Neurotrophic Corneal Ulcers Research Articles

Gómez-López-Hernández syndrome: another consideration in corneal neurotrophic ulcers

To report a case of a Gómez-López-Hernández syndrome (GLHS) variant with corneal neurotrophic ulcer. Case report and review of the literature. A 6-year-old child presented with watering in the right eye for 3 days without ocular inflammation or pain. He had a peculiar facial phenotype and scalp alopecia in the right side. Slit-lamp examination showed an epithelial defect in the right eye and a corneal scar around the defect. Belmonte noncontact esthesiometry showed reduced corneal mechanosensory and thermal sensitivity. In vivo confocal microscopy revealed the absence of innervation in the right cornea. There was also an evident insensitivity in the alopecic region. Despite normal magnetic resonance imaging, the phenotypic manifestations along with ocular features suggested the diagnosis of a GLHS variant. Patients with GLHS remain asymptomatic even when they develop a corneal ulcer. Parents should be advised regarding the susceptibility of an affected child to the development of corneal lesions and the importance of regular follow-up and prompt treatment to prevent vision-threatening abnormalities.

Prospective study of a new matrix therapy agent (RGTA) for the treatment of neurotrophic ulcers

AbstractPurpose To evaluate the efficacy of a new matrix therapy agent (RGTA, Cacicol®), an analogue of heparan sulphates, for management of severe neurotrophic keratopathy.Methods We carried out a prospective, single‐centre, uncontrolled study of 11 eyes in 11 patients, presenting corneal neurotrophic ulcers, despite use of preservative‐free artificial tears for 15 days. Mean age was 58 years. All patients had corneal anaesthesia. RGTA treatment was instilled in the morning,as the fist eyedrop, on alternate days. Main outcome measures were for each patient healing of the corneal surface and best corrected visual acuity during and after treatment.Results Eight patients displayed complete healing of the ulcer, after a mean period of 8.7 weeks (range; 1 to 22 weeks). Mean ulcer area decreased significantly, from 11.12% to 6.37% (p=0.0479) in the first week, to 1.56% (p=0.0054) at one month. Treatment failure was observed in three cases, requiring amniotic membrane transplantation in two patients and penetrating keratoplasty in one patient. At the end of the study, none of the patients displayed a significant improvement in visual acuity. None of the patients reported pain or discomfort during instillation of RGTA eyedrops.Conclusion This heparin mimetic, which may stimulate extracellular matrix healing, may be a possible, non‐invasive, alternative therapy in severe neurotrophic keratopathy. However, randomized studies are necessary.

Graft Failure as a Secondary Complication of Herpetic Neurotrophic Corneal Ulcer Treatment in a Patient With a History of Descemet's Stripping Automated Endothelial Keratoplasty and Penetrating Keratoplasty: A Case Report and Review

Graft Failure as a Secondary Complication of Herpetic Neurotrophic Corneal Ulcer Treatment in a Patient With a History of Descemet's Stripping Automated Endothelial Keratoplasty and Penetrating Keratoplasty: A Case Report and Review

Neurotrophic Corneal Ulcer Development Following Cataract Surgery with a Limbal Relaxing Incision

A 60-year-old man with bilateral corneal opacity underwent cataract extraction surgery involving the use of a limbal relaxing incision in his left eye. He had lower lid ectropion and lagophthalmos in both eyes. Eleven days after the surgery, a slit-lamp examination revealed a neurotrophic corneal ulcer with a punch-out epithelial defect and rolled edges at the center of the pre-existing corneal opacity. The patient was treated with sodium hyaluronate, autologous serum, and oral doxycycline. Six weeks after the surgery an improvement in corneal sensation was observed and the neurotrophic corneal ulcer subsequently healed over the course of one year. In this report, we present a case of neurotrophic keratitis that occurred after performing cataract surgery concurrent with a limbal relaxing incision. As such, we suggest that limbal relaxing incisions should be performed cautiously in patients with causative risk factors for corneal hypesthesia.

Neurotrophic corneal ulcer in an HIV patient

Case reportWe present the case of a 29 year-old man who came to the Emergency Department due to pain in the right eye. There was demonstrated a complete corneal deepithelialisation. There was no clinical improvement after appropriate treatment, which was complicated by migraine and vomiting. The computerized tomography (CT) scan showed images suggestive of cerebral toxoplasmosis. After the complete tarsorrhaphy a restitution ad integrum was observed. ConclusionThe diagnosis of a neurotrophic corneal ulcer due to an affected trigeminal nerve in the context of a cerebral toxoplasmosis, tarsorrhaphy is an effective procedure to take in account in corneal epithelial defects resistant to other treatments.

Treatment of a neurotrophic corneal ulcer with solid platelet-rich plasma and Tutopatch®

Case reportsWe present the case of a patient with neurotrophic queratitis in the left eye treated with a Tutopatch® cover and platelet-rich plasma (PRP). Solid autologous PRP was placed in the bed of the ulcer and Tutopatch® was sutured to the conjunctiva. DiscussionWe found this form of treatment very effective for progressive ulcers. Tutopatch® may constitute an alternative to amniotic membrane transplantation.

Úlcera corneal neurotrófica en paciente con VIH

Case report We present the case of a 29 year-old man who came to the Emergency Department due to pain in the right eye. There was demonstrated a complete corneal de-epithelialisation. There was no clinical improvement after appropriate treatment, which was complicated by migraine and vomiting. The computerized tomography (CT) scan showed images suggestive of cerebral toxoplasmosis. After the complete tarsorrhaphy a restitution ad integrum was observed. Conclusion The diagnosis of a neurotrophic corneal ulcer due to an affected trigeminal nerve in the context of a cerebral toxoplasmosis, tarsorrhaphy is an effective procedure to take in account in corneal epithelial defects resistant to other treatments.

Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin β4

Neurotrophic corneal defects are difficult to heal and all too often lead to scarring and vision loss. Medical management is often of limited success. We describe the results of nine patients (ages 37-84) with chronic nonhealing neurotrophic corneal epithelial defects who were treated with thymosin beta 4 (Tbeta4) sterile eye drops for 28 or 49 days with a follow-up period of 30 days. Those with geographic defects (six patients) showed dramatic healing without clinically significant neovascularization. Stromal thinning was observed in one patient. Three patients with punctate epithelial defects did not have a demonstrable change in their clinical findings. Reduced ocular irritation was reported by all patients soon after treatment initiation. Results from these compassionate use cases indicate that Tbeta4 may provide a novel, topical approach to wound healing in chronic nonhealing neurotrophic corneal ulcers.

Isolated Bilateral Trigeminal Neuropathy in Sarcoidosis Presenting with Neurotrophic Corneal Ulcers

Sarcoidosis is a multisystem granulomatous disease that may affect various organs. Nevertheless, involvement of the trigeminal nerve is exceedingly uncommon. This report presents a rare case of isolated bilateral trigeminal neuropathy presenting with neurotrophic corneal ulcers. The patient was treated with topical chloramphenicol and lubricants, as well as botulinum toxin injection to the upper eyelid to induce ptosis. Our case illustrates the importance of recognizing that bilateral corneal ulceration might be a manifestation of sarcoidosis. Physicians should be aware of this rare association, when treating sarcoidosis patients with eye related symptoms.

Nerve growth factor eye drops to treat glaucoma

Since the discovery of nerve growth factor (NGF) in the 1950s, scientists have had great expectations for NGF in the treatment of neurodegenerative diseases. The main obstacle to overcome was the blood-brain barrier, which NGF does not cross when administered systemically. Our research group has recently demonstrated that topically instilled NGF eye drops are effective in treating several ocular diseases such as neurotrophic and autoimmune corneal ulcers. Pharmacodynamic studies have also shown that NGF eye drops have the ability to target the optic nerve and brain, thus finally opening-up avenues of research in pursuit of a novel drug for neurodegenerative diseases. In this review, clinical trials of systemically and topically administered NGF are discussed, as well as recent progress in the production of biologically active recombinant human NGF and innovative delivery routes. The pharmacological activity of NGF eye drops in ocular surface, retina and optic nerve diseases are also discussed.

Role of epidermal growth factor receptor (EGFR) in corneal remodelling in diabetes

This study examined the role of epidermal growth factor receptor (EGFR) signalling on the organization and remodelling of collagen fibrils (CFs) and proteoglycans (PGs) in the stroma of diabetic rat cornea. Diabetes was induced in female Wistar rats (n = 5) by streptozotocin (STZ) injection (55 mg/kg). Treatment with a selective inhibitor of EGFR tyrosine kinase, AG1478, was started on the same day as the induction of diabetes and administered every other day for 4 weeks. Corneas were fixed in 4% paraformaldehyde at 4 degrees to allow for analysis of CF diameters and in 2.5% glutaraldehyde in sodium acetate buffer containing cuprolinic blue to enable the study of PG distribution. AnalySIS soft imaging software was used to analyse CFs and PGs. Epithelial thickness, and median diameter and area fraction of CF in corneal stroma were decreased in diabetic rat cornea compared with normal cornea (p < 0.001), whereas the median PG area and area fractions were significantly increased (p < 0.001). Treatment with AG1478, although it had no action on normal cornea, prevented these diameter and area fraction changes in CFs and PGs. The cornea of AG1478-treated diabetic rats showed a slight increase in CF diameter and area fraction and a decreased number density. These data show that the distribution of corneal stroma CFs and PGs was altered after 4 weeks of diabetes and that, furthermore, treatment with an EGFR signalling inhibitor normalized these abnormalities. The data suggest that EGFR plays an important role in the development of diabetes-induced corneal remodelling.

Observation à l’OCT Visante® de l’évolution d’un ulcère cornéen neurotrophique perforant traité par greffes de membranes amniotiques

The optical coherence tomography (OCT) Visante provides easy, high-resolution observation free of contact with the cornea and anterior segment. We present the progression of a neurotrophic corneal ulcer treated with amniotic membrane grafts studied with this system. A 71-year-old patient with facial nerve paresis secondary to vestibular schwannoma surgery presented with a neurotrophic perforated corneal ulcer. Since medical treatment had failed, we performed an amniotic membrane graft. The OCT Visante was used for follow-up for 2 months. Progression was slow but the perforation eventually closed. Cicatrization of the corneal ulcer was followed with the OCT Visante to document the healing process and corneal thickness. Optical coherence tomography Visante provides easy visualization and high-resolution documentation with no contact with the healing corneal ulcerations.

Neurotrophic ulcer after extra-capsular cataract operation

Although neurotrophic ulcers due to herpes zoster are seldom, there may be challenging cases. Especially neurotrophic corneal ulcers after cataract operations should arise the possibility of a previous herpes zoster attack and the treatment plan should be prepared accordingly. This case highlights the importance of thorough evaluation of cataract patients in order not to miss a previous diagnosis of herpes.

Effects of the Human Amniotic Membrane on Axonal Outgrowth of Dorsal Root Ganglia Neurons in Culture

Purpose: In order to investigate the potential underlying neurotrophic mechanisms of human amniotic membrane (AM) in the treatment of neurotrophic corneal ulcers, we evaluated whether or not there are significant differences in the neuritic growth of neuronal cell cultures on different surfaces of AM. Methods: Neurite outgrowth of dorsal root ganglia neurons was examined under two separate conditions: (1) in serum-free medium consisting of minimal essential medium (MEM), glucose, and L-glutamine, (2) in same medium additionally supplemented with horse serum, chick embryonic extract, and nerve growth factor. Neuritic outgrowth was labeled with antibodies against neurofilaments and tubulin and screened by confocal laser scanning microscopy. Moreover, Western blot analysis was performed with antibodies to neuronal cell adhesion molecule (NCAM), L1, pan-cadherin, semaphorin-3F, as well as various ephrins. Results: The basement membrane and the stromal surface promoted the outgrowth of an extensive neuritic network, whereas the epithelial surface did not. Interestingly, these differences of neuritic growth were evident in cell cultures treated with serum-free medium lacking neurotrophic factors and in standard medium containing neurotrophic factors. Western blot analysis revealed an abundant expression of ephrin A4 in intact AM but not in epithelium-denuded AM, and no significant difference of pan-cadherin and NCAM expression was found in intact AM compared with denuded AM. Additionally, no expression of L1, semaphorin-3F, and the ephrins A1, A2, B1, and B3 was detected. Conclusions: This study shows that AM exhibits location-dependent neuritic growth–promoting effects that might influence the clinical outcome of (amniotic membrane transplantation) in neurotrophic conditions.

Nerve growth factor effect on human primary fibroblastic-keratocytes: Possible mechanism during corneal healing

In response to corneal injury, cytokines and growth factors play a crucial role by influencing epithelial-stromal interaction during the healing and reparative processes which may resolve in tissue remodeling and fibrosis. While transforming growth factor-β1 (TGF-β1) is considered the main profibrogenic modulator of these process, recently the nerve growth factor (NGF) appears as a pleiotropic modulator of wound-healing and inflammatory responses. Interestingly in the cornea, where NGF, trkA NGFR and p75 NTR are expressed by epithelial cells and keratocytes, the NGF eye-drop induces the healing of neurotrophic or autoimmune corneal ulcers. During corneal healing, quiescent keratocytes are replaced by active fibroblast-like keratocytes/myofibroblasts. While the NGF effect on epithelial cells has been investigated, no data are reported for NGF effects on fibroblastic-keratocytes, during corneal healing. NGF, trkA NGFR and p75 NTR were found expressed by fibroblastic-keratocytes. NGF was able to induce fibroblastic-keratocyte differentiation into myofibroblasts, migration, Metalloproteinase-9 expression/activity and contraction of a 3D collagen gel, without affecting their proliferation and collagen production. These data also show a two-directional control of fibroblastic-keratocytes by NGF and TGF-β1. To sum up, the findings of this study indicate that NGF can modulate some functional activities of fibroblastic-keratocytes, thus substantiating the healing effects of NGF on corneal wound-healing.

Use of Nerve Growth Factor to Treat Congenital Neurotrophic Corneal Ulceration

This study was designed to assess the efficacy of nerve growth factor in the treatment of neurotrophic corneal ulceration in a child with bilateral congenital corneal anesthesia secondary to trigeminal insufficiency. A 5-month-old child presented to the casualty department with a 2-week history of red eyes and right corneal ulceration. Slit-lamp examination showed a central defect in the right corneal epithelium with underlying stromal opacification, only mild conjunctival inflammation with slight decreased tear production, and otherwise apparently normal eyes. Initially this was investigated as an infected ulcer and treated for several weeks as herpetic ulceration with no beneficial effect. Further clinical examination demonstrated bilateral decreased corneal sensation along with decreased facial sensation in keeping with congenital trigeminal nerve insufficiency. Investigation with magnetic resonance imaging showed no obvious abnormality. Conservative treatment with lubricants resulted in progressive right corneal stromal loss, and no healing occurred in the left corneal ulcer. Bilateral large lateral tarsorrhaphies were performed. Despite this, the left corneal ulcer demonstrated no improvement and increasing stromal opacification was noted. Topical nerve growth factor (NGF) was then used to treat the left cornea and resulted in epithelial healing within 1 week. Treatment was continued for a further 10 days after epithelial healing. Despite conventional treatment on 3 separate occasions, further epithelial breakdown occurred. Topical NGF treatment resulted in a rapid improvement and healing of the epithelial defect.'At present, the patient is receiving a 6-month continuous treatment plan of NGF. Persistent epithelial defects (PED) secondary to neurotrophic ulceration have responded to topical NGF on 3 separate occasions during a 2-year period. The corneal epithelium now remains intact, and the cornea has no vascularization; however, mild anterior stromal opacification has gradually increased despite prolonged NGF treatment. NGF seems to represent a safe and efficacious treatment option to restore the integrity of corneal epithelium in which there is congenital corneal anesthesia because of trigeminal insufficiency. However, this treatment alone is insufficient to prevent progressive anterior stromal opacification.

The Use of Nerve Growth Factor in Surgical Wound Healing of the Cornea

Background: Recent studies have shown how the topical application of nerve growth factor (NGF) has led to the repair of neurotrophic corneal ulcers with recovery of corneal surface sensitivity. The biological effect of NGF, at a corneal level, is mediated by the presence of specific receptors localized on the surfaces of the corneal and conjunctival cells. Objectives: To evaluate the efficacy of NGF to promote corneal wound healing after cataract surgery. Methods: Thirty patients were divided into two groups (groups A and B) and underwent cataract surgery. After surgery patients in group A received 1 drop of NGF solution (10 µg of NGF dissolved in 50 µl of saline solution, 0.9% of sodium chloride) in the conjunctival fornix every 2 h (from 6 a.m. to 12 p.m.) for 2 weeks and then 4 times a day for another week. The patients in group B received 1 drop of hyaluronic acid 0.2% eye drops in the conjunctival fornix every 2 h for 2 weeks and then 4 times a day for another week. With optical coherence tomography (OCT) we evaluated the corneal thickness at the side of the surgical wound, the endothelial cell count and the incision line in the stroma 1, 7 and 21 days after surgery. Results: Before surgery in group A and in group B, the endothelial cell count was 2,607.4 ± 261.0 versus 2,602.0 ± 266.6 (p < 0.991), and the temporal cornea edge thickness was 639.2 ± 24.7 versus 644.4 ± 31.9 µm (p < 0.605), respectively. At 24 h after surgery, the results were: 2,523.2 ± 280.5 versus 2,528.2 ± 235.7 (p < 0.988) and 804.4 ± 29.5 versus 802.6 ± 35.0 µm (p < 0.953). After 7 days the cell count values were: 2,511.4 ± 229.8 versus 2,490.0 ± 230.4 (p < 0.361) and corneal thickness 713.6 ± 16.5 versus 771.4 ± 36.5 µm (p < 0.047). Finally, 21 days after surgery, the number of endothelial cells was 2,540.2 ± 237.3 versus 2,503.4 ± 224.5 (p < 0.382) and corneal thickness 645.2 ± 22.6 versus 704.2 ± 11.8 µm (p < 0.002). In the patients treated with NGF, on day 21, we found with OCT a complete wound healing, and the stromal incision was not visible. Conclusions: This clinical experience shows that the topical administration of NGF is effective in accelerating the healing of surgical corneal wounds.

Amniotic membrane transplantation in refractory corneal ulcers. A randomized, controlled clinical trial

This study compared the efficacy of amniotic membrane transplantation with conventional management (tarsorrhaphy and bandage contact lens) in eyes with refractory neurotrophic corneal ulcers. Thirty eyes of 30 patients (14 males and 16 males; mean age = 37 ± 14.71 years) with neurotrophic corneal ulcers that had persisted for at least 4 weeks and were sterile on microbiologic examination were included and randomly divided into group 1 (n = 15), who received conventional management with a tarsorrhaphy (n = 11) or bandage contact lens (n = 4), and group 2 (n = 15) who underwent amniotic membrane transplantation (AMT). At the end of 3 months of follow-up, 10 (66.7%) eyes in group 1 and 11 (73.3%) eyes in group 2 showed complete re-epithelialization (P > .05). The median time for re-epithelialization in both groups was 21 days. Both groups showed similar improvement in best-corrected visual acuity. The conclusion was that both conventional therapy and amniotic membrane transplantation are effective treatment modalities for refractory neurotrophic corneal ulcers.—Michael D. Wagoner

Amniotic Membrane Transplantation in Refractory Neurotrophic Corneal Ulcers

This study was designed to compare and evaluate the efficacy of amniotic membrane transplantation with the conventional management (tarsorrhaphy and bandage contact lens) in eyes with refractory neurotrophic corneal ulcers. Thirty eyes of 30 patients (14 females and 16 males) with neurotrophic corneal ulcers refractory to medical management were included and divided randomly into group 1 (n = 15), who received conventional management with a tarsorrhaphy (n = 11) or bandage contact lens (n = 4), and group 2 (n = 15), who underwent Amniotic Membrane Transplantation. The outcome parameters evaluated were epithelialization time, duration of healing of corneal ulcers, and improvement in best corrected visual acuity. The mean age in our study was 37 +/- 14.71 years. At the end of 3 months follow-up, 10 of 15 patients (66.67%) in group 1 showed complete epithelialization and subsequent healing and 11 of 15 patients (73.33%) in group 2 showed complete epithelialization and healing (P > 0.05). The median time for complete epithelialization was 21 days in both groups. Both groups showed an improvement in the best-corrected visual acuity. Both amniotic membrane transplantation and conventional management (tarsorrhaphy or bandage contact lens) are effective treatment modalities for refractory neurotrophic corneal ulcers.

Suspension Made with Amniotic Membrane: Clinical Trial

To investigate if a suspension made with amniotic membrane could have a beneficial effect on ocular surface diseases. In the Imola branch of the Eye Bank of Emilia Romagna, the authors prepared a suspension containing homogenized amniotic membrane previously conserved at -80 degrees Celsius. Subsequently, the authors gave this preparation to 21 patients: 8 had undergone lamellar keratoplasty, 4 had undergone penetrating keratoplasty, 2 had undergone photorefractive keratectomy with a delay of epithelialization, 3 had neurotrophic corneal ulcers, 2 had corneal burning, 1 had torpid corneal ulcer, and 1 had Sjogren syndrome. Each patient had been treated with conventional therapy for at least, 4 months without any clinical improvement. In this sample of eyes the authors evaluated the transparency and integrity of epithelium before and after the therapy by means of a fluorescein staining test, examining the area of epithelial defect as well as the phlogistic situation and the symptoms referred by patients. Nine eyes from this group of patients were studied by impression cytology before and after 3 months of use of suspension. The follow-up was 5 months of once-weekly visits. In all patients, after 15 to 30 days the corneas became negative to fluorescein staining test and the epithelium seemed more complete and regular, there was an evident decrease of phlogistic situation in the conjunctiva, and an improvement of symptoms was referred by patients. The situation was stable during the whole follow-up. No side effects were noted. The impression cytology repeated 3 months after the treatment showed a significant corneal recovery of the cytologic situation with an important decrease of CK19+ cells on the corneal surface. This new therapy, which is less traumatic than an implant of amniotic membrane, is safe, and can be repeated for a long period, could help patients with corneal superficial defects.