Infectious Keratitis in a Neurotrophic Cornea

doi:10.62055/81075495Fp

 

ABSTRACT

BACKGROUND

Neurotrophic keratitis (NK) is a rare condition that results in loss of corneal sensitivity. Several common ocular and systemic diseases can contribute to NK development. There is a wide range of ocular consequences associated with NK, including corneal melt and blindness. This condition often goes undiagnosed until late-stage disease, which can have devastating complications. Early identification is imperative to improving patient outcomes.

CASE REPORT

A 58-year-old female with a history of Sjogren’s syndrome and diabetes mellitus type 2 presented to the emergency room with a recent history of redness and painless vision loss in the left eye. Examination revealed a severely neurotrophic cornea with a large infectious corneal ulcer. Appropriate treatment was pursued, but despite this, corneal scarring ensued, resulting in a reduction in best-corrected visual acuity.

CONCLUSION

Many patients present for routine examination with risk factors for neurotrophic eye disease, but often go undiagnosed until significant complications have occurred. There is a need to better identify patients who are at high risk for neurotrophic disease. Early detection means intervention can be delivered before an additional adverse health event occurs.

Keywords: neurotrophic keratitis, infectious keratitis, corneal ulcer, corneal sensitivity

 

INTRODUCTION

Neurotrophic keratitis is a condition defined by loss of corneal sensation. The cornea is innervated by the trigeminal nerve, and insult anywhere along this pathway from the brainstem to the cornea can result in this condition. This loss of sensation produces a cornea that is more susceptible to asymptomatic insult and can lead to significant corneal decompensation. Neurotrophic keratitis is staged by its level of associated keratopathy. The most severe cases result in corneal melt and perforation. Although typically sterile in nature, neurotrophic keratitis resulting in corneal ulceration may also present with a secondary infection of the cornea. Identifying secondary infection is critical, as treatment of a secondary microbial infection will differ greatly from treating a sterile ulcer. If there is a secondary microbial infection, the treating physician must manage both the elimination of the microbe and the rehabilitation of the neurotrophic cornea. This case illustrates a patient with neurotrophic keratitis who was ultimately diagnosed only after suffering from significant infectious corneal ulceration.

 

CASE REPORT

A 58-year-old white female presented to the emergency room with a 2-day history of redness, mucoid discharge, and blurry vision in the left eye. Notably, the patient reported no pain, itching, or other discomfort. Medical history was relevant for well-controlled type 2 diabetes and Sjogren’s syndrome. Ocular history was relevant for chronic filamentary keratitis OU secondary to Sjogren’s syndrome, which was being treated with topical acetylcysteine 5% TID OU, lifitegrast BID OU, preservative-free carboxymethylcellulose 0.5% 6x daily OU, lubricating ointment QHS OU, and full-time bandage contact lens wear OU. All medications and full-time bandage contact lens wear had been prescribed for about ten years by the cornea department of the hospital. The patient was unable to handle the contact lenses herself, so they were changed in the clinic on a monthly basis. She was also treated with once daily topical moxifloxacin OU as prophylaxis given the extended contact lens wear. The patient’s last eye exam and bandage contact lens change had occurred two weeks prior to the patient presenting to the emergency room. At that visit, best corrected visual acuity (BCVA) was 20/20 OD and OS, with both eyes in good health other than chronic dryness.

Upon initial examination in the emergency department, the left eye was fully matted shut with mucoid discharge. Once the eye was cleaned and opened, BCVA was 20/200 OS. There was no APD, and confrontation fields were full OD and OS. On slit lamp examination, there was 4+ conjunctival injection with mild diffuse chemosis, diffuse corneal edema, and a central 6 mm x 5 mm corneal ulcer with a similarly sized underlying infiltrate and approximately 30% thinning OS (Figure 1). The anterior chamber was formed with 3+ cells and flare and without hypopyon or hyphema OS. There was no contact lens present OS, as it had been removed and discarded by the emergency medicine physician before optometry was paged to examine the patient. Parameters in the right eye remained stable to prior description.

 

The differential diagnosis on initial examination included neurotrophic keratitis, bacterial keratitis, herpetic keratitis, fungal keratitis, acanthamoeba keratitis, and Mooren’s ulcer. The lack of pain with such a large corneal ulcer was strongly suggestive of neurotrophic keratitis. Formal corneal sensitivity was not tested at this time, as it was felt the presence of a large ulcer without pain was evidence of reduced sensation. The presence of a corneal infiltrate and significant mucoid discharge were suggestive of a secondary infectious process. There were no dendrites, pseudodendrites, or skin lesions indicative of a possible herpetic infection. There was no history of organic foreign body or injury that would raise the risk of fungal coinfection. This patient was at higher risk for both bacterial and acanthamoeba keratitis given the history of extended contact lens wear; however, bacterial keratitis is more common and this patient did not have a recent history of swimming in fresh water or hot tub use that would further increase her risk of acanthamoeba exposure. The location and shape of the corneal ulcer was inconsistent with the typical appearance of Mooren’s ulcer.

A tentative diagnosis of a bacterial corneal ulcer in the setting of neurotrophic keratitis OS was made. Corneal culturing and fortified antibiotics were not immediately available in this exam setting. Because of the severe level of corneal ulceration, the decision was made to initiate empirical treatment with topical moxifloxacin Q1H OS, with instructions to follow up 12 hours later when corneal culturing would be available. Topical steroid treatment was withheld due to concerns about inducing local immunosuppression and slowing wound healing, especially considering there was not yet a culture-confirmed diagnosis. A ten-day course of oral valacyclovir 1 gram TID was prescribed as a cautionary measure, although a herpetic etiology was low on the list of differential. The patient presented the next morning reporting good compliance with the medications, but that her vision had worsened overnight. Repeat examination revealed that BCVA decreased to 20/400 OS, and a 2 mm layered hypopyon had developed overnight. The corneal ulcer was cultured at this exam, topical moxifloxacin was discontinued, and fortified topical tobramycin 1.3%/cefazolin 5% was prescribed Q1H OS to provide broad spectrum coverage.^1,2 The patient was followed daily, with improvement in re-epithelization noted at each visit. After one week, the corneal ulcer had fully re-epithelialized and the hypopyon had resolved OS. Fortified topical antibiotics were discontinued, and moxifloxacin was restarted QID OS for one additional week.

The corneal culture was unsuccessful in identifying the causative agent of the patient’s corneal infectious ulcer OS. At resolution, the patient’s BCVA was 20/40 due to significant central stromal haze OS (Figure 2). The patient resumed monthly eye examinations with her corneal specialist who had been treating her filamentary keratitis OU. The patient restarted the same topical ocular medication regimen she had been on prior to this event, including the use of bandage contact lenses OU. Extensive patient education was provided regarding the new diagnosis of neurotrophic keratitis and the need for diligent self-surveillance between corneal examinations. The patient was made aware of the need for an urgent evaluation by optometry or ophthalmology if decreased vision or redness developed in either eye, even in the absence of pain or other accompanying symptoms.

 

DISCUSSION

Neurotrophic keratitis is a chronic degenerative cornea condition characterized by corneal hypoesthesia and impaired wound healing. This is a rare condition in the United States, with a prevalence of less than 50/100,000 people.³ The potential causes are numerous, as a lesion anywhere from the trigeminal nucleus to the termination of the ophthalmic branch may result in neurotrophic degeneration. The reduction of corneal neuronal function results in a downregulation of corneal epithelial mitosis, resulting in poor corneal re-epithelialization. This disruption to corneal homeostasis leads to a cornea that loses epithelial cells faster than they can be replaced, which may result in numerous consequences. Persistent epithelial defects may develop secondary infectious keratitis, and severe cases of neurotrophic keratitis may lead to sterile ulceration and corneal melt if the rate of re-epithelization becomes significantly impaired. The loss of corneal sensitivity also results in downstream reductions in reflex tearing and blinking, further predisposing the cornea to damage due to abnormal dryness and poor protection from external debris. This multifactorial loss of normal anatomical function leads to a cornea at risk for decompensation with or without additional external damage.⁴

The most common cause of neurotrophic keratitis is corneal herpetic disease, with both herpes simplex and herpes zoster capable of damaging corneal innervation.⁵ Other causes include corneal surgeries (e.g., LASIK, PRK, DALK, PKP), diabetes mellitus, excessive contact lens wear, chemical injury, thermal injury, radiation exposure, neurosurgery affecting the trigeminal nerve, intraocular surgery, trauma, and intracranial pathology affecting the trigeminal nerve (e.g., stroke, aneurysm).⁵

Neurotrophic keratitis is categorized by three stages according to the Mackie classification system. Stage one consists of non-specific superficial punctate epithelial defects and corneal epithelial irregularity, and is often misdiagnosed as dry eye syndrome. Stage two consists of the presence of a persistent epithelial defect without stromal involvement. The condition progresses to stage three when the corneal stroma is involved, resulting in sterile corneal ulceration that may progress to perforation in the absence of treatment. Classifying neurotrophic keratitis is critical, as the most appropriate treatment options vary significantly between stages. Stage one NK may be managed with diligent lubrication with preservative-free artificial tears or lubricating ointments, with a goal of improving epithelial clarity and reducing superficial punctate epithelial defects. Autologous serum tears, punctal occlusion, bandage contact lenses, therapeutic scleral lenses, and amniotic membranes may also be considered at this stage if the patient does not improve with topical lubrication alone. Stage two NK often involves the same treatment options as stage one, but with additional antibiotic coverage to prevent infection of persistent epithelial defects. Stage two treatment aims to resolve the epithelial defect to prevent corneal infection and progression to stromal involvement. Depending on the location of the epithelial defect, a partial tarsorrhaphy or Botox-induced ptosis may also be of benefit to provide additional protection to the cornea by limiting the rate of de-epithelialization. The management of stage three NK is geared towards healing corneal ulceration to prevent corneal perforation. Surgery is often indicated in these cases and may include a partial or full-thickness corneal transplant or conjunctival flap. Corneal transplant can be especially challenging in these cases, as there is no existing trophic network to support the graft.^4,6

Although the treatment options listed above help to restore corneal integrity by reducing the rate of corneal de-epithelialization, they do not address the underlying reduction in corneal sensation and poor corneal re-epithelialization that drives the disease process of neurotrophic keratitis. In 2018, the FDA approved the recombinant human growth factor (rhNGF) cenegermin 0.002% for the treatment of stage two and stage three NK. Nerve growth factor has previously been shown to maintain corneal homeostasis in animal models. Although the exact mechanism of cenegermin is not fully understood, researchers speculate that this treatment helps to restore the corneal nerve plexus, thereby increasing corneal re-epithelialization and improving corneal integrity.⁷ The REPARO phase II study compared 10 µg/mL cenegermin 6X/day, 20 µg/mL cenegermin 6X/day, and a vehicle drop 6X/day for 8 weeks in 156 patients with unilateral stage 2 or stage 3 neurotrophic keratitis. After 8 weeks, 43.1% of patients in the vehicle group, 74.5% of patients in the 10 µg/mL cenegermin group, and 74% of patients in the 20 µg/mL cenegermin group achieved corneal healing, defined as less than 0.5 mm lesion staining. Patients were followed for an additional 48 or 56 weeks, with 96% of patients in the cenegermin groups who achieved corneal healing after the initial 8 weeks of treatment having no recurrences through the final follow up. The few reported adverse effects with cenegermin were typically mild and did not require ceasing therapy or additional corrective treatment.⁷

Corneal neurotization (CN) is a surgical technique that aims to restore corneal nerve function by grafting other healthy nerve tissue to the diseased cornea. Studies have shown that this procedure can be successful in restoring corneal sensation. A 2020 review by Park et al. included 54 adult and pediatric patients with neurotrophic keratitis from various ocular and neurological causes who underwent corneal neurotization between 2008 and 2019. Corneal neurotization resulted in improved corneal sensitivity and visual acuity, with maximum sensitivity achieved in a mean of 8 months post-operation. On average, the entering Snellen acuity was 20/359 prior to surgery, and improved to an average acuity of 20/143 post surgically. Average Cochet-Bonnet esthesiometry improved from 2.18 mm to 40.10 mm. Data quantifying individual case results was unavailable in this study.⁸ The main barrier to visual acuity improvement was on-axis corneal scarring. This study identified itself as the “first and most extensive compilation of reported CN outcomes.” The relatively small sample size indicates the rarity of this procedure.

A variety of different surgical procedures for corneal neurotization are described in the literature. Both direct nerve grafting and indirect grafting via a conduit are possible. The infraorbital, supraorbital, and supratrochlear nerve are all candidates for direct grafting. Both the ipsilateral and contralateral nerves can be used. The sural nerve of the leg is often harvested for use in indirect neurotization procedures. Both autologous and allogenic procedures have been described.⁹ This technique is more invasive than medical therapy, and historically has been reserved for patients who fail medical treatment. Thus far, no preferred neurotization practice pattern has been identified.¹⁰ Case reports suggest that recovery of corneal sensation typically takes anywhere from 3 months to 2 years, and this sensitivity may be maintained for as long as 7 years or more. Immunohistochemistry studies of post-neurotization corneas have also shown evidence of corneal reinnervation.^11,12 This procedure is relatively uncommon, and it is unclear how the availability of cenegermin may affect the frequency of corneal neurotization in the future. For now, the treatment of neurotrophic keratitis remains organized in a stepwise fashion, i.e., the level of treatment is dictated by the severity of the disease. It is worth noting that the cost of treatment options listed above also vary greatly and can create financial barriers to care for patients in need. According to the Canadian Agency for Drugs and Technologies in Health, a full 8-week course of cenegermin costs approximately 118,230 Canadian dollars.¹³ In the United States, a full treatment course costs approximately 94,400 U.S. dollars.¹⁴

Microbial keratitis refers to infection of the cornea that can be caused by several microbes, most typically bacteria. Contact lens wear is a primary risk factor for developing this condition. Extended contact lens wear, overnight wear, and poor contact lens hygiene are all additional risk factors for microbial keratitis in contact lens users. Other risk factors include ocular trauma and dry eye syndrome, as damage to the corneal epithelium is required for most microbial species to invade the cornea. Microbial keratitis requires urgent treatment to prevent permanent vision loss.^15,16

A detailed history is critical in these cases, as it may help identify the causative agent. For example, recent organic trauma may increase the likelihood of a fungal infection. If the patient is a contact lens wearer, history focused on contact lens use and hygiene should be taken to assess if the patient may be at increased risk for contact lens-related infections. A thorough ocular assessment should also be performed. An epithelial defect or stromal thinning with an underlying infiltrate suggests an infectious process. Measurements should be taken to assess both the area of the defect and the amount of thinning present. A detailed examination of the anterior chamber should document both the presence and absence of any cells, flare, fibrin, or hypopyon.

Corneal scrapings should be obtained for culture in patients with high-risk corneal infectious ulcers. High risk features include size of >2 mm, location on the visual axis, chronicity or unresponsiveness to treatment, the presence of hypopyon, or multiple corneal infectious ulcers. Patient history of organic trauma, use of contaminated contact lens solution, exposure to untreated water or hot tubs, or immunosuppression all increase the risk of atypical infectious organisms and should be cultured as well. Scrapings should be taken from the edge of the lesion and applied directly to culture media. A basic list of culture media includes chocolate agar (for Haemophilus influenzae and Neisseria gonorrhea), blood agar (for aerobic bacteria), Sabouraud agar (for various fungi and yeasts), mannitol salt agar (for Staphylococcus species), non-nutrient agar with E. Coli overlay (for Acanthamoeba), and thioglycolate broth (for anaerobic bacteria). Gram stains should also be obtained.¹⁷ Giemsa staining may also be of value in identifying features such as multinucleated giant cells suggestive of possible herpetic disease.¹⁸ It is important to take corneal scrapings rather than trying to culture mucopurulent discharge, as this will significantly increase the odds of a successful culture. A new, sterile swab should be used for each scraping to prevent cross contamination of plating medias.¹⁹

Identifying the causative organism of a corneal infectious ulcer by clinical appearance alone is challenging. A 2012 survey of 15 corneal specialists aimed to see if accurate identification of bacterial vs. fungal keratitis was possible based on review of photographs. The specialists were shown 80 photos of either fungal or bacterial keratitis, all of which had been independently confirmed by culture/smear. The specialists were able to correctly identify the etiology of the corneal infection only 66% of the time, meaning one third of cases were incorrectly identified (and therefore would have been incorrectly treated) based on clinical examination. This study reinforces the importance of taking a broad approach to corneal culturing and using an array of agars as described above, as the clinical exam alone is insufficient to determine the causative microbe.²⁰

Broad-spectrum topical antibiotic coverage should be applied every hour while culture results are pending. Patients should be followed daily until the treating clinician is able to verify the infectious ulcer is responding to treatment and healing. Follow-up examination should note changes in the size and depth of the infectious ulcer, the anterior chamber reaction, and the patient’s subjective pain response. If there is no improvement or worsening of the corneal infection after initial treatment, a repeat culture or treatment with broad spectrum fortified antibiotics should be considered. A change in treatment should be considered if culture results suggest an etiology that may be more susceptible to a different targeted treatment. The average practitioner is unlikely to have immediate access to all the supplies listed above. In such cases, it may be prudent to immediately refer to a corneal specialist or hospital setting that can provide this level of care to minimize the risk of additional vision loss. A referral at the time of presentation may also be warranted if one or more high-risk features are present, or if the patient’s presentation and/or history is consistent with atypical infections such as Acanthamoeba or fungal keratitis. A tertiary eye care setting may have access to additional diagnostic tests such as polymerase chain reaction studies or specialized fungal stains that are not always available in the community setting. Infectious keratitis without high-risk features can often be treated in the primary eye care setting, even if culturing is unavailable. It is important to follow these patients daily and make a referral for specialty care if initial treatment efforts are unsuccessful.

Some studies have shown that treatment of infectious corneal ulcers with fourth-generation fluoroquinolones produces comparable end results to treatment with combination fortified antibiotics. A 2010 randomized clinical study by Shah et al. compared the use of moxifloxacin 0.5% monotherapy, gatifloxacin 0.3% monotherapy, and cefazolin 5%/tobramycin 1.3% combination therapy in the treatment of bacterial corneal ulcers 2-8 mm in size. After corneal scrapings were obtained, all groups received their assigned medication on an hourly basis for 48 hours, and then tapered as clinically appropriate. This study failed to find a difference in efficacy in treatment strategies, and concluded that moxifloxacin 0.5% and gatifloxacin 0.3% are legitimate treatment options for bacterial keratitis. Thus, fourth-generation fluoroquinolones are often used as a reasonable first treatment measure. However, fortified antibiotics remain a powerful tool in a clinician’s arsenal, and should be considered in cases that do not respond to other treatment options. This is especially important to consider as recent studies have indicated there may be an increase in fluoroquinolone-resistant bacteria present in the environment.^21,22

As antibiotic resistance continues to rise, clinicians are in greater need of new treatment modalities. One area of current research is the use of antiseptic based treatment in infectious keratitis. Some studies have shown the use of ophthalmic povidone-iodine as a potential treatment option, especially in treating gram positive agents. More research is needed to verify the validity of this treatment, but this may offer a low-cost treatment option for corneal infection in the future.^23,24

Corneal cross-linking is also being explored for the treatment of infectious keratitis. In this treatment, riboflavin and ultraviolet-A light are applied to the cornea, which results in an increased number of covalent bonds throughout the corneal stroma.²⁵ This process reinforces the cornea against stromal melt that may result from a significant infection. The combination of riboflavin and UV light also causes oxidative damage to microbial DNA and RNA, and thus may have value in treating a wide array of infectious organisms. Further study is needed to determine the effectiveness of corneal cross-linking in the treatment of infectious keratitis; it is worth noting that the technical challenges of performing cross-linking and financial cost may cause additional barriers to care.²⁶

In this case, the patient had multiple pre-existing risk factors for the development of neurotrophic keratitis (Sjogren’s syndrome, diabetes, extended contact lens wear, and likely excessive exposure to benzalkonium chloride due to the use of multiple topical ocular medications). The stage of pre-existing neurotrophic keratitis was unknown for this patient, as it was never suspected until a severe secondary infection had formed. By the time the patient presented to the emergency room, staging was impossible as additional microbial insult and ulceration had already taken place. It is not uncommon for cases of neurotrophic keratitis to have a multivariant etiology, such as with our patient.

Corneal sensitivity testing is a low-cost, fast clinical technique that can provide valuable information about a patient’s ocular health. A sterile cotton-tipped applicator can be twisted into a fine wisp that can gently be applied to all four quadrants of the corneal surface. A cornea with normal sensitivity should produce a blink reflex, and the patient should be able to signal that they feel contact from the wisp. This testing should be done after refractive testing, but before topical diagnostic agents are applied to ensure the results are accurate. It is important to consider this exam technique when evaluating patients with signs that are concerning for NK (i.e., unilateral superficial punctate keratitis/dryness without other explanation such as ectropion, unilateral chronic red eye, signs of dryness that significantly outweigh symptoms). More diligent testing of corneal sensation in patients with signs and risk factors suggestive of NK will help the clinician detect these cases earlier when outcomes are most likely to remain optimal.

CONCLUSION

This case demonstrates a patient with neurotrophic keratitis who developed a painless infectious central corneal ulcer. The ulcer was managed appropriately and ultimately healed, although there was some final reduction in BCVA due to on-axis scarring. There is a need for clinicians to identify patients with neurotrophic corneal disease in early stages, as they often do not present acutely unless there is already significant corneal insult. Early detection will result in appropriate treatment at early stages of disease and help mitigate the risk of permanent vision loss and need for corneal surgery. Providing appropriate patient education will also empower these patients to better monitor for changes they otherwise may not notice, given the reduced pain associated with their condition. The historical treatment of neurotrophic keratitis has mostly been supportive therapy, but recent pharmacological and surgical advances may change the treatment of this condition going forward. Neurotrophic keratitis can arise from some ocular and neurological disorders including past corneal injury, herpetic infection, numerous ocular and neurosurgical procedures, diabetes mellitus, and others. A clinician should consider the possibility of NK when a patient presents with a unilateral painless keratopathy without other obvious explanation, and should test corneal sensitivity to confirm this diagnosis. Early detection of NK will allow clinicians to begin treatment in earlier stages and help preserve vision for patients.

 

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