February 2023

Chief Complaint

Corneal ulcer in the left eye

History of Present Illness

A 10-year-old female referred to the ophthalmology clinic for worsening bacterial corneal ulcer while on fortified antibiotics for over one week and negative cultures.  

Ocular History

• Corneal ulcer OS
• Exposure keratopathy OS s/p tarsorrhaphy
• Failed amniotic membrane graft
• Eye trauma OS 
• Blepharitis OU

Past Medical History

• Brain tumor s/p resection (several years ago)

Medications

• Artificial tears 
• Moxifloxacin ophthalmic
• Fortified Tobramycin ophthalmic
• Fortified Vancomycin ophthalmic

Allergies

• No known drug allergies

Family History

• None

Social History

• None

Review of Systems

• As noted in HPI, otherwise negative

Ocular Exam

Imaging

Laboratory Testing

• HSV 1/2 PCR: negative 
• Aerobic Bacterial Culture: staphylococcus hominis in broth only 

Differential Diagnosis

• Infectious corneal ulcer
• Neurotrophic corneal ulcer

Clinical Course

A 10-year-old female with a past medical history of a brain tumor with residual CN 5-7 palsy presented to the ophthalmology clinic as referral for corneal ulcer OS. She was initially treated with Vigamox but continued to have a worsening ulcer despite starting on topical fortified antibiotics and with negative cultures at one week. Her past ocular history was notable for a history of corneal ulcer OS, exposure keratopathy s/p tarsorrhaphy, and neurotrophic keratitis OS. She underwent a repeat infectious work up including an HSV1/2 PCR and aerobic bacterial culture, which returned positive only for staph hominis growth only in broth. After infection was ruled out, fortified antibiotics were tapered and she was started on low dose topical steroids and topical recombinant human nerve growth factor (cenegermin-bkbj ophthalmic solution). She was also advised to liberally lubricate the eye with drops and gel, take supplemental oral Vitamin C, and tape the eyelid at night throughout her course. The defect resolved and was complicated by corneal neovascularization which was managed and stabilized with topical steroids and cyclosporine. She continues to follow up on a regular basis for corneal monitoring and intraocular pressure checks.

Discussion

A corneal ulcer is a defect in the corneal epithelium and can be due to infectious or noninfectious causes. Among the infectious etiologies of ulcers, bacteria is the most common cause, with the most common pathogens being Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Pseudomonas aeruginosa (Byrd, 2022). Such pathogens typically enter through a break in the corneal epithelium, which can occur due to a number of mechanisms including contact lens wear and ocular trauma leading to corneal abrasions. 

The two main differential diagnoses considered for this patient’s corneal ulcer were infectious and neurotrophic etiologies. Due to persistent symptoms following initial therapy for bacterial keratitis, the patient was started on cenegermin-bkbj ophthalmic solution, sold under the brand name of Oxervate. This drug contains recombinant human nerve growth factor and is the first-ever FDA approved topical medication for the treatment of neurotrophic keratitis (Deeks, 2020). Human nerve growth factor plays a significant role in the cornea by supporting corneal nerve cell growth and healing. Randomized control trials studying Oxervate have shown its efficacy in achieving complete corneal healing after just eight weeks of treatment, as was seen in the case of this patient.

As demonstrated by this patient’s clinical course, corneal ulcers may lead to a complication known as corneal neovascularization. Corneal neovascularization (cNV) is a sight-threatening condition characterized by the formation and subsequent stromal invasion of abnormal capillaries within the cornea. Corneal neovascularization affects 1.4 million people per year, 12% of whom suffer from vision loss. It can develop from traumatic, infectious, or degenerative damage to the distinctly avascular cornea. It can also present secondary to corneal ulcers, herpes infection, graft rejections, contact lenses, and surgery (Sharif, 2019). Normally, following epithelial injury, limbal stem cells are crucial for regenerating the corneal epithelium and maintaining corneal integrity through anti-angiogenic and immunomodulatory homeostatic mechanisms. However, in corneal neovascularization, apoptosis of limbal stem cells and inappropriate repair by these cells can occur, resulting in an excess production of inflammatory cytokines (IL-6, IL-7, IL-8) and vascular endothelial growth factor (VEGF) (Sharif, 2019). This imbalance between angiogenic and antiangiogenic factors leads to the presence of blood vessels in the cornea, which impair vision by blocking and diffracting light. 

The incidence of the various etiologies underlying cNV vary in different parts of the world. In Western countries the most common etiology is herpes simplex keratitis, with approximately 500,000 cases of ocular herpes simplex virus reported every year (Lasagni, 2021). In regards to non infectious etiologies, contact lenses have been reported to be the most common non infectious cause of cNV in the US, affecting approximately 11–30% of the contact lens wearers (Lasagni, 2021). The patient presented in this case did not have any evidence of these common etiologies. The patient appears to be a demographic outlier as a recent study also showed that the median age of onset for cNV is 50.9 years of age (Lasagni, 2021).



Obtaining a diagnosis of cNV can be done in the clinical setting by slit lamp biomicroscopy under indirect and retro illumination. Neovascularization occurs rapidly, making early diagnosis difficult. Therefore, the risk for developing cNV should be assessed at regular time intervals during routine eye examinations. Among high-risk groups, such as contact lens wearers, screening should occur at shorter intervals to minimize the chance of vision loss (Sharif, 2019). In the present case, the patient received a routine slit lamp examination and intraocular pressure check every 6 months given her complicated ocular history of corneal ulceration and neurotrophic and infectious keratitis – all risk factors for cNV.

The cNV observed in this case must be understood in the context of the patient’s complex ocular history. Following surgical resection of an intracranial tumor, she developed CN 5-7 palsy. Consequently, trigeminal corneal innervation was damaged and severe corneal sensory impairment ensued, leading to a higher risk for corneal ulceration (Bonnie, 2003). With adequate corneal innervation, tear production and stimulation of the blinking reflex are crucial in maintaining an intact epithelium and minimizing external threats. However, in the absence of sufficient nerve function, the cornea is subject to insult from external stimuli, such as pathogens, xenobiotics, heat, and mechanical irritants (Yang, 2018). This explains the pathophysiological mechanism behind the patient’s presumed infectious keratitis. Certainly, corneal innervation is crucial for maintaining corneal health.



Finally, regarding the development of cNV in this patient, findings from several mouse model studies shed light on the possible mechanism at play. The cornea is avascular, yet remains the most densely innervated tissue in the body. Therefore, recent investigations have aimed to elucidate the relationship between nerves and neovessels. Interestingly, results demonstrate that both superficial and deep stromal corneal sensory nerves disappeared in those areas where neovessels were formed, while those in nonvascularized regions remained (Ferrari, 2013). Additionally, ablation of the ophthalmic branch of the trigeminal nerve led to cNV.

Injections and topical treatments can be used in the management of neovascularization. Steroids and anti-VEGF medications have been used as interventions for years. Topical steroids like dexamethasone have shown to be antiangiogenic and inhibit neovascularization in addition to their other anti-inflammatory effects. While steroids continue to be the mainstay of treatment, anti-VEGF therapies have begun to gain favor as a more specific therapy (Maddula, 2011). VEGF (vascular endothelial growth factor) is a growth factor that stimulates the formation of blood vessels. It has been implicated as a crucial factor in inflammatory neovascularization and anti-VEGF therapeutics have been developed in order to specifically target its proangiogenic effects (Maddula, 2011). Bevacizumab, a monoclonal antibody, is a commonly used anti-VEGF therapy. Previous studies on bevacizumab have shown a 36% reduction in neovascularization (Sharif, 2019).



Corneal transplantation is currently the most successful approach for treating cNV. However, the most common complication involved in this approach is the risk of transplant rejection. This risk is exacerbated by the presence of cNV, making this patient population a high-risk transplant recipient. It has been observed that the extent of neovascularization directly correlates to the risk of rejection. In a study dividing patients into mild, moderate and heavy neovascularization, 65% of the transplants were rejected in the heavy neovascularization group, despite immunosuppressive therapy (Di Zazzo, 2016).



In addition to transplant, another treatment option for neovascularization includes laser phototherapy. An argon laser can be used to pass through the cornea with the hemoglobin from new vessels absorbing the argon energy. The absorption of this energy causes vessels to coagulate, reversing the neovascularization (Sharif, 2019). Photodynamic therapy is a treatment that combines a photosensitizing compound, light, and oxygen. The compound is absorbed by the neovascular tissue and is activated through an additional laser treatment, causing free radicals to be released, which destroy the surrounding neovascular tissue and reverse the cNV (Sharif, 2019). Though laser phototherapy options have been used frequently in the treatment of neovascularization, more studies need to be conducted in order to confirm its efficacy in comparison to other approaches to neovascularization treatment.



Overall, cNV is a sight-threatening condition with several primary and secondary etiologies, making early diagnosis challenging. High risk patients, such as those with herpes simplex keratitis, corneal ulcers, or contacts should be routinely examined for cNV via slit lamp examination and imaging. As for the young patient presented here, cNV and the preceding neurotrophic and infectious keratitis were likely a result of impaired corneal innervation due to trigeminal nerve palsy. This case is a reminder of the importance of corneal innervation in preserving and maintaining corneal health.

References

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Byrd LB, Martin N. Corneal Ulcer. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan.

Deeks ED, Lamb YN. Cenegermin: A Review in Neurotrophic Keratitis. Drugs. 2020 Apr;80(5):489-494. doi: 10.1007/s40265-020-01289-w. PMID: 32185680.

Di Zazzo, A., Kheirkhah, A., Abud, T. B., Goyal, S., & Dana, R. (2017). Management of high-risk corneal transplantation. Survey of ophthalmology, 62(6), 816–827. https://doi.org/10.1016/j.survophthal.2016.12.010 

Ferrari, G., Hajrasouliha, A. R., Sadrai, Z., Ueno, H., Chauhan, S. K., & Dana, R. (2013). Nerves and neovessels inhibit each other in the cornea. Investigative Ophthalmology & Visual Science, 54(1), 813. https://doi.org/10.1167/iovs.11-8379 

Khodadoust, A. A., & Silverstein, A. M. (1972). Studies on the nature of the privilege enjoyed by corneal allografts. Investigative ophthalmology, 11(3), 137–148.

Lasagni Vitar, R. M., Triolo, G., Fonteyne, P., Acuti Martellucci, C., Manzoli, L., Rama, P., & Ferrari, G. (2021). Epidemiology of Corneal Neovascularization and Its Impact on Visual Acuity and Sensitivity: A 14-Year Retrospective Study. Frontiers in medicine, 8, 733538. https://doi.org/10.3389/fmed.2021.733538

Maddula, S., Davis, D. K., Maddula, S., Burrow, M. K., & Ambati, B. K. (2011). Horizons in therapy for corneal angiogenesis. Ophthalmology, 118(3), 591–599. https://doi.org/10.1016/j.ophtha.2011.01.041

Sharif, Z., & Sharif, W. (2019). Corneal neovascularization: updates on pathophysiology, investigations & management. Romanian journal of ophthalmology, 63(1), 15–22.

Yang, A. Y., Chow, J., & Liu, J. (2018). Corneal Innervation and Sensation: The Eye and Beyond. The Yale journal of biology and medicine, 91(1), 13–21.