Treatment of Neurotrophic Keratopathy with Nicergoline

CLINICAL SCIENCE

Treatment of Neurotrophic Keratopathy With Nicergoline

Young-Chun Lee, MD, and Su-Young Kim, MD

mellitus (DM), and abuse of topical anesthetics. Untreated Purpose: The aim of this study was to determine the effect of neurotrophic keratopathy leads to persistent epithelial de- nicergoline in patients with neurotrophic keratopathy. fects, stromal ulcers, corneal opacity, and decreased visual 3 Methods: This is a prospective, noncomparative interventional acuity. study. The study included 27 eyes of 24 patients with neurotrophic Topical nerve growth factor (NGF) and autologous keratopathy who were unresponsive to conventional therapy. serum eye drops are promising treatments of neurotrophic Patients were treated with 10 mg of oral nicergoline twice daily keratopathy. Topically applied exogenous NGF is known to improve corneal sensitivity and to restore the corneal surface for at least 2 weeks. Slit-lamp examination, photography, corneal 4–6 fluorescein dye testing, Cochet–Bonnet corneal sensitivity, and best- in patients with neurotrophic ulcers. The application of corrected visual acuity tests were performed before and after autologous serum eye drops leads to healing of neurotrophic keratopathy, and topical autologous plasma therapy pro- treatment. Tear nerve growth factor levels were measured before 7,8 and after treatment. moted nerve regeneration in neurotrophic keratopathy. Autologous serum eye drops contain many growth factors, Results: In 23 eyes (85%), epithelial defects healed completely including fibronectin and neurotrophins, and NGF in between 7 and 30 days of treatment with nicergoline (mean, 15.6 6 particular.7 8.0 days). Epithelial defects persisted in 4 eyes (15%). The mean Nicergoline (Sermion, 10a-methoxy-1,6-dimethylergoline- corneal sensitivity before and after treatment with nicergoline was 8b-methanol-5-bromonicotinate) is an ergoline derivative 20.5 6 8.5 and 30.2 6 10.8 mm, respectively (P , 0.001). The best- used to treat cognitive impairment after degenerative demen- corrected visual acuity (measured in units according to the logarithm tia and stroke.9–11 As previously reported, nicergoline of the minimum angle of resolution) was significantly improved accelerates healing of corneal epithelial wounds in rat from 1.1 6 0.6 to 0.8 6 0.6 (P , 0.001). The tear nerve growth corneas. The positive effects in corneal epithelial wound factor levels were significantly higher ranging from 3.2 6 0.3 to healing are likely related to increased levels of NGF in rat 6.2 6 0.3 pg/mL (P , 0.001). corneas and rat lacrimal glands.12 This study evaluates the effect of nicergoline in patients with neurotrophic Conclusions: Treatment with nicergoline helps patients with keratopathy. neurotrophic keratopathy in whom conventional treatment has failed. Key Words: corneal sensitivity, neurotrophic keratopathy, nicergoline MATERIALS AND METHODS (Cornea 2015;34:303–307) The protocol was reviewed and approved by our institutional review board, and written informed consent was obtained from all patients after receipt of ntact corneal nerves are essential for the health of the a detailed description of the study. Patients with gastric Icornea. A decreased corneal sense induces decreased discomfort (gastritis) or liver disease were excluded from mitotic rates in the corneal epithelium and reduced the study. acetylcholine.1,2 Twenty-seven eyes of 24 patients diagnosed with Neurotrophic keratopathy is a degenerative disease noninfectious, neurotrophic corneal ulcers associated that is characterized by decreased corneal sensation, which with decreased corneal sensitivity were enrolled for this can be caused by many local ocular and systemic conditions prospective uncontrolled study. Patients with less than 50 such as herpes virus infections, fifth nerve palsy, diabetes mm in Cochet–Bonnet corneal sensitivity at the central cornea were included. None of the patients had responded to conventional therapy (patch or soft contact lens, Received for publication July 17, 2014; revision received November 11, artificial preservative-free tears, and ointment) for over 2 2014; accepted November 11, 2014. Published online ahead of print months. According to the Mackie classification of clinical January 22, 2015. From the Department of Ophthalmology and Visual Science, College of staging of neurotrophic keratopathy, patients had more Medicine, The Catholic University of Korea, Seoul, Korea. than stage 2 disease (12 eyes in stage 3 and 15 eyes in The authors have no funding or conflicts of interest to disclose. stage 2).3 Reprints: Su-Young Kim, MD, Department of Ophthalmology, College of Patients were treated with oral nicergoline in 10-mg Medicine, The Catholic University of Korea, Uijeongbu St. Mary’s fi Hospital, #271 Cheonbo-ro, Uijeong bu-si, Gyeonggi-do 480-717, Korea doses twice daily for at least 2 weeks in addition to arti cial (e-mail: [email protected]). preservative-free tears. Nicergoline medications were discon- Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. tinued 1 week after resolution of the corneal lesions in

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patients with low corneal sensitivity. Nicergoline medications NGF levels were measured before treatment and 7 to 10 days were continued for 2 months in 4 patients with no tendency after treatment. to heal. Statistical analyses were performed using SPSS soft- Slit-lamp examination, photography, corneal fluores- ware (version 10.0, SPSS, Inc). The paired t test was used to cein dye testing, Cochet–Bonnet corneal sensitivity at the determine statistical significance associated with the BCVA, central cornea, and best-corrected visual acuity (BCVA) tests corneal sensitivity, and NGF levels of human tears. A P , were performed at pretreatment of nicergoline, the time of 0.05 was considered significant. healed epithelial defect, 3 months, and last follow-up. The BCVA results were converted to logarithm of the minimum angle of resolution values (logMAR = log1/Snellen visual RESULTS acuity). Ages of patients ranged from 44 to 80 years with Tears were collected using a bonded polyester fiber a mean of 59.7 6 10.9 years. Twenty-nine percent (7/24) of rod (Transorb Wicks; Filtrona, Richmond, VA) from 16 the patients were women, and 71% (17/24) were men. Causes eyes. The concentrations of NGF were measured by of neurotrophic keratopathy in patients’ eyes were DM in 15 enzyme-linked immunosorbent assay methods using the eyes, neurosurgery in 5 eyes, post-herpes infections in 2 eyes, DuoSet ELISA development kit (R & D Systems Inc, retinal surgery in 4 eyes, and orbital/facial trauma in 1 eye Minneapolis, MN) according to the manufacturer’sprotocol. (Table 1). Epithelial defects were observed with no

TABLE 1. Summary of the Patients and Outcomes The Largest Tear NGF Tear NGF Corneal Corneal Sensitivity Diameter of Time to Before After Sensitivity After Treatment at Affected Underlying Epithelial Defect, Complete Treatment, Treatment, Before the Last Follow-up, Case Age/Sex Eye Disease mm Healing, d pg/mL pg/mL Treatment, mm mm 1 60/F R Diabetes 3.0 13 3.4 6.3 25 40 L 2.2 14 3.3 6.2 25 45 2 80/F R Herpes 3.2 21 2.9 6.1 25 25 keratitis 3 45/F R Diabetes 3.3 21 3.4 6.3 20 30 L 2.5 30 NA NA 25 40 4 46/M R Neurosurgery 5.6 20 NA NA 10 30 5 47/F R Diabetes 3.2 9 3.8 6.5 35 40 6 50/M R Diabetes 2.5 17 3.4 6.5 30 30 7 71/M R Herpes 5.0 21 NA NA 20 25 keratitis 8 55/F R Diabetes 2.7 7 3.5 6.4 35 40 9 47/M R Orbital/facial 4.2 14 NA NA 30 35 trauma 10 60/M R Retinal 3.8 7 3.2 6.2 35 60 surgery 11 59/F L Diabetes 4.1 7 3 5.9 20 35 12 78/F R Diabetes 3.5 NA 3.3 6.1 20 25 13 67/M R Diabetes 4.1 NA 3.0 6 20 20 14 55/M R Neurosurgery 3.5 NA NA NA 15 15 15 67/M L Diabetes 3.2 7 3.6 6.2 20 25 16 55/M R Neurosurgery 2.8 7 3.6 6.4 10 15 17 75/M R Neurosurgery 3.5 NA NA NA 10 10 18 60/M R Diabetes 2.2 7 2.9 5.5 15 30 L 2.4 14 2.9 5.9 10 25 19 64/M R Retinal 1.9 15 2.5 6.0 25 35 surgery 20 58/M R Retinal 3.5 21 NA NA 15 20 surgery 21 44/M L Neurosurgery 3.2 30 NA NA 20 30 22 58/M L Retinal 2.8 30 NA NA 20 30 surgery 23 54/M L Diabetes 2.5 14 NA NA 10 35 24 78/M L Diabetes 2.5 14 NA NA 10 25

L, left eye; NA, not applicable; R, right eye.

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FIGURE 1. Case 4. Neurotrophic keratopathy caused by neurosurgery before (A and B) and after (C) treatment with nicergoline. The largest diameter of the epithelial defect was 5.6 mm. After 20 days of treatment, the corneal ulcer was completely healed and corneal sensitivity improved from 10 to 30 mm at the time of the last follow-up visit. The treatment period with nicergoline was 27 days. Case 19. Neurotrophic keratopathy caused by retinal surgery before (D and E) and after (F) treatment with nicergoline treatment. The largest diameter of the epithelial defect was 1.9 mm. After 15 days of treatment, the corneal ulcer was completely healed. Treatment with nicergoline was continued for 6 days additionally. Corneal sensitivity improved from 25 to 35 mm at the time of the last follow-up visit.

underlying stromal inflammation. The average of the largest DISCUSSION diameter of epithelial defect was 3.2 6 0.9 mm before Sensory denervation of the cornea or corneal nerve nicergoline treatment. damage induces depletion of acetylcholine, which can cause The epithelial defects healed completely in 23 of 27 a decrease in the mitotic rates of the corneal epithelium.1,2 eyeswithin7to30daysoftreatment with nicergoline NGF may improve corneal nerve sensitivity through release 6 (mean, 15.6 8.0days).Figures1and2showhealingof of several neuropeptides together with its trophic effects, a neurotrophic ulcer before and after treatment with which include neurite sprouting or restoration of injured nicergoline. Epithelial defects persisted in 4 of the 27 neurons of the peripheral nervous system.13–16 eyes (2 eyes with DM and 2 eyes with neurosurgery). The NGF directly promotes proliferation and differentiation mean corneal sensitivity before and after treatment with of epithelial cells,17 and it stimulates corneal epithelial healing nicergoline was 20.5 6 8.5 and 30.2 6 10.8 mm, by indirectly increasing the amount of substance P and respectively (P , 0.001). Improvement of corneal sensi- – calcitonin gene-related peptides.14,17 23 tivity (.10 mm) was observed in 14 eyes (52%). One eye In in vivo studies, nicergoline has been shown to (a case of neurotrophic keratopathy after retinal surgery) achieved normal corneal sensitivity (60 mm). Values of increase release of acetylcholine in rat brains with age-related fi 9 the BCVA before and after treatment were 1.1 6 0.6 and de cits of acetylcholine. In addition, nicergoline supports 6 , . cholinergic neurons that increase the content of NGF and 0.8 0.6, respectively (P 0.001). Improvement 1 line 10,11 of the Snellen test for BCVA was observed in 17 (63%) of brain-derived neurotrophic factors in brains of aged rats. 27 eyes. The BCVA increased by .2 lines in 9 (33%) of In a previous animal study, nicergoline was shown to 27 eyes. NGF levels before and after treatment were 3.2 6 accelerate healing of corneal epithelial wounds in corneas of 0.3 and 6.2 6 0.3 pg/mL, respectively. NGF levels after rats. This finding is mediated by increased NGF levels in treatment were significantly higher than those before lacrimal glands or corneal tissue of rats.12 Nicergoline treatment (P , 0.001). The mean follow-up period was treatment increased the corneal nerve area in rats after 6.1 6 4.9 months (range, 3–24 months). There were no photorefractive keratectomy.24 systemic or local side effects from nicergoline treatment. This study found positive effects of nicergoline in 85% Recurrence of the epithelial defect was not observed in (23/27) of patients with neurotrophic ulcers. We postulate that patients with healing. nicergoline facilitates healing of epithelial defects in patients

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FIGURE 2. Case 9. Neurotrophic keratopathy caused by orbital/ facial trauma before (A) and after (B) treatment with nicergoline. The largest diameter of epithelial defect was 4.2 mm. After 14 days of treatment, the corneal ulcer was completely healed and corneal sensitivity improved from 30 to 35 mm. Treatment with nicergoline was continued for 7 days additionally after healing. Case 7. Neurotrophic keratopathy caused by herpes keratitis before (C) and after (D) treatment with nicergoline. The largest diameter of the epithelial defect was 5.0 mm. After 21 days of treatment, the corneal ulcer was completely healed and corneal sensitivity improved from 20 to 25 mm. Treatment period with nicergoline was 30 days. Case 11. Neurotrophic keratopathy caused by DM before (E) and after (F) treatment. The largest diameter of the epithelial defect was 4.1 mm. After 7 days of treatment, the corneal ulcer was completely healed and corneal sensitivity improved from 20 to 35 mm. Treatment with nicergoline was continued for 7 days additionally after healing.

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