Published in Ocular Surface

You've Got Some Nerve! Calming the Neurotrophic Keratitis Patient with Advanced Treatments

This is editorially independent content
10 min read

In this session from Eyes On Dry Eye, Clark Y. Chang, OD, MSA, MSc, FAAO, FSLS, and David R. Hardten, MD, discuss treatments for neurotrophic keratitis.

You've Got Some Nerve! Calming the Neurotrophic Keratitis Patient with Advanced Treatments

Eyes On Dry Eye 2023 provided eyecare professionals (ECPs) with the latest research and education, live sessions, and interactive Q&As with renowned specialists. Attendees could earn up to 7 hours of free COPE-accredited CE on topics directly related to patient care, including how to get started with a dry eye practice, learning about the most promising treatments in the pipeline, and many more.

Enjoy this presentation from Clark Y. Chang, OD, MSA, MC, FAAO, FSLS, and David R. Hardten, MD, and don't forget to check out our list of future events!

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Though not all persistent epithelial defects are linked to neurotrophic keratitis (NK), more patients may suffer from this disease than once assumed.
There are numerous contributing factors to the development of NK, including ocular conditions, corneal and other surgeries, systemic disease, environmental factors, and dry eye. As these increase, so does the prevalence of NK.
The risks associated with neurotrophic keratitis are infection, scarring, stromal melting, and perforation, all of which can lead to severe vision loss. Therefore knowing how to diagnose, classify, and treat NK is paramount to effective management and co-management.
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What is neurotrophic keratitis?

Neurotrophic keratitis is a degenerative disease characterized by corneal sensitivity reduction, spontaneous epithelial breakdown, and impaired corneal healing. Left untreated, as a degenerative disease, NK progresses to a severe disease state that can result in profound vision loss secondary to scarring and corneal perforation. The basis for NK is impaired trigeminal innervation of the corneal and ocular tissues; however, do not underestimate the feedback component.

With NK, it is essential to realize that things flow both ways in relation to neurotrophic support.

In addition, any disruption within the trigeminal pathway affects tear production and blink rate, further compromising the epithelia. The corneal surface provides feedback that stimulates the growth factors and neurotrophin, allowing them to flourish and proliferate.
This means ocular surface health plays a pivotal role.

Classification of neurotrophic keratitis

The most common classification of NK is derived from the Mackie scale, which grades the disease as mild, moderate, and severe, with loss of stroma being the biggest factor.
Table 1 features the Mackie neurotrophic keratitis classification system with the stages and their associated symptoms.
StageSymptoms
Stage 1: MildCorneal hypoesthesia or anesthesia in less than one quadrant, punctate keratitis, decreased TBUT and/or rose bengal staining of inferior conjunctiva, increased viscosity of tear mucus, superficial neovascularization, stromal scarring
Stage 2: ModerateCorneal hypoesthesia or anesthesia in one quadrant, persistent epithelial defect with smooth and rolled edges, stromal swelling, Descemet's membrane folds, no stromal defect or loss
Stage 3: SevereCorneal hypoesthesia or anesthesia in more than one quadrant, ulcer present, stromal melting, perforation
Table 1: Courtesy of Semeraro et al.

Risk factors for neurotrophic keratitis

Risk factors for NK span from contact lens wear to genetic components to cataract surgery but can be broken down into ocular, systemic, genetic, and central nervous system (CNS).

Ocular risk factors for neurotrophic keratitis include:

  • Herpes: Approximately 13% of patients develop NK after Zoster and 7% after simplex
  • Infections
  • Injury, including chemical burn
  • Surgeries: Cataract, LASIK, PRK, DALK vitrectomy, etc.
  • Overall ocular surface health:
    • Contact lenses (i.e., scleral, rigid-gas permeable [RGP] lenses)
    • Diseases: Meibomian gland dysfunction (MGD), blepharitis, lagophthalmos, floppy lid, trichiasis, and allergies
    • Topical medications: NSAIDs, steroids, drops containing preservatives, and anesthetics
    • Environmental: Allergens, low humidity, and excessive screen time
  • Corneal dystrophies

Systemic risk factors for neurotrophic keratitis include:

  • Disease: Diabetes, rheumatoid arthritis, allergies, Sjögren’s syndrome, amblyopia, and vitamin A deficiency
  • Medications: antihistamines and decongestants

Genetic risk factors for neurotrophic keratitis include:

  • Riley-Day syndrome (familial dysautonomia)
  • Goldenhar-Gorlin syndrome
  • Mobius syndrome
  • Familial corneal hypoesthesia

Central nervous system risk factors for neurotrophic keratitis include:

  • Stroke
  • Aneurysm
  • Neoplasm
  • Degenerative CNS disorders
  • Post-neurosurgical procedures
  • Trigeminal nerve injury/surgery

Diagnosing neurotrophic keratitis

With NK, there is often a discrepancy between clinical findings and symptoms. Since most patients with NK do not experience pain, due to corneal hypoesthesia/anesthesia, the primary complaint is often blurred vision and reduced acuity. Obviously, this complaint can be linked to a number of other ocular conditions, including dry eye.
Therefore, the key to diagnosis is assessing major risk factors for the development of persistent epithelial defects and determining whether or not there is corneal sensitivity loss. In his practice, Dr. Hardten has found patients with herpetic eye infections to be the number one candidates for NK, followed by diabetic and post-surgical patients.

After establishing corneal hypoesthesia or anesthesia, a slit lamp and dilated fundus exams are required to gain better insight into etiology and classification.

Testing for corneal sensitivity

Using an aesthesiometer, sensitivity is quantified by filament length; the shorter the length, the greater the pressure needed to produce a sensation upon contact, indicating compromised sensitivity. Testing of the central quadrant is conventionally thought to be the most important.
As an alternative, pull a wisp from a Q-tip or use sterile dental floss. These “plus or minus” tests are based on the patient feedback of “yes” or “no.”  On a scale of normal, hypoesthesia, and anesthesia, look for interocular and intraocular asymmetry.

Treatment options for neurotrophic keratitis

Unless there is already significant stromal deterioration, it is appropriate to begin with a conservative approach, focusing on comorbidities and the ocular surface. If a medical regimen does not slow the progression of NK, a more direct surgical approach is required.

Topical treatments for neurotrophic keratitis

The first line of treatment is topicals to address dry eye, herpetic and other infections, ocular rosacea, and so on. These include preservative-free artificial tears, corticosteroids, autologous serum drops, and antibiotics.
One highly effective topical solution specifically designed for treating neurotrophic keratitis is OXERVATE.

OXERVATE: the new gold standard for treating NK

In August of 2018, treatment for neurotrophic keratitis was revolutionized when the FDA approved OXERVATE (cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL), Dompé). OXERVATE is structurally identical to nerve growth factor (NGF), which is responsible for the differentiation, growth, and maintenance of neurons.
By rebuilding and reinvigorating the trigeminal pathway, cenegermin-bkbj not only heals the epithelial defect but sends signals that restore a normal blink rate improving ocular surface health.

Both European and FDA studies found that with an 8-week course of OXERVATE drops, taken every 2 hours, approximately 72% of patients achieved complete corneal epithelial healing.

Even more impressive—especially considering a disproportionate number of these patients began with true epithelial defects or stromal ulceration—80% of these patients remained healed at the 48-week mark. Note that investigators could administer a second consecutive 8-week course of treatment at their discretion.

In-office procedures to treat neurotrophic keratitis

There are also several in-office procedures that can prove helpful in treating NK. Among them are therapeutic contact lenses, punctal occlusion, non-surgical eyelid closure, tissue adhesives, and sutureless amniotic membranes.

Scleral lenses to treat neurotrophic keratitis

Though not preferred as a chronic solution, scleral lenses can offer short-term protection and promote healing for cases with epithelial breakdowns once or twice a year.
Recent research states patients are less likely to develop corneal ulceration with scleral lenses as opposed to bandage lenses, but with any contact lens, there is a risk of infectious keratitis.

Amniotic membranes to treat neurotrophic keratitis

Available in cryopreserved forms (Prokera, BioTissue) and dehydrated (AcellFX, acellular amniotic membrane, Théa Pharma), amniotic membranes accompanied with eye taping or another non-surgical eye closure can be highly beneficial.

Surgical procedures to treat neurotrophic keratitis

More aggressive surgical intervention is required if a patient proves non-responsive to ocular surface treatments and starts to develop stage 2 neurotrophic keratitis with persistent field defect and stromal melting.

Tarsorrhaphy

Though now secondary to OXERVATE as the first-line treatment for NK with stromal deficit, permanent tarsorrhaphy is still the top surgical intervention for neurotrophic keratitis.

Punctal cauterization and punctal plugs

When the NK is combined with verified aqueous deficiency, inferior punctal plugs are utilized for management. However, if they do not deliver the desired results, superior vicryl plugs may increase ocular surface homeostasis.
As gravity and lid movement make upper punctal plugs challenging, cauterization of the upper puncta is also a viable option.

Sutured amniotic membrane transplant (AMT)

Amniotic membranes also have a place in the surgical suite. A multilayer, sutured amniotic membrane transplant in conjunction with tarsorrhaphy offers ongoing restoration for up to 8 weeks.

Corneal transplant

A corneal transplant can serve as a short-term solution to the perforation but does not offer permanent healing.

Corneal neurotization (re-innervation)

First introduced in 2009, corneal neurotization involves rerouting part of the supraorbital or supratrochlear nerve from the unaffected eye and grafting it under the conjunctiva of the affected eye to restore corneal sensitivity. The original procedure was invasive and had the potential for donor site morbidity; over the years, it has been fine-tuned to reduce this risk.

Using an endoscopic approach, a much less invasive technique has been developed in which a de-cellularized cadaveric nerve graft is attached to a smaller piece of healthy donor graft.

In closing

In the not-so-distant past, dry eye disease was considered a rare condition, and there were no set parameters for classification and diagnosis. Now, it is identified as one of the more common roots of many complaints.

In that same realm, neurotrophic keratitis is frequently underdiagnosed.

With the incredible impact this degenerative disease can have on vision, it is vital to learn to recognize and treat neurotrophic keratitis at the earliest stage possible. Offering sooner and better treatment to our patients reduces morbidity and increases overall ocular health.
Clark Y. Chang, OD, MSA, MSc, FAAO, FSLS
About Clark Y. Chang, OD, MSA, MSc, FAAO, FSLS

Dr. Clark Chang is the Director of Specialty Contact Lenses in Cornea Service at Wills Eye Hospital (Philadelphia, USA) and Medical Affairs Manager at Glaukos.

He is also the host of the popular podcast show “Chang reaction.” Upon completing his residency program at Salus University, Dr. Chang further completed a 2-year Corneal and Contact Lens fellowship. Additionally, Dr. Chang was involved in the pre-clinical trials that later led to the FDA approval of corneal cross-linking in 2016.

In recent years, he has been honored as The ”Top Doctor of 2020” by the National Keratoconus Foundation, the 2021 recipient of AOA’s “Luminary Award for Distinguished Practice,” and the “World’s Top 100 Doctors” in 2022.

Clark Y. Chang, OD, MSA, MSc, FAAO, FSLS
David R. Hardten, MD
About David R. Hardten, MD

Dr. David R. Hardten, a board-certified ophthalmologist and founding partner of Minnesota Eye Consultants, is a prominent leader in the treatment of the cornea, external disease, anterior segment, cataract, refractive and laser surgery - as well as in research and education.

As a past director for Minnesota Eye Consultants’ Clinical Research Department, Dr. Hardten has led research projects surrounding LASIK Eye Surgery, refractive surgery, complex case management, cataract surgery, natural lens replacement surgery, glaucoma management, corneal transplantation, iris reconstruction, surgical instrumentation and drug therapies. Dr. Hardten has received numerous awards for his dedication to the eye care industry, including the 2011 Casebeer Award for outstanding contribution to the research and development of refractive surgery from the International Society of Refractive Surgery, the 2011 Allina HOPE (Hospital Outstanding Patient Experience) Award, and the 2010 American Academy of Ophthalmology Lifelong Education for the Ophthalmologist Continuing Education Recognition Award.

He attended the University of Kansas undergraduate and medical schools, and was then accepted into the University of Minnesota Department of Ophthalmology residency program. He completed his fellowship training in cornea and external disease at the University of Minnesota and Phillips Eye Institute and received the ARVO/National Eye Institute Fellow Award. Dr. Hardten entered private practice in 1993 with Drs. Richard L. Lindstrom and Thomas W. Samuelson, also founding partners of Minnesota Eye Consultants. He is an attending ophthalmologist at Phillips Eye Institute in Minneapolis, Minnesota, as well. In addition to an active clinical and surgical practice, Dr. Hardten has focused on education throughout his career. He is an adjunct associate professor of ophthalmology at the University of Minnesota Department of Ophthalmology and serves as an adjunct professor for the Illinois College of Optometry.

Dr. Hardten has held leadership positions in many professional organizations, including board director for the International Society of Refractive Surgery and the Contact Lens Association of Ophthalmologists; co-medical director for Laser Vision Centers, Inc.; clinical advisory board for TLCVision; board of directors and program director for the Refractive Surgery Interest Group of the American Academy of Ophthalmology. While serving for the American Academy of Ophthalmology, he received its distinguished achievement award in 1999 and the senior achievement award in 2006 for his countless efforts on behalf of the Academy.

David R. Hardten, MD
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