaction, and a cascade of events follow associated with the release of inflammatory mediators from cells;
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`hyperemia is commonly an outcome of the event. There is some difficulty in distinguishing a true ocular allergy.
`Grading systems of ocular allergies are not consistent because the presentation and location can be quite variable.
`The other difficulty is the issue of defining what a true allergy is. Hyperemia, pruritus, folliculosis, and conjunctival
`allergy have been all or partially included under the umbrella of ocular allergy, and the presence or absence of some
`of those will influence the measured incidence of allergy in a particular study. For the conjunctival reaction, it may be
`proper to include all 3 -- hyperemia, pruritus, and conjunctival follicles -- to fully describe the allergic reaction.
`Periocular dermatitis, a type IV delayed cell-mediated hypersensitivity associated with scaling, crusting, and
`erythema around the area of involvement, is a clinical diagnosis not requiring a grading system.
`
`The importance of tolerability as it affects adherence to medication usage cannot be underestimated. Therefore,
`patients with red eyes require a systematic evaluation of symptoms and signs to be successfully diagnosed and
`treated. A comprehensive ocular-visual assessment should begin with first principles to determine the source of the
`problem.
`
`Initially, it is essential that problems such as marginal blepharitis, meibomian gland dysfunction, and underlying dry
`eyes be identified and managed. A significant percentage of glaucoma patients are women older than the age of 50,
`and this group of patients tends to be much more predisposed to dry eyes.[4] It has also become clear that the use of
`multiple medications, either because of the medications themselves or the associated preservatives, will aggravate
`this dry eye condition.[5,6] The use of Schirmer's evaluation, fluorescein, and rose Bengal staining to evaluate the
`tear film can confirm an underlying dry eye problem. The dry eye can then be managed with the use of
`nonpreservative tears and gel, and ideal lid hygiene.
`
`Contact type allergies (type IV) have extension of erythema well beyond the lid margin, and can occur with many
`medications, but tend to be more common with sulfa-based preparations. An underlying problem, blepharitis, is
`commonly associated with the elderly population, and the earlier the identification and intervention -- with
`improvement of lid hygiene -- the more rapidly symptoms can be controlled.
`
`A final point of confusion is seasonal allergies. Airborne allergens, including pollen, dust, and molds, cause
`inflammation on the ocular surface, especially for patients who already have dry eyes. It is imperative that this
`problem be differentiated from responses to glaucoma medications. This is usually accomplished by attention to the
`patient's history and transient nature of the symptoms. It then can be treated with appropriate anti-allergic
`medications not requiring the discontinuation of the patient's ocular medications.
`
`Medication and Red Eyes
`More difficult problems in effective treatment arise when the red eyes prove to be a response to the medications
`themselves. Various sources have noted the association of conjunctival hyperemia with virtually all topical IOP-
`lowering medications -- alpha-adrenergic agonists, beta-adrenergic antagonists, carbonic anhydrase inhibitors,
`prostaglandin analogs, and prostamide analogs.[7,8] The class that is associated with the highest incidence of
`hyperemia is the prostaglandin analogs. Although the incidence of initial hyperemia when starting the 3 medications
`is different -- latanaprost is noted at 5%-15%,[9] bimatoprost at 15%-45%,[10] and travoprost at 35%-50%[11] --
`incidence rates have been shown to change over time. For example, hyperemia peaks with bimatoprost at day 1
`while the vast majority of cases return to near baseline levels by day 28.[12] It is theorized that the aqueous may
`need sudden access to the ocular circulation on initiation of treatment, thereby resulting in an autoregulatory
`vasodilatation. After a new homeostasis becomes established, the vessels gradually adapt and the vasodilatation
`decreases. Several cross-over studies[13,14] have also noted that patients who have had previous exposure to
`prostaglandins display less hyperemia when switched to another drug in the class, a phenomenon that may be
`explained by this chain of events.
`
`Based on these findings, it should be emphasized how important it is to educate patients starting on this class of
`glaucoma medications that the hyperemia, if it occurs, is usually mild and of short duration. Given the effective IOP
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`reduction associated with this class, patient management of the early symptoms while maintaining the same
`medication may be the best approach.[15] Also of note is the presence of preservatives in glaucoma medications.
`They can be a potential agent for erythema and may be considered in the event of red eye.[16,17]
`
`The alpha-adrenergic agents have been shown to have the highest incidence of true allergic reactions, although that
`rate varies widely depending on study. The drug apraclonidine has a reported rate of 14%-48% depending on the
`concentration from 0.5 to 1%.[3,18] Brimonidine 0.2% has a reported rate between 4.2-25.7% if both allergic
`conjunctivitis and contact dermatitis are included. As with defining ocular allergy, the problem lies with the various
`interpretations of what comprises an allergic reaction. For example, a study[19] looking at allergic reactions to
`brimonidine required only hyperemia and follicular conjunctivitis for a diagnosis; pruritus, weeping, discharge, or
`discomfort were not necessary for the diagnosis of allergic conjunctivitis. The use of such a broad definition may
`help explain why there was such a high reported rate of allergic reactions at 25.7%.
`
`In a pivotal study comparing the fixed combination 0.2% brimonidine/0.5% timolol given twice a day with
`monotherapy with either timolol or brimonidine given 3 times a day, there was a noted significant difference in
`treatment-related adverse events.[20] It was shown that there was a significantly lower rate of hyperemia (22.8% to
`14.5%) and allergic conjunctivitis (9.4% to 5.2%) in the fixed combination group compared with the brimonidine one.
`This low rate of treatment-related adverse events in the brimonidine/timolol group has been seen in Canada where
`the drug has been in use for over 3 years.[21,22] The lower level also appears to be sustained over time.[23] There
`have been several theories put forward to try to explain this difference; the most persuasive is by Alvarado based on
`previous research.[24,25] He has shown in a cell culture model that alpha-adrenergic agonists cause cells to shrink,
`thereby opening intercellular spaces within the conjunctiva that would allow a path for pro-inflammatory mediators,
`such as drugs, preservatives, airborne allergens, lipid secretion, and other potential toxic agents, to reach the
`subconjunctival space. The addition of a beta-blocker has been shown to prevent this cell shrinkage, thereby
`stabilizing the conjunctival epithelium as a barrier to the subconjunctival space. Because it is in the subconjunctival
`space where the cellular and vascular response to inflammation is developed, the maintenance of the natural barrier
`effect of the conjunctiva may explain the statistically significant reduction in all components of allergy and
`inflammation comparing the fixed combination of brimonidine/timolol vs brimonidine alone in the 1-year pivotal study
`by Sherwood.[20] Indeed, there is speculation about the role that beta-blockers may play regarding the local allergic
`effects of the other glaucoma drug classes. Interesting results have been seen in combining beta-blockers with
`prostaglandins as fixed combination in Canada and Europe, where it has been suggested that the beta-blocker
`effect may extend to minimizing the hyperemia effect of second-generation prostaglandins such as travoprost and
`bimatoprost.[3,7,8,26-28]
`
`Conclusion
`Hyperemia in glaucoma patients is not uncommon, particularly among patients taking 2 or more medications. What
`is important, however, is that physicians be able to adequately diagnose and manage the hyperemia. Is it the result
`of a seasonal allergy or some other underlying disorder? Or does it stem directly from the medication itself?
`Distinguishing between different causes will direct treatment. If the hyperemia is found to result from a seasonal
`allergy or underlying ocular disorder, that condition can be directly treated and the patient should be able to remain
`on the existing medication. On the other hand, if the hyperemia results directly from the medication, steps can be
`taken to ease the hyperemia and improve tolerability. If the hyperemia is seen early, especially with the use of a
`prostaglandin, its severity should decrease after 6-12 weeks. In such cases, patients may be fine remaining on the
`same drug. However, if the hyperemia persists, then switching drugs is an option. The first step is usually to switch
`within the class, while another alternative is to change to another class of medications. The patient also may be
`switched to a fixed combination, where research suggests the addition of a beta-blocker may help minimize allergic
`reactions. Once such a successful determination is made, medication tolerability should be improved, along with
`patient adherence -- resulting in the maintenance of long-term stability of IOP control.
`
`This activity is supported by an independent educational grant from Allergan.
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`References
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