Diagnostic Uses of Common Eye Drops

Diagnostic Uses of Common Eye Drops

Eye drops are a common form of medication prescribed by eye care professionals in the treatment of various ocular conditions. An essential aspect of eye drop administration is their use in diagnosis. This may be by virtue of their pharmacological effects, through augmenting the action of other drops, unmasking the clinical course of ocular pathology or even serendipitously. Therefore, in addition to treatment response, many eye drops have diagnostic applications unrelated to their primary therapeutic indication. Conversely, mydriatic eye drops are primarily used for enhanced visualization of intraocular structures and detection or screening of disease but have additional therapeutic indications. This article aims to review the diagnostic uses of commonly administered or prescribed eye drops and highlights uses which may be most pertinent to the eye care team, in their daily practice.

Eye drops that exhibit therapeutic and diagnostic utility can occur when a concurrent response to treatment provides an indication of the underlying pathology. An example of this duality is demonstrated when instituting empirical treatment with antibiotic eye drops for presumed mild microbial keratitis, which strongly suggests a bacterial infection when convalescence ensues. In contradistinction, the therapeutic response can sometimes obfuscate the diagnosis or even exacerbate the clinical course of disease. For instance, undiagnosed acanthamoeba keratitis may initially improve following topical antibiotic treatment through reduced availability of Escherichia coli bacteria as a nutrient source but ultimately result in protracted keratopathy and sequelae. ¹ Ciprofloxacin may also have a partial clinical response due to its weak amoebicidal activity. ²

Similarly confounding, early introduction of steroid eye drops may improve microbial keratitis in the incipient stages but eventually worsen disease, particularly if undetected or intercurrent fungal infection is present.^3,4 Diagnoses therefore declare themselves when the therapeutic response is atypical or nonresponsive to eye drop treatment.

Treatment withdrawal may yield useful information in the diagnosis of conjunctivitis medicamentosa. For example, over-the-counter medications, which contain alpha-adrenergic receptor analogues such as Naphazoline (Table 1), are commonly used as a decongestant to provide relief from “red eye.” Unfortunately, protracted use results in a tachyphylactic response (due to upregulation of adrenergic receptors) whereby conjunctival injection persists despite treatment and furthermore, prompt discontinuation results in fulminant rebound hyperemia. ⁵ Decongestant abuse should be ruled-out and any potential underlying condition further investigated. Eliminating polypharmacy is also imperative to clarify the diagnosis. An ultimate improvement in “red eye” leads the eye care professional to suspect self-treatment or eye drop misuse.

Topical Anesthetic Eye Drops

Enhancing the synergistic effect of eye drops by sequenced co-administration is an advantageous clinical tool. An example of this is Lidocaine, which potentiates the mydriatic and cycloplegic effect of Tropicamide by increasing their corneal penetrance. ⁶ In addition, Lidocaine exerts an independent (although attenuated) cycloplegic and mydriatic effect that is detectable in eyes with pale irides. ⁷

Local anesthetic drops such as Tetracaine are of multiuse in that they provide analgesia, facilitate ophthalmic interventions, enable surgery of the anterior segment, and assist in diagnostic assessment. Sklar et al. found that topical anesthesia in the diagnosis of corneal pathology had a sensitivity of 80% and specificity of 86% ⁸ —this is therefore a useful test in the diagnosis of ocular surface pain with undifferentiated oculodynia, particularly when signs are subtle, such as subclinical keratopathy. This rationale can also be applied to the scenario where the cornea, with intact pain reflexes, registers an irritant response from anesthetic eye drops, whereas the insensate cornea does not. This is relatively atraumatic in that doesn't induce superficial corneal erosions when evaluating sensation such as with direct touch-tests.

Spastic entropion is a condition arising from ocular irritation or inflammation. Inversion of the eyelid results from preseptal orbicularis oculi muscle overriding the oppositional action of the lid retractors. ⁹ Other causes of entropion can be excluded by the topical administration of local anesthetic—transient reversal of the entropion suggests an ocular irritant cause, inferring a diagnosis of spastic entropion, which can then be managed or referred accordingly.

Mydriatic Eye Drops

Eyes that undergo the process of atrophia or phthisis bulbi may present as a “painful blind eye.” There are various causes of amaurotic pain such as inflammation, intraocular pressure (IOP) induced oculodynia, corneal decompensation, ischemia, and nonspecific dysesthesia. Atropine eye drops are thought to alleviate pain in a phthisical eye by reducing ciliary spasm. ¹⁰ In this situation, atropine provides diagnostic information regarding the etiopathogenesis of pain, as the cause may not be obvious on clinical examination or when treatment of intraocular inflammation with steroid eye drops has been unsuccessful.

Phenylephrine (PE) is a sympathomimetic agent commonly available in 2.5% and 10% concentrations. Instillation of PE 2.5% blanches conjunctival vessels allowing differentiation between conjunctivitis and episcleritis. PE 10% vasoconstricts the superficial episcleral vascular network, sparing the deep plexus and hence distinguishes episcleritis from scleritis. ¹¹ Single-drop posology of PE 1% concentration may also be employed when localizing postganglionic Horner's syndrome, by leading to pupil dilation, whereas a central lesion will show no change in pupil size and a preganglionic lesion little to no dilation. ¹²

Following a clinic visit, patients may contact their eye care professional, concerned about the appearance of a droopy lid—in this scenario, one should consider an apparent ptosis due to upper lid retraction of the contralateral eye that had received in-clinic PE eye drops. This pharmacological action is the basis for PE testing in the surgical planning of ptosis surgery by Muller's muscle conjunctival resection (MMCR); Mullers muscle is a smooth muscle with sympathetic innervation responsive to PE eye drops causing upper lid elevation. ¹³ A positive test (reversal of ptosis) is predictive of successful MMCR surgery and diagnostic for mild aponeurotic ptosis. ¹³

Cyclopentolate is a cycloplegic, mydriatic agent that has been extensively studied in IOP provocation testing. Patients that experience an IOP rise of ≥5 mmHg upon dilation is suggestive of untreated or suspected open-angle glaucoma. ¹⁴ Provocative testing to precipitate an acute angle closure event is strongly not recommended in this context. Pigment liberation in the aqueous may also occur with cyclopentolate drops, indicating underlying pseudoexfoliation or pigment dispersion syndrome. ¹⁵ In this diagnostic “pigment dispersion test,” granules are released from the iris pigment epithelium due to pupillary movement seen with irido-zonular or irido-lenticular contact. ¹⁵

Another scenario whereby cyclopentolate instillation may yield diagnostic results is when patients present to their optometrist with advancing myopic refractive error. This may be the result of overstimulation of the eye's accommodative mechanism known as pseudomyopia. Relaxation by cycloplegia enables an accurate refractive assessment and diagnosis of the cause of myopic shift. ¹⁶

Eye Drops with IOP Lowering Effects

Pilocarpine is an acetylcholine receptor agonist that binds to muscarinic receptors; it is a miotic eye drop with weak IOP lowering properties. ¹⁷ Acetylcholine, when used intraoperatively, can indirectly confirm the presence of transparent vitreous in the anterior chamber by visualization of a peak-shaped pupil. ¹⁸ Postoperative cataract surgical patients' with “Seidel Positive” testing at the clear corneal incision may be due to vitreous wick syndrome—a strand of vitreous traversing the anterior chamber to the corneal wound causing incisional nonclosure and fluorescein-positive aqueous egress. ¹⁹ This can be subtle and not easily observed at the slit lamp (Fig. 1). Pilocarpine eye drops can assist diagnosis similar to acetylcholine testing whereby pupillary constriction reveals iris peaking caused by the diaphanous vitreous wick.

OPEN IN VIEWER

FIG. 1.

Schematic of “vitreous wick syndrome” with the semitransparent vitreous strand at the corneal incision (top image) and upon instillation of pilocarpine 1% eye drops, pupil peaking (bottom image)

Diagnostic testing with pilocarpine eye drops is also useful in the setting of anisocoria. A 0.125% dilution does not constrict a normal pupil, but produces miosis in an Adie's tonic pupil due to the upregulated cholinergic receptor-associated hypersensitivity. If the pupil is nonresponsive, this can then be re-challenged with pilocarpine 1%. If the pupil then produces constriction at the higher dose, it is diagnostic for an oculomotor nerve palsy, whereas no response indicates a pharmacological cause for the anisocoria. ²⁰

Upper eyelid retraction in the context of thyroid eye disease has been theorized as occurring secondary to circulating catecholamines (among other causes) and their effect on Mullers muscle activation. ²¹ Timolol, an aqueous suppressant beta-blocker eye drop, is highly absorbed across mucous membranes such as the conjunctiva and therefore able to act antagonistically on adrenergic receptors located in Mullers muscle. ²³ While further validation is required, it can be conceptualized that topical administration of beta-blocker eye drops may be diagnostic as abatement of the lid retraction infers a thyroid-related cause.

Topical apraclonidine 0.5% acts as a partial alpha-1 agonist, with high affinity for alpha-2 adrenergic receptor activation, producing aqueous suppression and therefore an IOP lowering effect. ²⁴ Alpha-1 receptors are upregulated in Horner's syndrome leading to a denervation supersensitivity response upon activation. This manifests with reversal of the miotic pupil, showing pupillary dilation; hence, diagnosing a Horner's pupil in undifferentiated anisocoria. ²⁵

Controlled-Medicine Eye Drops

Eye drops used in diagnosis may be difficult to procure due to the regulatory standards imposed on potential drugs of misuse. Topical cocaine drops (Table 2) are an alternative agent in the diagnosis of Horner's syndrome in children where apraclonidine is contraindicated. It is a postsynaptic norepinephrine reuptake inhibitor which produces dilation in the normal pupil but no response in the sympathectized Horner pupil. This pupil reaction is in contrast to apraclonidine eye drops, where the miotic Horner pupil becomes larger than the normal pupil (reversal of anisocoria). ²⁰

Hydroxyamphetamine 1% eye drops act by indirect alpha-adrenergic agonism—releasing norepinephrine at the sympathetic presynapse. Dilation is observed in healthy eyes given hydroxyamphetamine and similarly, eyes affected by a central or pre-ganglionic focus in Horner's syndrome are typically symmetric in their mydriatic response. Failure of pupil enlargement in the affected eye (or diminished dilatation) in comparison to the unaffected eye is diagnostic of a postganglionic lesion in Horner's syndrome and is due to neuronal dysfunction, whereby stores of norepinephrine required for transmission across the synaptic cleft are depleted^.20

Summary

Eye drops are widely understood for their prescribed therapeutic applications; however, a greater appreciation for their diagnostic utility is of great benefit to the eye care professional by expanding their clinical repertoire and providing comprehensive patient care. Eye care professionals should be aware of the pharmacological effects of eye drops, including potential side effects and contraindications, when utilizing these tests for diagnostic purposes.