Use of nicergoline as adjunctive treatment of neurotrophic keratitis in routine clinical practice: a case series

Depósito de Investigación de la Universidad de Sevilla https://idus.us.es/ This is an Accepted Manuscript of an article published by Taylor & Francis in Ocular Immunology and Inflammation, Vol. 30, Issue 7-8, on 2022, available at: https://doi.org/10.1080/09273948.2021.1976214 1 Title: Use of nicergoline as adjunctive treatment of neurotrophic keratitis in routine clinical practice: a case series. Authors: Miguel-Escuder L1 MD, Rocha-de-Lossada C1 MD, FEBO, Sabater-Cruz N1 PhD, Spencer F1 MD, Marín-Martínez S1 MD, Batlle-Ferrando S1 MD, Carreras- Castañer X1 MD, Torras J1 MD, Peraza-Nieves J1 MD. Author’s affiliations1: Hospital Clinic of Barcelona, Clínic Institute of Ophthalmology, University of Barcelona, 08028, Barcelona, Spain. Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, the authorship and/or publication of this article. The authors received no financial support for the research, authorship and/or publication of this article. Corresponding author: Miguel Escuder Lucía MD, Hospital Clínic de Barcelona, Instituto de Oftalmología, 08028 Sabino de Arana 1, Barcelona (Spain). Number phone +34680332866 E-mail: [email protected] Keywords: nicergoline, neurotrophic keratitis, persistent corneal epithelial defect, corneal ulcer 2 Abstract: Purpose: To describe the effectiveness and safety of nicergoline in patients with epithelial corneal defect or corneal ulcer due to neurotrophic keratitis. Methods: A prospective case series review was performed in 14 patients (14 eyes) with neurotrophic keratopathy who started treatment with nicergoline as an off-label prescription from January to November of 2020. Patients with a epithelial defect or corneal ulcer due to neurotrophic keratitis were treated with 10 mg of oral nicergoline twice daily. Results/Serial cases: Complete corneal healing was observed in 10 (71.4%) of the 14 patients after 25.6 ± 26.60 days (range 7-90) with nicergoline. In three (21.5%) patients the wound healing was not achieved (all of them with autoimmune disease), and one patient (7.1%) was lost to follow-up. Eleven patients (79%) were females; the average age at consultation was 69 years (44-96). The mean time between diagnosis and the starting of nicergoline was 10.92 ± 8.85 days (0-28). No adverse effects of nicergoline were observed in any subject. Conclusion: Nicergoline as an adjunctive treatment for neurotrophic keratitis showed a potential use in the healing of epithelial defect with a good tolerance in real-life clinical practice. Introduction: 3 The cornea is the most densely innervated tissue in the body. Corneal innervation plays an important role in the maintenance and proliferation of the corneal epithelium, and therefore, in wound healing.1 A partial or total loss of corneal sensitivity leads to the development of neurotrophic keratitis (NK).1 NK is a rare degenerative entity which prevalence has been estimated at approximately 1.6-4.2 / 10,000.2 However, recently has been suggested that NK may be more frequent than previously reported.2 A wide range of ocular or systemic conditions can cause NK, including chronic use of topical drugs (such as glaucoma medications, anaesthetics and/or nonsteroidal antiinflammatory drugs), ocular surgery, severe dry eye disease, diabetes, neurosurgical procedures, and the most frequent condition, herpetic keratitis. All of them are characterized by corneal hypoesthesia or anaesthesia.3 Untreated NK leads to a decrease in visual acuity and can lead to severe complications putting ocular integrity at risk. Therefore, it is suggested that NK-specific treatment should be initiated as soon as the diagnosis is suspected.4 NK requires a specific therapeutic approach depending on the degree of severity and the evolution over time. Although almost all current therapies aim to promote wound healing and prevent injury progression, they are not able to actively stimulate nerve regeneration.1 Nicergoline, (Sermion® [Biogenesis AntiAging, Fish Hock, South Africa]), is an ergot alkaloid derivative clinically available from the 1970s. Nicergoline has neurotrophic and antioxidant properties; it is widely used in the treatment of cognitive impairment secondary to ischemic stroke and other degenerative dementias, migraine or, dizziness.5 Nicergoline has been reported to accelerate wound healing in rat corneas.6 Likewise, recently a prospective study demonstrated with the off-label use of nicergoline a wound healing rate of 85% in patients with NK refractory to conventional therapy.7 In this series of cases, our aim is to describe the effectiveness and safety of the off-label use of 4 nicergoline in patients with NK in real-life clinical practice, reinforcing previous outcomes.7 Methods: A prospective review was performed of serial cases of patients with NK who started treatment with nicergoline as an off-label prescription at a single tertiary centre from January to November of 2020. The Mackie’s classification was used to assess the NK stage: stage 2 (persistent epithelial defect of more than 14 days without stromal involvement) or 3 (corneal ulcer) according to Mackie’s classification.4 The patients received oral nicergoline in 10mg doses twice daily; previous and concomitant treatment were variable according to medical criteria. The association of nicergoline with conventional treatment, as well as the duration of the treatment and the frequency of follow-up consultations, were decided according to individualized medical criteria depending on the clinical evolution of each patient. A comprehensive medical and ophthalmic history was elicited in each patient. Diagnosis was based on slit-lamp examination and fluorescein staining. Complete healing was defined as negative corneal fluorescein staining. Treatment outcome was considered successful if total corneal epithelial healing was achieved without requiring further additional interventions after initiation of nicergoline. Healing of the epithelial corneal defect was assessed by fluorescein staining and measurement by slit lamp. Impairment of corneal sensitivity was assessed at the initial diagnosis of NK with a cotton tip, but was not evaluated during treatment with nicergoline. Adverse events were checked by anamnesis in every follow-up visit. The diagnosis of microbial keratitis was excluded by culture of the corneal sample took by a sterile swab. 5 The study protocol was reviewed and approved by the Ethics Committee of Clinic Hospital of Barcelona. The data collection was done in compliance with the Declaration of Helsinki (October 2013). Results/case series: Fourteen eyes of 14 patients were reviewed. No patient had a bilateral NK during treatment with nicergoline. Eleven patients (79%) were females and three were males. The average age at consultation was 69 years (range 44-96). Herpes virus infection (one herpes simplex and two varicella zoster) were the most frequent aetiology (21%) of NK. The other causes of NK were: autoimmune condition in two patients, graft versus host disease (GVHD) in two patients, severe exophthalmos in a patient with active thyroidassociated orbitopathy, a patient with a history of lacrimal gland excision one year ago due to nodular fasciitis, a patient with toxic corneal epitheliopathy induced by topical treatment for severe glaucoma and in four patients during the postoperative period after corneal transplantation. Regarding patients with autoimmune disease, one had an ocular mucous membrane pemphigoid (treated with rituximab, mycophenolate and dapsone) and the other, severe dry eye disease secondary to a primary biliary cirrhosis in an advanced stage (the fellow eye had been eviscerated due to recurrent ocular perforations). Half of all patients had history of corneal transplantation (six penetrating keratoplasty and one Descemet Stripping Automated Endothelial Keratoplasty - DSAEK); three of them had received more than one graft. Three of the 14 patients were also diabetic. The mean time between diagnosis and the starting of nicergoline was 10.92 ± 8.85 days (0-28). In two cases (cases 1 and 8), nicergoline was started at the time of diagnosis of 6 the epithelial defect according to the Ophthalmologist criteria due to previous success in epithelial healing in other patients. These two cases were diagnosed as NK in Mackie’s stage 3 (stromal involvement, with associated epithelial defect) due to clinical characterised. The average of the largest diameter of epithelial defect at diagnosis was 4.0mm (0.5-9.0). Regarding the location of the epithelial defect, it was central in nine (64%) cases. The Mackie’s classification stage at diagnosis was stage 2 in three patients and stage 3 in nine patients. Two patients (cases 4 and 14) presented NK with an epithelial defect but with a duration of epithelial defect of less than 14 days at the time of initiation of nicergoline. In both cases, the margins of the defect were rolled and in case 4 there were also Descemet’s folds. Both clinical features (rolled margins and Descemet folds) are typical of NK. The baseline best corrected visual acuity (BCVA) for eight (57%) eyes was counting fingers or less. All patients were on artificial tears containing sodium hyaluronate, 79% were on topical antibiotics and 29% on oral antivirals prior to the initiation of nicergoline. Complete corneal healing was observed in 10 (71.4%) of the 14 patients after 25.6 ± 26.60 days (range 7-90) with nicergoline. In three (21.5%) patients the wound healing was not achieved (in case 9, the defect finally healed, but required amniotic membrane transplantation (AMT) therefore, a favourable outcome with nicergoline is not completely considered), In one patient (7.1%) there was a loss to follow-up, although a 50% reduction in the size of the epithelial defect was observed in the first visit after starting nicergoline. Corneal wounds healed one week after starting nicergoline in three eyes, between the first and second week in three eyes, in two patients wound healing was observed at 30 days and two eyes required more than one month (60 and 90 days, respectively). The mean epithelial defect duration was 10.92 ± 8.85 days (ranged from 0 to 28 days) and the treatment success duration was 25.63 ± 26.60 days (ranged from 7 to 7 90 days). Epithelial defect was separated within less than one week and more than one week. In less than one-week epithelial defect duration (2.83 ± 2.63 days) treatment success duration was 23.60 ± 22.41 days and in more than one-week epithelial defect duration (17.00 ± 6.50 days) treatment success duration was 27.33 ± 31.72 days (P = 0.83) During follow-up, we observed one case of recurrence after the total wound healing while nicergoline was ongoing. In this case, the treatment with nicergoline was maintained as well as the topical antibiotic and immunomodulator, and a therapeutic contact lens was placed. The epithelial defect healed successfully again after 10 days. . The mean duration of nicergoline treatment (taking into account all patients except the one with loss of follow-up) was 33 days (13-90). No adverse effects (AE) of nicergoline were observed in any subject. Overall, 3 (21%) patients required surgical procedures during treatment with nicergoline due to decompensation from their underlying disease: tectonic lamellar keratoplasty, AMT and symblepharon ring implant to treat an ocular perforation (26 days after starting nicergoline) in the patient who suffered mucous membrane pemphigoid, and amniotic membrane implantation because of persistence of epithelial defect in two patients (cases 5 and 9). The baseline characteristics and clinical evolution after starting nicergoline are summarized in Table 1 and Table 2, respectively. Figures 1 and 2 show healing of a neurotrophic epithelial corneal defect before and after treatment with nicergoline. Discussion: 8 Treatment of epithelial defect associated to NK remains as a challenging management in routine clinical practice. Adjunctive treatment with oral nicergoline has shown to be effective and safe in our case series. Under normal conditions, corneal nerve fibers release neuromediators (such as substance P) that provide trophic support to the ocular surface and maintaining the anatomical integrity. At the same time, epithelial cells release growth factors such as nerve growth factor (NGF) that stimulate the differentiation and maturation of the corneal nerve fibers and epithelial cells.8 NK etiopathology leads to spontaneous epithelial breakdown and corneal ulceration. The management of this condition currently is a challenge due to the lack of pathophysiology treatments targeting nerve regeneration. To overcome this limitation, the use of neuropeptides and NGF for the treatment of NK is being evaluated in several promising studies. It has been observed in various studies that the combination of substance P and insulin-like growth factor-1 induces a synergistic effect; as an example, in 26 eyes with NK-associated persistent epithelial defect, the epithelial defects resurfaced completely in 73% of the cases within 4 weeks after treatment.9 Recently, the NGF0214 trial evaluated the use of topical recombinant human NGF. At 8 weeks, 69.6% of NGF-treated patients achieved <0.5mm staining lesion vs 29.2% vehicle-treated patients.10 Similar results were obtained in the REPARO phase II study.11 The use of topical insulin in refractory epithelial defect has also been successfully evaluated.12 In this group of therapies targeting the pathogenic mechanisms of NK, nicergoline may play an important role. In vivo studies demonstrated that nicergoline has a protective effect on the degeneration of cholinergic neurons induced by NGF deprivation in the brain of aged rats.13 Based on these findings, the effect of nicergoline on corneal tissue has been evaluated. 15 One week after starting nicergoline, a 50% decrease in the size of the ulcer was observed. Table 1. Summary of baseline characteristics. Case Age/ Sex Affected Eye Underlying Condition BCVA (Decimal) Mackie Classification Stage Wound Location Largest Diameter of Epithelial Corneal Defect (mm) 1 92/F R Toxic corneal epitheliopathy/Diabetes 0,05 3 Central 2 2 77/F L Ocular pemphigoid CF 3 Inferior 5 3 71/F R Graft rejection after PK 0,1 3 Central 6 4 73/F R Postoperative of PK CF * Central 4 5 49/F R Primary biliary cirrhosis/Postoperative of PK CF 3 (corneal melting) Central 6,5 6 78/M L Lacrimal gland excision CF 3 Nasal 2,5 7 72/F L Herpes simplex keratitis/PK Postoperative HM 2 Inferior Interface host-donor (IV–VIII hours) 8 51/F L PK Postoperative HM 3 Central 2,5 9 70/F L Severe thyroid-associated orbitopathy LP 3 Central 9 10 73/F L Ocular GVHD (recurrent corneal melting in 0.16 2 Central 3,5 the other eye) 11 56/F L Ocular GVHD (PK 5 years ago) CF 3 (corneal melting) Central 3 12 71/M R DSAEK postoperative/Diabetes 0,2 3 Central 6 13 96/F L Herpes zoster keratitis 0,1 2 Inferior 0,5 14 44/M L Herpes zoster keratitis/Diabetes 0,5 * Temporal 2 *: Patient with neurotrophic keratitis without stromal involvement, and an epithelial defect of less than 14 days. BCVA: best corrected visual acuity; F: female; M: male; R: right; L: left; PK: penetrating keratoplasty; GVHD: graft versus host disease; DSAEK: Descemet stripping with automated endothelial keratoplasty; CF: counting finger; HM: hand movement; LP: light perception. Table 2. Summary of the clinical course of the patients. Case Previous Treatment (excluding artificial tears) Time between Diagnosis and Nicergoline (days) Time to complete Healing from Nicergoline (days) Days on nicergoline Treatment Recurrence Surgery 1 - 0 30 42 No No 2 Oral valaciclovir, oral doxycycline, chloramphenicol, dexamethasone 3 Netilmicin, therapeutic soft contact lens 14 8 - 30 25 14 - No Tectonic LK Symblepharon ring No 4 Ofloxacin 3 60 80 No No 5 Ofloxacin, therapeutic soft contact lens 28 - 30 - AMT 6 Vancomycin, ceftazidime 3 7 37 No No 7 Oral valaciclovir, ofloxacin 14 13 13 No No 8 Netilmicin, ofloxacin, therapeutic soft 0 7 14 No No 9 contact lens Vancomycin, ceftazidime, doxycycline, 24 14 14 No AMT 10 amphotericin Ofloxacin, doxycycline, ciclosporin, 14 10 40 Yes No tacrolimus 11 Doxycycline, moxifloxacin 7 14 14 No No 12 Ofloxacin, therapeutic soft contact lens 20 90 90 No No 13 Oral valaciclovir 14 7 14 No No 14 Oral valaciclovir 4 NA* NA NA No *: 50% reduction in the diameter of the defect in the first control, subsequently the follow-up was lost. NA: not available; LK: lamellar keratoplasty; AMT: amniotic membrane transplantation.