Topikal Anestetik Alışkanlığı Keratopatisi ve Klinik Progresyonu

1. 1Department Of Ophthalmology, Adnan Menderes University, Aydin, Turkey
2. 2Department Of Ophthalmology, Aydin Atatürk State Hospital, Aydin, Turkey

Sorumlu Yazar: We herein present three consecutive topical anesthetic abuse cases at various stages of the disease progression. The late diagnosis of the second case had given us the opportunity to view a significant part of the natural history of the disease. Combining this information with the first and third cases had enabled us to stage the progression of the disease process. To our knowledge, this is the first attempt to stage the natural history of topical anesthetic abuse given below: Stage I: Punctate epithelial defects enlarging and forming a full central epithelial defect. Severe conjunctival injection is present at all stages. Eyelids and surrounding skin can be edematous and erythematous. Stage II: Formation of a white opaque corneal infiltrate that forms a ring shape exactly matching the edge of the epithelial defect. Cornea central to the infiltrate is relatively transparent. If the epithelial defect and infiltrate is confined to the central cornea, inadequate treatment at this stage leads to widening of the epithelial defect up to corneal periphery with the formation of a second white opaque corneal infiltrate corresponding to the borders of the new epithelial defect. Cornea between the rings is hazy but not as opaque as the ring itself. White fluffy keratic precipitates and hypopyon can be seen at this stage. Stage III: Superficial and then deep corneal neovascularization develops up to the peripheral edge of ring starting inferiorly and probably working its way up circumferentially. Stage IV: Faster and continuous lysis of the cornea at the edge of the epithelial defect and the corneal infiltrate by lytic enzymes brought by neovascularization leads to a spontaneous corneal button perforation. Topical anesthetic abuse is an infrequent encounter. Hence, most ophthalmologists do not see and treat one until they are well into practice. Although its signs as non-healing epithelial defect and ring shaped white corneal infiltrate have been suggested to be included in the differential diagnosis of herpetic, Gram-negative bacterial, fungal, mycobacterial, and Acanthamoeba keratitis, we believe that the appearance of the ring-shaped white corneal infiltrate does not look like any other ophthalmic disease and is typical for uncomplicated topical anesthetic abuse.1 Nevertheless, all cases should be scraped for microbiological examination, but most cases are proven to be non-infectious although sometimes a causative agent of infection can be determined.2 The mainstay of treatment is prevention of anesthetic use. This can be successfully done with pain management. Intramuscular opiate analgesia and sedation, oral diclofenac, topical diclofenac, oral indomethacin, or as in our last two cases, intramuscular diclofenac can be used.1,3-5 Choosing delivery routes other than topical for pain management might be a better approach. Topical diclofenac inhibits corneal epithelial migration at high doses but not at clinical doses; moreover, it can induce expression of matrix metalloproteinases in corneal tissue.6,7 Its preservative, benzalkonium chloride, induces cell growth arrest and death in conjunctival epithelium, as well as cytotoxicity to corneal epithelial cells. Moreover, bandage contact lenses frequently used in these cases may behave as a reservoir for topically used medications accentuating their side effects.8,9 The injury caused by topical anesthetic can be due to direct/indirect effects.10 The mechanism of toxic effects of topical anesthetics on ocular tissues is still uncertain. Three possible mechanisms have been proposed. First, because even a single dose of topical anesthetics may cause mild punctate epithelial keratopathy, the toxic effects of topical anesthetics on ocular tissues were suggested to be direct. Evidence showed that anesthetics interrupted the migration of corneal epithelial cells and delayed epithelial wound healing.11 Disruption of epithelial motility complexes like vinculin and actin filaments is the main cause of this delayed healing process.11 As a result, overdosing of topical anesthetics might result in the presence and/or persistence of the epithelial defects. The epithelial defects then, allow the topical anesthetics greater access to the inner corneal layers and may be directly toxic to these deeper tissues, thereby disrupting the healing process. A second proposed mechanism was that breakdown of the epithelial cells by anesthetics releases antigens that provoke an antigen–antibody immunologic response that may be associated with the stromal ring–like or disciform infiltration. This immune reaction has been postulated to be responsible for the primary destruction of the corneal epithelium, stromal cellular injuries, and tissue destruction, thus resulting in cornea thinning or scarring.10 Third, it was suggested that the preservatives in eye drops were also toxic to the corneal cells and contributed to the toxicity of topical anesthetics.10 The toxicity of preservatives in eye drops and precipitation of intraepithelial proteins are other factors that may contribute to corneal damage.12 Besides corneal toxicities, topical ocular anesthetic agents can compromise tear function by decreasing aqueous tear secretion, disturbing tear film stability, and decreasing blinking rate.10 Numerous studies have revealed that there are deleterious corneal effects associated with benzalkonium chloride (BAC) that include destabilization of the tear film, death of corneal and conjunctival epithelial cells, morphological changes in the corneal epithelial cells, and reduction of the corneal epithelial barrier function.13 Corneal anesthesia and toxicity may predispose individuals to infections. Superinfections with Candida species have been reported to occur during topical anesthetic abuse.2 Furthermore, as in our Case # 2, the signs and symptoms related to topical anesthetic abuse can masquerade as Acanthamoeba keratitis because of similarities such as disproportionate pain, use of bandage contact lenses, and corneal ring infiltration.10 In fact, the differential diagnosis for ring infiltrate is quite broad, and includes herpes simplex keratitis, gram-negative bacterial keratitis, fungal keratitis, and mycobacterial keratitis, but as we mentioned before, we believe that the appearance of ring-shaped white corneal infiltrate does not look like any other ophthalmic disease and is typical for uncomplicated topical anesthetic abuse. Persistent epithelial defects can give an opportunity for superimposed infection which can interfere with diagnosis and increase the difficulty of treating toxic keratitis. Smears and cultures of Acanthamoeba and other pathogens should be obtained to rule out any possible superinfection. Delayed diagnosis of toxic anesthetic keratitis can result in corneal perforation and severe loss of vision. Topical anesthetic agents are frequently applied in ophthalmic practice. Proparacaine 0.5% is the one most commonly used and was reported to reduce bacteria in the conjunctival flora when used before medical and surgical procedures.14 This may be the reason why secondary bacterial infection is not encountered often in topical anesthetic abuse in our cases. History taking, giving emphasis to patient’s occupation, is crucial in arriving to the correct diagnosis. The ophthalmologist must also be familiar with the corneal signs of the disease. Otherwise, incorrect diagnosis, as in our Case #2, results in loss of valuable time. Topical anesthetic abusers mostly have psychiatric problems, so while managing the disease psychiatric consultation should also be kept in mind. All three cases were put together in a report and sent to the General Directorate of Pharmaceuticals and Pharmacy, Ministry of Health, Ankara, Turkey. We learned that similar reports were also sent by other ophthalmologists nationwide. As a result, it was concluded that proparacaine ophthalmic solution should only be prescribed by ophthalmologists, the pharmacy selling the product should keep a copy of the stamped prescription for a period of one year, and that maximum four boxes per month in the form of prescription can be sold providing that the doctor is an ophthalmologist with documented submit. A letter regarding the subject was sent to the Turkish Pharmacists Association stating that criminal action will be taken against the pharmacies who sell the relevant drug disregarding these provisions. Address for Correspondence/Yazisma Adresi: Esin Tunca Kirikkaya MD, Department of Ophthalmology, Aydin Atatürk State Hospital, Aydin, Turkey Phone: +90 532 395 72 40 E-mail: kesintunca@yahoo.com Received/Gelis Tarihi: 06.05.2012 Accepted/Kabul Tarihi: 16.11.2012