To evaluate corneal healing in patients with moderate and severe neurotrophic keratitis (NK) treated with topical rh-NFG (Cenegermin).
Methods
Twenty-one patients (12F and 9M) aged from 21 to 93 years (62.5 ± 19.4) with moderate and severe NK were enrolled in the study. The patients were divided into 2 groups accordingly to the severity of the disease. The underlying causes of NK were determined. The VAS questionnaire was dispensed. The ocular examination comprised slit lamp evaluation, ocular surface assessment with Keratograph 5M (Oculus, Germany), corneal sensitivity with Cochet-Bonnet esthesiometer (Lunneaux, France) and corneal thickness measurement with AC-OCT (DRI, Triton, Topcon, Japan). The drops of Cenegermin 0.002% were administrated 6 times daily for 8 weeks. All participants were evaluated at baseline, after 4 and 8 weeks of the treatment. The area of corneal defect with maximum diameter less than 0.5 mm was considered as healed. The main outcome measures were corneal healing, corneal sensitivity recovery and corneal thickness in the ulcer group.
Results
The herpetic keratitis was the most common cause of NK. Thirteen eyes were affected by severe grade of NK with corneal ulcer and 8 eyes presented a moderate grade. After 8 weeks a complete healing of the corneal defects was registered both in moderate and severe NK. Significant increase of the corneal sensitivity and thickness were registered.
Conclusions
The rh-NGF (Cenegermin) resulted effective in the treatment of the severe and moderate NK with significant recovery of the corneal sensitivity and healing of the corneal defects in both groups.
MarfurtCFCoxJDeekS, et al.Anatomy of the human corneal innervation. Exp Eye Res2010; 90: 478–492.
2.
LabetoulleMBaudouinCCalongeM, et al.Role of corneal nerves in ocular surface homeostasis and disease. Acta Ophthalmol2019; 97: 137–145.
3.
MüllerLJMarfurtCFKruseF, et al.Corneal nerves: structure, contents and function. Exp Eye Res2003; 76: 521–542.
4.
Al-AqabaMAAnisFSMohammedI, et al.Nerve terminals at the human corneoscleral limbus. Br J Ophthalmol2018; 102: 556–561.
5.
ShaheenBSBakirMJainS. Corneal nerves in health and disease. Surv Ophthalmol2014; 59: 263–285.
6.
YouLKruseFEVölckerHE. Neurotrophic factors in the human cornea. Invest Ophthalmol Vis Sci2000; 41: 692–702.10711683
7.
ChenLWeiRHTanDT, et al.Nerve growth factor expression and nerve regeneration in monkey corneas after LASIK. J Refract Surg2014; 30: 134–139.
8.
DiGQiXZhaoX, et al.Corneal epithelium-derived neurotrophic factors promote nerve regeneration. Invest Ophthalmol Vis Sci2017; 58: 4695–4702.
9.
BoniniSRamaPOlziD, et al.Neurotrophic keratitis. Eye (Lond)2003; 17: 989–995.
10.
ArakiKOhashiYKinoshitaS, et al.Epithelial wound healing in the denervated cornea. Curr Eye Res1994; 13: 203–211.
11.
SemeraroFForbiceEBragaO, et al.Evaluation of the efficacy of 50% autologous serum eye drops in different ocular surface pathologies. Biomed Res Int2014; 2014: 826970.25136628
12.
DuaHSSaidDGMessmerEM, et al.Neurotrophic keratopathy. Prog Retin Eye Res2018; 66: 107–131.
13.
SacchettiMLambiaseA. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol2014; 8: 571–579.24672223
14.
MastropasquaLNubileMLanziniM, et al.In vivo microscopic and optical coherence tomography classification of neurotrophic keratopathy. J Cell Physiol2019; 234: 6108–6115.
15.
DonnererJSchuligoiRSteinC. Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience1992; 49: 693–698.
16.
BrownSMLambertsDWReidTW, et al.Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1. Arch Ophthalmol1997; 115: 926–927.
17.
TripathiBJKwaitPSTripathiRC. Corneal growth factors: a new generation of ophthalmic pharmaceuticals. Cornea1990; 9: –9.
18.
Di ZazzoAVaracalliGMoriT, et al.Long-term restoration of corneal sensitivity in neurotrophic keratopathy after rhNGF treatment. Eur J Ophthalmol2020; 27: 1120672120953343.
19.
VersuraPGiannaccareGPellegriniM, et al.Neurotrophic keratitis: current challenges and future prospects. Eye Brain2018; 10: 37–45.
20.
LambiaseARamaPBoniniS, et al.Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med1998; 338: 1174–1180.
21.
BoniniSLambiaseARamaP, et al.REPARO study group. Phase I trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology2018; 125: 1468–1471.
22.
BoniniSLambiaseARamaP, et al.REPARO study group. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology2018; 125: 1332–1343.
23.
PflugfelderSCMassaro-GiordanoMPerezVL, et al.Topical recombinant human nerve growth factor (Cenegermin) for neurotrophic keratopathy: a multicenter randomized vehicle-controlled pivotal trial. Ophthalmology2020; 127: 14–26.
24.
NornMS. Measurement of sensitivity. In: NornMS (ed) External eye diseases. Methods of examination. Copenhagen, Denmark: Munksgaard International Publisher Ltd, 1974.
25.
BelmonteCAcostaMCSchmelzM, et al.Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer. Invest Ophthalmol Vis Sci1999; 40: 513–519.
26.
HamrahPCruzatADastjerdiMH, et al.Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology2010; 117: 1930–1936.
27.
LockwoodAHope-RossMChellP. Neurotrophic keratopathy and diabetes mellitus. Eye (Lond2006; 20: 837–839.
28.
PortnoySLInslerMSKaufmanHE. Surgical management of corneal ulceration and perforation. Surv Ophthalmol1989 Jul-Aug; 34: 47–58.
29.
LugoMArentsenJJ. Treatment of neurotrophic ulcers with conjunctival flaps. Am J Ophthalmol1987; 103: 711–712.
30.
LeeSHTsengSC. Amniotic membrane transplantation for persistent epithelial defects with ulceration. Am J Ophthalmol1997; 123: 303–312.
31.
KhokharSNatungTSonyP, et al.Amniotic membrane transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea2005; 24: 654–660.
32.
ChenHJPiresRTTsengSC. Amniotic membrane transplantation for severe neurotrophic corneal ulcers. Br J Ophthalmol2000; 84: 826–833.
33.
KruseFERohrschneiderKVölckerHE. Multilayer amniotic membrane transplantation for reconstruction of deep corneal ulcers. Ophthalmology1999; 106: 1504–1510.
34.
MackieIA. Neuroparalytic keratitis. In: FraunfelderFTRoyFHGroveJ (eds) Current ocular therapy. 4th ed. Philadelphia: W. B. Saunders, 1995, pp.452–454.
35.
TurkogluECelikEAlagozG. A comparison of the efficacy of autologous serum eye drops with amniotic membrane transplantation in neurotrophic keratitis. Semin Ophthalmol2014; 29: 119–126.
36.
MatsumotoYDogruMGotoE, et al.Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology2004; 111: 1115–1120.
37.
QuintoGGCamposMBehrensA. Autologous serum for ocular surface diseases. Arq Bras Oftalmol2008; 71: 47–54.
38.
Lopez-PlandolitSMoralesMCFreireV, et al.Plasma rich in growth factors as a therapeutic agent for persistent corneal epithelial defects. Cornea2010; 29: 843–848.
39.
JengBHDuppsWJJr. Autologous serum 50% eyedrops in the treatment of persistent corneal epithelial defects. Cornea2009; 28: 1104–1108.
40.
RaoKLevequeCPflugfelderSC. Corneal nerve regeneration in neurotrophic keratopathy following autologous plasma therapy. Br J Ophthalmol2010; 94: 584–591.
41.
AifaAGueudryJPortmannA, et al.Topical treatment with a new matrix therapy agent (RGTA) for the treatment of corneal neurotrophic ulcers. Invest Ophthalmol Vis Sci2012; 53: 8181–8185.
42.
GuerraMMarquesSGilJQ, et al.Neurotrophic keratopathy: therapeutic approach using a novel matrix regenerating agent. J Ocul Pharmacol Ther2017; 33: 662–669.
43.
DunnSPHeidemannDGChowCY, et al.Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta4. Ann N Y Acad Sci2010; 1194: 199–206.
44.
FerrariMPMantelliFSacchettiM, et al.Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. BioDrugs2014; 28: 275–283.
45.
MastropasquaL LanziniMDuaHS, et al.In Vivo Evaluation of Corneal Nerves and Epithelial Healing After Treatment With Recombinant Nerve Growth Factor for Neurotrophic Keratopathy. Am J Ophthalmol. 2020; 217: 278–f286.
