Article

Neurotrophic Keratopathy: New Treatment Strategies

By Kenneth R. Kenyon, MD and Deborah Pavan-Langston, MD, FACS

SPECIAL REPORT

Neurotrophic Keratopathy: New Treatment Strategies

By Kenneth R. Kenyon, MD and Deborah Pavan-Langston, MD, FACS

Among the major determinants of ocular surface health, specifically tears, lids, blinks, stem cells and sensation, the latter is frequently the most important. With loss of sensory function of the nasociliary branch of the trigeminal nerve, neurotrophic keratopathy will develop and result in degenerative corneal and conjunctival changes of varying severity.1 Minor manifestations include conjunctival and corneal punctate epithelial irregularity (fluorescein or rose bengal staining) with or without decreased tear production or decreased tear film stability (accelerated breakup time). However, such abnormalities can also progress to involve persistent corneal epithelial defects, stromal inflammatory reaction and most ominously, enzymatic stromalysis with ulceration potentially leading to perforation (Figure 1).

Figure 1. Following herpes simplex keratitis, neurotrophic changes result in persistent epithelial defect, stromal inflammatory infilration and sterile stromalysis (“melting”).

Clinical Evaluation

Apart from seeing specific etiologic cause(s)(Table 1), careful clinical evaluation is vital to assess risk factors and concomitant contributory conditions as well as to devise and optimize management. This is done not only by determining corneal sensation itself (by thin wisp of cotton applicator, waxed dental floss [3 cm.] or Cochet-Bonnet aesthesiometer), but also by blink adequacy and frequency, tear function (basic Schirmer + staining) and meibomian gland dysfunction (MGD). Additionally, lid malposition and keratinization disorders must be assessed as these multiple co-morbidities can also be contributory.3

Table 1. Etiology
Multiple ocular and systemic causes can be responsible for neurotrophic keratopathy.
Potential Ocular CausesPotential Systemic Causes
► Herpes zoster or simplex2► Trigeminal nerve palsy: (trigem neuralgia), tumor (acoustic neuroma), aneurysm, facial trauma
► Ocular surface injury (chemical/thermal burn)► Diabetes mellitus
► Multiple surgical procedures (cornea, refractive, glaucoma, conjunctiva, vitreo-retinal)► Vitamin A deficiency
► Topical drugs (glaucoma, anesthesia, eye drop preservatives)► Congenital (Riley-Day), Goldenhaar, Bassen-Kornzweig
► Corneal dystrophy (lattice, granular)► Aging
► Contact lens wear
► Infection ficanthamoeba, leprosy, Lyme)
► Other chronic epithelial injury and/or stromal inflammation

Conventional Management

There are multiple management strategies, and, depending on the degree of severity, these must be escalated and combined so “the punishment fits the crime.” Traditional medical and surgical approaches include: preservative-free lubricants (artificial tears, gels and ointments of varying viscosity), autologous serum drops (20% in sterile physiologic saline or non-preserved tears), topical steroid and non-toxic antibiotic prophylaxis, MGD management, therapeutic soft contact lenses (e.g. Kontur [Kontur Lens Co.], Permalens [CooperVision], Acuvue Oasys [Johnson & Johnson]) or Boston scleral lens [PROSE, Boston Foundation for Sight], punctal occlusion, moist chamber glasses, lid taping, lid malposition repair, lateral tarsorrhaphy or Botoxinduced ptosis, cycanocarylate tissue adhesive (such as Indermil, Nexacryl or Histoacryl), conjunctival flap, keratoplasty, Boston keratoprosthesis and herpes zoster vaccination (Zostavax, Merck).4,5

Conventional penetrating keratoplasty procedures have variable success due to the poor healing capabilities of neurotrophic tissues, the risks of persistent epithelial defect and sterile ulcerative stromalysis being of greatest concern.

New Treatment Strategies

New treatment strategies for neurotrophic keratopathy and their potential benefits include the following:

Nerve growth factor as well as other neurotransmitters and neuropeptides with vital healing properties are present in serum.1,6 Topical application of autologous serum eyedrops promotes reinnervation and wound healing.7,8

Limbal stem cell replacement: If stem cell deficiency is present, then limbal auto- or allo-graft or ex vivo limbal expansion graft, or oral mucous membrane graft can be restorative.9

Amnion membrane transplantation: inlay (for stromal ulceration) and/or overlay (for PED) grafts of fresh frozen (BioTissue) or dehydrated (AmbioDry) amnion membrane in various configurations, either sutured, fibrin glued or self-retaining.10

Amnion membrane extract: Recognizing the exceptional benefits of amnion membrane (AM) to promote corneal epithelial wound healing as well as to suppress ocular surface inflammation and corneal neovascularization, Ghinelli devised a technique whereby fresh human AM could be minimally manipulated to form a lyophilized extract. The AM extract (AMX, KEERA srl, Italy) has been demonstrated to retain its growth factor activity in vitro & vivo, and can be applied topically. AMX prolongs and increases the effect of an AM graft, while avoiding the operative time and costs of surgical AM implantation.

Clinical experience with AMX has been positive in its ability to reduce inflammation and promote epithelial healing (Figure 2). This was confirmed in a European multicenter, open-label clinical trial that demonstrated 100% safety and 96% efficacy in healing persistent corneal epithelial defects (Kenyon, Ghinelli et al., presented at Italian Ophthalmological Society, 2011). AMX was approved by the Italian FDA for use in Europe. Future clinical testing in the United States is anticipated.

Figure 2. Neurotrophic keratitis post-herpes zoster. Initial findings (upper left) include vision reduced to counting fingers with conjunctival inflammation, corneal PED 3x6 mm (lower left), stromal infiltrate with 50% thinning and sterile hypopyon. After 8 weeks of amnion membrane extract (AMX) therapy (upper right), vision has improved to 0.6 [20/40), as conjunctival, stromal and anterior chamber inflammation have completely subsided, and the corneal epihelium has healed (lower right). This patient has remained stable for 6 years.

Lamellar keratoplasty plus amnion membrane graft: Conventional penetrating keratoplasty in the neurotrophic keratopathy setting presents a high-risk scenario due to chronic inflammation plus surface epithelium and stromal wound-healing complications. To minimize these risks, we have modified our keratoplasty technique in such cases to comprise deep anterior lamellar keratoplasty (DALK), AM overlay graft and minimal (4 mm) lateral tarsorrhaphy.11

The surgical techniques per se are standard and post-op management involves only moderate (e.g. q.i.d.) topical antibiotic and steroid (plus oral acyoclovir only for herpes simplex cases), bandage SCL retained until corneal epithelialization is complete and AM dissolved and/or removed, running suture adjustment at 2 months for astigmatism control, and tarsorrhaphy release at 3 months if the corneal surface remains stable.

In a series of 30 such procedures in neurotrophic keratopathy eyes (including 12 herpes zoster and 11 herpes simplex cases), all with corneal anesthesia and many exhibiting persistent epithelial defects, stromal ulceration and neovascularization, long-term (range 6 to 84 months) post-op success (defined as improved visual acuity, stable epithelial surface and clear keratoplasty) was attained in 90% (27/30 eyes) of eyes. (Kenyon, presented at New England Ophthalmological Society, 2012.) (Figure 3). Thus, we invariably use this surgical approach in the neurotrophic situation. We also believe that when DALK is not applicable, the results of conventional penetrating keratoplasty (PK) are substantially improved by the adjunctive utilization of AM overlay grafting and mini-tarsorrhaphy.

Figure 3. Neurotrophic keratopathy in a 36-year-oid man with herpes zoster ophthalmicus. Top ieft: Vision is reduced to hand motions due to central stromal scarring. Middle: At higher magnification, active stromal neovascularization is evident at 3:00. Stromal opacity also contains dense cholesterol and lipid deposits consequent to vascular leakage. Bottom: At 6 months following lamellar keratoplasty and amnion membrane transplantation, visual acuity has improved to 20/60. Although there is minor residual stromal lipid, neovascularization has abated completely. Current follow-up is 8 years with stable vision and no recurrence of neovascularization.

Conclusion

Given the management challenges of neurotrophic keratopathy with vision-threatening risks of corneal PED, stromal ulceration and perforation, a multi-faceted strategy must be devised to promote corneal epithelial defect healing and to prevent stromalysis. Apart from the several conventional medical and surgical options enumerated, we emphasize two newer developments, specifically: topical amnion membrane extract for medical healing of corneal PEDs, and lamellar keratoplasty (DALK) plus AM transplantation when surgical tectonic and/or visual rehabilitation is required. ■

References

1. Müller FJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res 2003;76:521-542.
2. Pavan-Langston D. Herpes Zoster Ophthalmicus and Ocular Herpes Simplex. In: Melki SA, Fava MA, eds. Cornea and Refractive Atlas of Clinical Wisdom. Thorofare, NJ: Slack Books; 2011:79-90.
3. Kenyon K. Persistent Corneal Epithelial Defects, ibid, pp 39-54.
4. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-2284.
5. Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA 2011;305:160-166.
6. Friere V, Andollo N, Etxebarria J, Duran JA, Morales MC. In vitro effects of three blood derivatives on human corneal epithelial cells. Invest Ophthalmol Vis Sci 2012;53:5571-5578.
7. Matsumoto, Y., Dogru, M. Goto, E., et al. Autologous serum application in the treatment of neurotrophic keratopathy, Ophthalmology. 2004; 111:6, 1115-1120.
8. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000;107:1347- 1351.
9. Ahmad S, Osei-Bempong C, Dana R, Jurkunas U. The culture and transplantation of human limbal stem cells. J Cell Physiol 2010;225:15-19.
10. Dekaris I, Gabrïc N, Mravicïc I, et al. Multilayer vs. monolayer amniotic membrane transplantation for deep corneal ulcer treatment. Coll Antropol 2001;25 suppl:23-28.
11. Wang J, Zhao G, Xie L. Therapeutic effect of deep anterior lamellar keratoplasty for active or quiescent herpetic stromal keratitis. Graefes Arch Clin Exp Ophthalmol 2012;250:1187-1194.

Deborah Pavan Langston, MD, FACS, is Professor of Ophthalmology at Harvard Medical School, Massachusetts Eye & Ear Infirmary Surgeon in Ophthalmology, and Director of Clinical Virology, Massachusetts Eye & Ear Infirmary.

Kenneth R. Kenyon, MD, is the founder of Cornea Consultants International and is Clinical Professor of Ophthalmology at Tufts Medical School, Associate Clinical professor of Ophthalmology at Harvard Medical School and Senior Clinical Scientist at Schepens Eye Research Institute, Boston, Mass.
Dr. Kenyon has a financial interest in KEERA, srl (Italy), the developer of amnion membrane extract.