Neurotrophic keratitis (NK) is a rare degenerative corneal disease characterized by impaired corneal sensation and reduced corneal healing ability. It is caused by damage or dysfunction of the trigeminal nerve, which supplies sensory innervation to the cornea.
NK is a challenging condition to manage due to its chronic nature and potential for severe vision loss. Its overall incidence rate is said to be around 0.05%.1
Manifestation of neurotrophic keratitis
This condition can manifest in several stages, each presenting unique clinical features and challenges for diagnosis and management.
The progression of neurotrophic keratitis is as follows:
- Stage 1: Patients exhibit mild symptoms such as ocular discomfort, foreign body sensation, and dryness due to reduced tear production and decreased blink reflex.
- Stage 2: The condition advances, leading to the development of superficial punctate keratitis, epithelial erosions, and persistent epithelial defects.
- Stage 3: Corneal ulcers develop.
- Stage 4: In the most severe cases, this final stage is characterized by corneal melting, perforation, and the potential for vision-threatening complications.
Understanding these distinct stages is crucial for healthcare providers as it guides the selection of appropriate treatment strategies, ranging from lubrication and topical medications in the early stages to more aggressive interventions like amniotic membrane transplantation or surgical procedures in advanced cases.
Moreover, identifying and addressing neurotrophic keratitis at its initial stages can significantly improve patient outcomes and prevent the progression to more severe and challenging clinical presentations.
Although there can be overlap, the critical distinguishing feature of neurotrophic keratitis that establishes its presence in a given cornea is the reduction or absence of corneal sensation, which can be objectively measured through esthesiometry.
To learn about new treatment options for persistent epithelial defects secondary to NK, check out New Options for Non-Healing Epithelial Defects!
Etiologies of NK related to this case report
Etiologies of neurotrophic keratitis include:
- Herpes simplex virus (HSV) infection affecting the trigeminal nerve
- Diabetes mellitus, which can cause neuropathy and impair corneal innervation
- Direct trauma or surgical damage to the corneal nerves
- Long-term use of contact lenses or preserved eye drops
- Certain systemic diseases, such as multiple sclerosis and Guillain-Barré syndrome
Timolol
While timolol eye drops have shown promise as a therapeutic option for glaucoma, it is essential to acknowledge the possibility of adverse effects and exacerbation of neurotrophic keratitis in some cases.2
Timolol is a non-selective beta-blocker, and its use can lead to reduced corneal sensitivity, a key characteristic of neurotrophic keratitis. Corneal anesthesia may further compromise the epithelium, potentially worsening the condition by inhibiting the protective blink reflex and increasing the risk of corneal ulceration or infection.
Moreover, systemic absorption of timolol can occur, potentially causing systemic side effects, such as bradycardia, bronchoconstriction, and hypotension, which may have detrimental consequences for patients, especially those with underlying cardiovascular or respiratory conditions.
Therefore, the administration of timolol eye drops in neurotrophic keratitis should be approached with caution, and close monitoring of patients for adverse effects is imperative to ensure its safety and appropriateness as a treatment option in individual cases. In our patient, timolol eye drops were held, and this may have also contributed to the improvement of corneal sensation and symptoms
Pars plana vitrectomy
Neurotrophic keratitis following retinal procedures, specifically pars plana vitrectomy (PPV), is a rare but concerning complication that can lead to substantial morbidity.
While the overall incidence rate of neurotrophic keratitis is said to be around 0.05%, it is estimated that post-vitrectomy, this number can reach as high as 2%.3-5 PPV is a surgical technique involving the removal of the vitreous gel from the eye through small incisions in the pars plana region of the eye.
PPV is performed for various retinal conditions, including retinal detachment, macular hole, vitreous hemorrhage, and epiretinal membrane. The surgery may involve the use of instrumentation near the cornea, which can potentially affect corneal nerves and lead to neurotrophic changes.
In recent years, there has been increased recognition of the association between NK and PPV.3-5 PPV can disrupt the delicate balance of corneal innervation, leading to reduced corneal sensitivity and compromised healing ability.3-5 Corneal nerve damage, ischemia, and decreased trophic factors contribute to the pathogenesis of NK following PPV.3-5
Endophotocoagulation
Endophotocoagulation is often used to repair retinal detachment and retinal tears; however, it may result in neurotrophic keratitis by damaging the ciliary nerves in the suprachoroidal space on their way to the pupil.3-5
The risk of neurotrophic keratitis should be weighed against the dose of laser retinopexy necessary and sufficient to obtain a sustained retinal reattachment. If circumferential endophotocoagulation is implemented, it is sensible to monitor corneal sensitivity and implement post-operative treatment if necessary.
Clinicians should be mindful of the long ciliary nerves intra-operatively and, where possible, avoid heavy confluent laser treatment at these sites without compromising the need for adequate retinopexy. If corneal anesthesia occurs, it is important to recognize it early and treat it promptly to minimize the risk of ulceration and visual loss.
Pearl: If patients have persistent epithelial defects following retina surgery, retina surgeons should involve their corneal colleagues or consider neurotrophic keratitis.
Case presentation
A 60-year-old female with recurrent retinal detachments underwent three pars plana vitrectomy surgeries in her right eye over 2 years. Following the third PPV, the patient complained of persistent pain, photophobia, and a gradually worsening visual acuity.
Clinical examination revealed:
- Corneal epithelial defects
- Conjunctival injection
- Decreased corneal sensitivity as measured by corneal esthesiometer
Slit-lamp biomicroscopy and corneal fluorescein staining confirmed the diagnosis of neurotrophic keratitisc (Figure 1). Traditional treatments, including lubrication, bandage contact lens, and preservative-free artificial tears, were initiated but failed to yield substantial improvement over 6 weeks.
Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) was started, right lower and upper punctal plugs were placed, and right lower lid punctal cautery was performed. Additionally, a timolol eye drop was held, which had been used previously for ocular hypertension due to its reported association with NK.
Figure 1: Slit lamp image of the patient before initation of cenegermin-bkbj therapy.
Figure 1: Courtesy of John C Affeldt, MD, Kakarla V Chalam, MD, Loma Linda University.
Treatment and outcome
Given the refractory nature of the neurotrophic keratitis, the decision was made to initiate treatment with cenegermin-bkbj ophthalmic solution 0.002% (20mcg/mL, Oxervate, Dompé), a recombinant human nerve growth factor. The patient received daily topical application of cenegermin-bkbj for 8 weeks.
Clinical improvement was noted at subsequent follow-up visits, including corneal re-epithelialization, pain reduction, and visual acuity.
Clinical examination revealed:
- Visual acuity improved from 20/400 to 20/200
- Schirmers improved from 1 to 12mm
- Corneal sensation improved from 5 to 42mm, as measured by esthesiometer
By the end of the treatment period, the patient's cornea had completely healed, and her visual acuity had improved (Figure 2).
Figure 2: Slit lamp image 5 weeks after the initiation of Oxervate therapy.
Figure 2: Courtesy of John C Affeldt, MD, Kakarla V Chalam, MD Loma Linda University.
In conclusion
Prompt diagnosis and tailored therapeutic intervention are essential to prevent permanent visual impairment. The successful resolution of neurotrophic keratitis in this case with cenegermin-bkbj underscores the potential utility of this novel treatment approach in managing cases that are not manageable with historically first-line therapies.
This case highlights the occurrence of neurotrophic keratitis as a possible complication after multiple pars plana vitrectomies and emphasizes the successful resolution achieved with cenegermin-bkbj treatment.
As retinal procedures continue to advance, ophthalmologists should remain vigilant for potential corneal complications and consider innovative therapeutic strategies, such as cenegermin-bkbj, to effectively manage and mitigate the impact of neurotrophic keratitis in this clinical context.
Importantly, one must also remember that agents such as cenegermin-bkbj, do not need to only be utilized in advanced or recalcitrant cases of neurotrophic keratitis, but can also be employed early on.
