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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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Watch the full lecture from Drs. Chang and Hardten on diagnosing and treating neurotrophic keratitis!
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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.
| Stage | Symptoms |
|---|---|
| Stage 1: Mild | Corneal 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: Moderate | Corneal 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: Severe | Corneal 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.
