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Severe keratomalacia after 12 months of continuous hydrogel contact lens wear in a psychiatric patient
Contact Lens & Anterior Eye 38 (2015) 138–141
Contents lists available at ScienceDirect
Contact Lens & Anterior Eye journal homepage: www.elsevier.com/locate/clae
Case report
Severe keratomalacia after 12 months of continuous hydrogel contact lens wear in a psychiatric patient Laura Rico-Sergado a,∗ , Jose L. Pérez-Canales a , Juan J. Pérez-Santonja a,b , Sonia Cigüenza-Sancho c a
Department of Ophthalmology, Alicante University General Hospital, Alicante, Spain Cornea Unit, OftalVist Group, Alicante, Spain c Department of Pathology, Alicante University General Hospital, Alicante, Spain b
a r t i c l e
i n f o
Article history: Received 18 August 2014 Received in revised form 29 October 2014 Accepted 29 October 2014 Keywords: Hydrogel contact lens Contact lens wear Keratomalacia Vitamin A deficiency
a b s t r a c t A 53-year-old cachectic patient diagnosed with major depressive disorder was referred to our department for evaluation of a visible deformation of the right eye. She had been wearing hydrogel contact lenses on a continuous basis without removal for the last 12 months, influenced by low self-esteem and social isolation. Slit-lamp examination of the right eye showed a conical cornea, extensive neovascularization, severe stromal melting with descemetocele formation and forward bulging of the iris. Examination of the left eye revealed multiple corneal opacities, deep stromal neovascularization and anterior chamber inflammation. No sign of infection was present. Vitamin A deficiency was suspected and later confirmed. The patient required evisceration of the right eye and psychiatric treatment. Inflammatory signs of the left eye resolved within 1 week of initiating treatment. This case illustrates the synergistic effect of soft contact lens abuse and vitamin A deficiency in a psychiatric patient, and emphasizes the importance of instructing vulnerable patients on appropriate lens use and care. © 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Vitamin A deficiency has been associated with severe malnutrition, and is still a major cause of blindness in many parts of the world, particularly in Africa and Asia. However, it is a rare event in the United States (USA) and Europe [1]. Although vitamin A deficiency has been directly related to xerosis, keratomalacia and nyctalopia, the pathogenesis of keratomalacia is usually complex, requiring the combination of multiple factors in vulnerable patients. Since their introduction in the USA and Europe in the 1960s, hydrogel contact lenses have been frequently associated with corneal disorders such as epithelial erosions, infectious keratitis and stromal neovascularization [2]. Contact lenses interact with corneal tissue in several different ways and may interfere with normal corneal physiology. Hydrogel contact lenses act as a physical barrier to oxygen transmission, reducing the oxygen supply to the cornea. It has been suggested that chronic hypoxia is responsible for changes in corneal structure and function, inducing
∗ Corresponding author. Tel.: +34 965933000. E-mail address: [email protected] (L. Rico-Sergado).
dysregulation of the wound-healing process, corneal neovascularization and stromal thinning [3]. This report details the case of a patient diagnosed with major depressive disorder and vitamin A deficiency who admitted a 12-month history of continuous hydrogel contact lens wear, presenting with severe keratomalacia, stromal melting and extensive corneal neovascularization.
2. Materials and methods A 53-year-old woman was admitted to the emergency room with a history of 25 kg weight loss over 12 months, constant listlessness and depressed mood. On admission, she reported feeling depressed and worthless since her daughter’s death 1 year ago. She had complete loss of appetite and erratic eating habits. She met the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for a current depressive episode (depressive mood, anhedonia, weight loss, feeling of worthlessness and sleep disturbances) and was diagnosed with major depressive disorder. After psychiatric assessment, the patient was referred to our department for further evaluation of a visible deformation of the right eye. Her past medical history showed no evidence of previous ocular disease, surgery or treatment, except myopia. She had been
http://dx.doi.org/10.1016/j.clae.2014.10.005 1367-0484/© 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
L. Rico-Sergado et al. / Contact Lens & Anterior Eye 38 (2015) 138–141
139
Fig. 1. (A) Macroscopic photograph of the right eye. (B) Slit-lamp image showing extensive corneal neovascularization, severe corneal melting, descemetocele and forward bulging of the iris.
wearing conventional hydrogel (omafilcon A) contact lenses (Proclear® ; CooperVision Inc., Irvine, CA, USA), and had never consulted an ophthalmologist before. Asked about contact lens habits, she revealed she had been wearing them on a continuous basis (24 h a day) for the last 12 months, probably influenced by low self-esteem and social isolation. On our initial examination, best corrected visual acuity (BCVA) was no light perception in her right eye and 20/40 in her left eye. Contact lens was still present in the left eye. Macroscopically, the right eye showed a conical cornea. Slit-lamp examination revealed conjunctival injection without mucopurulent discharge, extensive corneal neovascularization (4 quadrants) and severe keratomalacia with stromal melting and subsequent descemetocele formation (Fig. 1). Further examination of the left eye revealed conjunctival hyperemia, ciliary congestion, deep corneal neovascularization, stromal haze and non-specific endothelial precipitates associated with inflammatory cells in the anterior chamber (approximately 5–15 cells per field of 1 mm × 1 mm) (Fig. 2). No Bitot’s spots were found in either eye. Corneal scraping revealed no microorganisms. Bacterial and fungal cultures were negative. Laboratory studies showed normocytic anemia and hypoproteinemia. Serum vitamin A level was low (<10 g/dl; reference range, 30–120 g/dl). No connective tissue disorders were identified.
All available treatment options were considered and discussed with the patient. After informed consent was obtained, evisceration of the right eye was performed. The left eye was initially treated with moxifloxacin 0.5% eye drops (Vigamox® , Alcon Cusí SA, Barcelona, Spain) four times daily, prednisolone 1% eye drops (Pred Forte® , Allergan SA, Madrid, Spain) four times daily and cyclopentolate 1% eye drops (Colircusí Cicloplejico® ; Alcon Cusí SA, Barcelona, Spain) twice daily. 3. Results Histological examination of the cornea showed mild epithelial hyperplasia and microcysts, severe thinning of the central stroma, and deep stromal neovascularization and patchy lymphoplasmacytic infiltrates with absence of multinucleated giant cells at the peripheral cornea (Fig. 3). One month after surgery, the patient reported subjective improvement of ocular discomfort. Conjunctival injection and anterior chamber reaction of the left eye subsided within 1 week of initiating treatment. Stromal haze and neovascularization remained. Prednisolone eye drops were tapered down and discontinued after four weeks of therapy. Final BCVA was 20/32 in the left eye. 4. Discussion
Fig. 2. Slit-lamp photograph of the left eye showing ciliary congestion, deep stromal neovascularization and stromal haze.
In subjects with severe nutritional disorders, vitamin A deficiency has been reported to induce keratomalacia and stromal melting [1]. This may explain to some extent the observed corneal changes in this patient. However, although vitamin A may induce disruption of corneal metabolism and keratocytes [4], keratomalacia is a complex phenomenon that usually arises from the converging action of several pathogenic processes. Despite continuous advances in contact lens design, extended contact lens wear has been for long associated with a wide range of ocular surface and corneal disorders, such as dry eye, giant papillary conjunctivitis, epithelial erosions, infectious keratitis and stromal neovascularization [2]. Hypoxia is considered to be one of the major factors contributing to corneal disorders in contact lens
140
L. Rico-Sergado et al. / Contact Lens & Anterior Eye 38 (2015) 138–141
Fig. 3. Hematoxilin and eosin-stained section of the cornea. (A) Section of the central cornea showing epithelial microcysts and severe stromal thinning. (B) Section of the peripheral cornea showing superficial and deep stromal neovascularization (arrows). (C) Patchy infiltrates of lymphocytes and plasma cells are noted at the peripheral cornea.
wearers [5], and it is usually associated with inappropriate overnight wear. According to some studies, the partial pressure of oxygen is reduced from approximately 155 to 55 mmHg with lid closure [6]. The average oxygen transmissibility of Proclear® lenses is 52.3 × 10−9 (cm × ml O2 )/(s × ml × mmHg) [7], significantly reducing the oxygen flux into the cornea under closed-eye conditions, as they are not intended for overnight wear. In that respect, long-term exposure to hypoxia has been reported to strongly affect corneal physiology and structure, inducing epithelial microcysts, stromal neovascularization, development of corneal opacities and stromal thinning [8]. This may have potentiated the effects of vitamin A deficiency on the corneal metabolism and contributed to the fatal outcome. Epithelial microtrauma is frequent in contact lens wearers due to blink-related lens movements. This, combined with the fact that the corneal wound-healing process is compromised under hypoxic conditions and vitamin A deficiency [9], increases the risk of recurrent epithelial defects and corneal infections. Therefore, the differential diagnosis in this case should also include infectious keratitis. Herpetic stromal keratitis is probably the most common cause of corneal melting and stromal neovascularization in healthy subjects [10]. In fact, although no sign of infection was initially present and no evidence of giant cells or granulomatous inflammation was observed in the corneal button, the possibility of previous herpetic keratitis cannot be entirely ruled out. Furthermore, persistent corneal epithelial defects significantly increase the risk of
bacterial keratitis. However, cultures were negative for both bacteria and fungi. Systemic disorders have occasionally been reported to induce progressive stromal thinning affecting the central cornea. Among immune disorders, rheumatoid arthritis and granulomatosis with polyangiitis are the most frequently associated with corneal melting [11]. Both conditions were excluded in this patient. Finally, an association between extended contact lens wear and topical anesthetic eye drops abuse should also be considered in the differential diagnosis of sterile corneal melting [12], although anesthetic use was unlikely in our patient. She had never consulted an ophthalmologist before and specifically denied any previous ocular treatment. In summary, this case illustrates an uncommon and fatal complication derived from the improper use of hydrogel contact lenses in a psychiatric patient. Corneal changes observed in this case may be the result of the synergistic effect of continuous soft contact lens wear and vitamin A deficiency. This emphasizes the importance of instructing the patients on appropriate lens use and care, especially when dealing with vulnerable or psychiatric patients.
Consent Informed consent was obtained from the patient for publication of this case report and accompanying images.
L. Rico-Sergado et al. / Contact Lens & Anterior Eye 38 (2015) 138–141
Conflict of interest The authors declare no conflict of interest. Funding No financial support was received. References [1] McLaughlin S, Welch J, MacDonald E, Mantry S, Ramaesh K. Xerophthalmia – a potential epidemic on our doorstep? Eye (Lond) 2014;28(May (5)):621–3. [2] Foulks GN. Prolonging contact lens wear and making contact lens wear safer. Am J Ophthalmol 2006;141:369–73. [3] Jalbert I, Stapleton F. The corneal stroma during contact lens wear. Cont Lens Anterior Eye 2005;28:3–12. [4] Hayashi K, Cheng HM, Xiong J, Xiong H, Kenyon KR. Metabolic changes in the cornea of vitamin A deficient rats. Invest Ophthalmol Vis Sci 1989;30:769–72.
141
[5] Bonanno JA, Polse KA. Corneal acidosis during contact lens wear: effects of hypoxia and CO2 . Invest Ophthalmol Vis Sci 1987;28:1514–20. [6] Efron N, Carney LG. Oxygen levels beneath the closed eyelid. Invest Ophthalmol Vis Sci 1979;18:93–5. [7] Lorentz H, Heynen M, Kay L, Dominici CY, Khan W, Ng WW, et al. Contact lens physical properties and lipid deposition in a novel characterized artificial tear solution. Mol Vis 2011;17(December):3392–405. [8] Liu Z, Pflugfelder SC. The effects of long-term contact lens wear on corneal thickness, curvature, and surface regularity. Ophthalmology 2000;107: 105–11. [9] Wilson SE, Kim WJ. Keratocyte apoptosis: implications on corneal wound healing, tissue organization, and disease. Invest Ophthalmol Vis Sci 1998;39: 220–6. [10] Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol 2012;57:448–62. [11] McKibbin M, Isaacs JD, Morrell AJ. Incidence of corneal melting in association with systemic disease in the Yorkshire Region, 1995-7. Br J Ophthalmol 1999;83:941–3. [12] Aksoy A, Baskan AM, Aslan L, Aslankurt M. Topical proparacaine abuse resulting in evisceration. BMJ Case Rep 2013;2013.
Contents lists available at ScienceDirect
Contact Lens & Anterior Eye journal homepage: www.elsevier.com/locate/clae
Case report
Severe keratomalacia after 12 months of continuous hydrogel contact lens wear in a psychiatric patient Laura Rico-Sergado a,∗ , Jose L. Pérez-Canales a , Juan J. Pérez-Santonja a,b , Sonia Cigüenza-Sancho c a
Department of Ophthalmology, Alicante University General Hospital, Alicante, Spain Cornea Unit, OftalVist Group, Alicante, Spain c Department of Pathology, Alicante University General Hospital, Alicante, Spain b
a r t i c l e
i n f o
Article history: Received 18 August 2014 Received in revised form 29 October 2014 Accepted 29 October 2014 Keywords: Hydrogel contact lens Contact lens wear Keratomalacia Vitamin A deficiency
a b s t r a c t A 53-year-old cachectic patient diagnosed with major depressive disorder was referred to our department for evaluation of a visible deformation of the right eye. She had been wearing hydrogel contact lenses on a continuous basis without removal for the last 12 months, influenced by low self-esteem and social isolation. Slit-lamp examination of the right eye showed a conical cornea, extensive neovascularization, severe stromal melting with descemetocele formation and forward bulging of the iris. Examination of the left eye revealed multiple corneal opacities, deep stromal neovascularization and anterior chamber inflammation. No sign of infection was present. Vitamin A deficiency was suspected and later confirmed. The patient required evisceration of the right eye and psychiatric treatment. Inflammatory signs of the left eye resolved within 1 week of initiating treatment. This case illustrates the synergistic effect of soft contact lens abuse and vitamin A deficiency in a psychiatric patient, and emphasizes the importance of instructing vulnerable patients on appropriate lens use and care. © 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Vitamin A deficiency has been associated with severe malnutrition, and is still a major cause of blindness in many parts of the world, particularly in Africa and Asia. However, it is a rare event in the United States (USA) and Europe [1]. Although vitamin A deficiency has been directly related to xerosis, keratomalacia and nyctalopia, the pathogenesis of keratomalacia is usually complex, requiring the combination of multiple factors in vulnerable patients. Since their introduction in the USA and Europe in the 1960s, hydrogel contact lenses have been frequently associated with corneal disorders such as epithelial erosions, infectious keratitis and stromal neovascularization [2]. Contact lenses interact with corneal tissue in several different ways and may interfere with normal corneal physiology. Hydrogel contact lenses act as a physical barrier to oxygen transmission, reducing the oxygen supply to the cornea. It has been suggested that chronic hypoxia is responsible for changes in corneal structure and function, inducing
∗ Corresponding author. Tel.: +34 965933000. E-mail address: [email protected] (L. Rico-Sergado).
dysregulation of the wound-healing process, corneal neovascularization and stromal thinning [3]. This report details the case of a patient diagnosed with major depressive disorder and vitamin A deficiency who admitted a 12-month history of continuous hydrogel contact lens wear, presenting with severe keratomalacia, stromal melting and extensive corneal neovascularization.
2. Materials and methods A 53-year-old woman was admitted to the emergency room with a history of 25 kg weight loss over 12 months, constant listlessness and depressed mood. On admission, she reported feeling depressed and worthless since her daughter’s death 1 year ago. She had complete loss of appetite and erratic eating habits. She met the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for a current depressive episode (depressive mood, anhedonia, weight loss, feeling of worthlessness and sleep disturbances) and was diagnosed with major depressive disorder. After psychiatric assessment, the patient was referred to our department for further evaluation of a visible deformation of the right eye. Her past medical history showed no evidence of previous ocular disease, surgery or treatment, except myopia. She had been
http://dx.doi.org/10.1016/j.clae.2014.10.005 1367-0484/© 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
L. Rico-Sergado et al. / Contact Lens & Anterior Eye 38 (2015) 138–141
139
Fig. 1. (A) Macroscopic photograph of the right eye. (B) Slit-lamp image showing extensive corneal neovascularization, severe corneal melting, descemetocele and forward bulging of the iris.
wearing conventional hydrogel (omafilcon A) contact lenses (Proclear® ; CooperVision Inc., Irvine, CA, USA), and had never consulted an ophthalmologist before. Asked about contact lens habits, she revealed she had been wearing them on a continuous basis (24 h a day) for the last 12 months, probably influenced by low self-esteem and social isolation. On our initial examination, best corrected visual acuity (BCVA) was no light perception in her right eye and 20/40 in her left eye. Contact lens was still present in the left eye. Macroscopically, the right eye showed a conical cornea. Slit-lamp examination revealed conjunctival injection without mucopurulent discharge, extensive corneal neovascularization (4 quadrants) and severe keratomalacia with stromal melting and subsequent descemetocele formation (Fig. 1). Further examination of the left eye revealed conjunctival hyperemia, ciliary congestion, deep corneal neovascularization, stromal haze and non-specific endothelial precipitates associated with inflammatory cells in the anterior chamber (approximately 5–15 cells per field of 1 mm × 1 mm) (Fig. 2). No Bitot’s spots were found in either eye. Corneal scraping revealed no microorganisms. Bacterial and fungal cultures were negative. Laboratory studies showed normocytic anemia and hypoproteinemia. Serum vitamin A level was low (<10 g/dl; reference range, 30–120 g/dl). No connective tissue disorders were identified.
All available treatment options were considered and discussed with the patient. After informed consent was obtained, evisceration of the right eye was performed. The left eye was initially treated with moxifloxacin 0.5% eye drops (Vigamox® , Alcon Cusí SA, Barcelona, Spain) four times daily, prednisolone 1% eye drops (Pred Forte® , Allergan SA, Madrid, Spain) four times daily and cyclopentolate 1% eye drops (Colircusí Cicloplejico® ; Alcon Cusí SA, Barcelona, Spain) twice daily. 3. Results Histological examination of the cornea showed mild epithelial hyperplasia and microcysts, severe thinning of the central stroma, and deep stromal neovascularization and patchy lymphoplasmacytic infiltrates with absence of multinucleated giant cells at the peripheral cornea (Fig. 3). One month after surgery, the patient reported subjective improvement of ocular discomfort. Conjunctival injection and anterior chamber reaction of the left eye subsided within 1 week of initiating treatment. Stromal haze and neovascularization remained. Prednisolone eye drops were tapered down and discontinued after four weeks of therapy. Final BCVA was 20/32 in the left eye. 4. Discussion
Fig. 2. Slit-lamp photograph of the left eye showing ciliary congestion, deep stromal neovascularization and stromal haze.
In subjects with severe nutritional disorders, vitamin A deficiency has been reported to induce keratomalacia and stromal melting [1]. This may explain to some extent the observed corneal changes in this patient. However, although vitamin A may induce disruption of corneal metabolism and keratocytes [4], keratomalacia is a complex phenomenon that usually arises from the converging action of several pathogenic processes. Despite continuous advances in contact lens design, extended contact lens wear has been for long associated with a wide range of ocular surface and corneal disorders, such as dry eye, giant papillary conjunctivitis, epithelial erosions, infectious keratitis and stromal neovascularization [2]. Hypoxia is considered to be one of the major factors contributing to corneal disorders in contact lens
140
L. Rico-Sergado et al. / Contact Lens & Anterior Eye 38 (2015) 138–141
Fig. 3. Hematoxilin and eosin-stained section of the cornea. (A) Section of the central cornea showing epithelial microcysts and severe stromal thinning. (B) Section of the peripheral cornea showing superficial and deep stromal neovascularization (arrows). (C) Patchy infiltrates of lymphocytes and plasma cells are noted at the peripheral cornea.
wearers [5], and it is usually associated with inappropriate overnight wear. According to some studies, the partial pressure of oxygen is reduced from approximately 155 to 55 mmHg with lid closure [6]. The average oxygen transmissibility of Proclear® lenses is 52.3 × 10−9 (cm × ml O2 )/(s × ml × mmHg) [7], significantly reducing the oxygen flux into the cornea under closed-eye conditions, as they are not intended for overnight wear. In that respect, long-term exposure to hypoxia has been reported to strongly affect corneal physiology and structure, inducing epithelial microcysts, stromal neovascularization, development of corneal opacities and stromal thinning [8]. This may have potentiated the effects of vitamin A deficiency on the corneal metabolism and contributed to the fatal outcome. Epithelial microtrauma is frequent in contact lens wearers due to blink-related lens movements. This, combined with the fact that the corneal wound-healing process is compromised under hypoxic conditions and vitamin A deficiency [9], increases the risk of recurrent epithelial defects and corneal infections. Therefore, the differential diagnosis in this case should also include infectious keratitis. Herpetic stromal keratitis is probably the most common cause of corneal melting and stromal neovascularization in healthy subjects [10]. In fact, although no sign of infection was initially present and no evidence of giant cells or granulomatous inflammation was observed in the corneal button, the possibility of previous herpetic keratitis cannot be entirely ruled out. Furthermore, persistent corneal epithelial defects significantly increase the risk of
bacterial keratitis. However, cultures were negative for both bacteria and fungi. Systemic disorders have occasionally been reported to induce progressive stromal thinning affecting the central cornea. Among immune disorders, rheumatoid arthritis and granulomatosis with polyangiitis are the most frequently associated with corneal melting [11]. Both conditions were excluded in this patient. Finally, an association between extended contact lens wear and topical anesthetic eye drops abuse should also be considered in the differential diagnosis of sterile corneal melting [12], although anesthetic use was unlikely in our patient. She had never consulted an ophthalmologist before and specifically denied any previous ocular treatment. In summary, this case illustrates an uncommon and fatal complication derived from the improper use of hydrogel contact lenses in a psychiatric patient. Corneal changes observed in this case may be the result of the synergistic effect of continuous soft contact lens wear and vitamin A deficiency. This emphasizes the importance of instructing the patients on appropriate lens use and care, especially when dealing with vulnerable or psychiatric patients.
Consent Informed consent was obtained from the patient for publication of this case report and accompanying images.
L. Rico-Sergado et al. / Contact Lens & Anterior Eye 38 (2015) 138–141
Conflict of interest The authors declare no conflict of interest. Funding No financial support was received. References [1] McLaughlin S, Welch J, MacDonald E, Mantry S, Ramaesh K. Xerophthalmia – a potential epidemic on our doorstep? Eye (Lond) 2014;28(May (5)):621–3. [2] Foulks GN. Prolonging contact lens wear and making contact lens wear safer. Am J Ophthalmol 2006;141:369–73. [3] Jalbert I, Stapleton F. The corneal stroma during contact lens wear. Cont Lens Anterior Eye 2005;28:3–12. [4] Hayashi K, Cheng HM, Xiong J, Xiong H, Kenyon KR. Metabolic changes in the cornea of vitamin A deficient rats. Invest Ophthalmol Vis Sci 1989;30:769–72.
141
[5] Bonanno JA, Polse KA. Corneal acidosis during contact lens wear: effects of hypoxia and CO2 . Invest Ophthalmol Vis Sci 1987;28:1514–20. [6] Efron N, Carney LG. Oxygen levels beneath the closed eyelid. Invest Ophthalmol Vis Sci 1979;18:93–5. [7] Lorentz H, Heynen M, Kay L, Dominici CY, Khan W, Ng WW, et al. Contact lens physical properties and lipid deposition in a novel characterized artificial tear solution. Mol Vis 2011;17(December):3392–405. [8] Liu Z, Pflugfelder SC. The effects of long-term contact lens wear on corneal thickness, curvature, and surface regularity. Ophthalmology 2000;107: 105–11. [9] Wilson SE, Kim WJ. Keratocyte apoptosis: implications on corneal wound healing, tissue organization, and disease. Invest Ophthalmol Vis Sci 1998;39: 220–6. [10] Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol 2012;57:448–62. [11] McKibbin M, Isaacs JD, Morrell AJ. Incidence of corneal melting in association with systemic disease in the Yorkshire Region, 1995-7. Br J Ophthalmol 1999;83:941–3. [12] Aksoy A, Baskan AM, Aslan L, Aslankurt M. Topical proparacaine abuse resulting in evisceration. BMJ Case Rep 2013;2013.