Overview

Neurotrophic keratoconjunctivitis (NK), a rare degenerative eye disease, occurs when nerves that innervate the cornea get damaged or impaired, resulting in reduced corneal sensitivity and disrupted vision. This is often due to a recurrent herpes simple virus infection that damages the trigeminal nerve, affecting corneal sensitivity. Symptoms do not always appear in the early stages, however, you may experience eye pain, redness, or blurred vision. 

Common clinical diagnostic criteria include decreased corneal sensation, and corneal defects, for example, punctate epithelial erosions, persistent epithelial defects,  ulceration, and thinning, which can lead to perforation (an opening into the interior of the eye). This can result in infection or, in some cases, loss of vision. Early diagnosis allows for doctors to intervene and treatment help prevent irreversible corneal damage.^1,2,3

Anatomy and physiology

The cornea, one of the most densely innervated organs in the human body, receives sensory nerves from the trigeminal nerve. These nerves detect somatosensory stimuli, such as touch, pain, and temperature. They play a key role in regulating our eyeblink reflex, tear secretion, and promoting wound healing. Without proper innervation to the cornea, like in NK, these protective mechanisms begin to break down, causing damage to the delicate membrane of our eye.   It can lead to epithelial breakdown, causing stromal damage and ulceration.^1,2,3 

Pathophysiology of nerve damage

Common causes or risk factors of nerve damage include:

• Herpes simplex/zoster infections
• Chemical burns
• Systemic conditions (diabetes, leprosy, and multiple sclerosis)
• Prolonged contact lens use
• Surgical procedures involving the trigeminal nerve include corneal surgery, ablative treatments for trigeminal neuralgia, and jaw fracture reduction surgeries
• Intracranial lesions, such as aneurysms, meningiomas, and schwannomas
• Congenital syndromes, including Riley-Day, Goldenhar-Gorlin, and Möbius syndromes
• Inherited conditions, including congenital insensitivity to pain with anhidrosis and corneal hypesthesia^1,2,3

Clinical stages

• Stage 1 (Mild): Corneal epithelial changes (dry and cloudy corneal exterior), superficial punctate keratopathy (small, pinpoint-like lesions on the cornea's surface), corneal edema (swelling), dryness, and irritation (often asymptomatic due to loss of sensation)
• Stage 2 (Moderate): Frequent and/or persistent epithelial defects (usually seen at the top half of the cornea), corneal infiltrates (inflammatory cells), and corneal thinning
• Stage 3 (Severe): Corneal ulcer causing corneal melting, perforation, or rupture and leading to severe blurred vision or complete vision loss^1,4

Diagnosis

Diagnosis of NK is characterised by decreased corneal sensitivity usually confirmed by an esthesiometry test. It is also dependant on your clinical history associated with trigeminal impairment, persisting epithelial defects or ulcers, and decreased corneal sensitivity. Diagnosis can often be delayed as the disease progresses gradually and is considered asymptomatic in the early stages.^1,2,3 Therefore, more research needs to be done to enhance clinical diagnosis, facilitating faster interventions to prevent damage from occuring.  

History and clinical exam

Thorough clinical history and examination by doctors and nurses will provide an accurate diagnosis. Key testing measures and findings include:

• Corneal sensitivity reduction, assessed using a cotton wisp or an esthesiometer 
• Persistent epithelial defects and corneal changes, assessed in clinic under light or with eye staining procedure

For example, a slit-lamp examination can identify reduced tear meniscus height along with epithelial irregularities, punctate keratopathy, and stromal opacities. Additionally, fluorescein and rose bengal staining help visualise the extent of epithelial and conjunctival damage^1,2,3

Imaging and tests

Several advanced imaging and diagnostic techniques can help confirm NK diagnosis as well as visualise the extent of damage and therefore rate its severity. For example:

• Anterior segment optical coherence tomography quantifies corneal thinning, ulcer depth, stromal changes, and tear film dynamics
• In vivo confocal microscopy allows for visualisation of the subbasal nerve plexus, including nerve density, beading, fragmentation, and, in advanced cases, keratocyte apoptosis
• Impression cytology and biomarker analysis can help evaluate ocular surface inflammation and epithelial dysfunction
• Corneal nerve imaging provides insights into nerve integrity and its regenerative potential
• Corneal esthesiometry, with confocal microscopy, provides information for monitoring disease progression and evaluating treatment response

Treatment strategies

Treatment strategies depend on the stage of degeneration NK has reached (disease severity), and individual eye differences. They include more conservative, non-invasive, regenerative approaches as well as invasive surgical procedures, to promote corneal healing, restore nerve function, and prevent further complications down the line.^1,2,3

Conservative medical therapy

• Lubrication with preservative-free artificial tears or hydrogel inserts
• Use of autologous serum tears maintains ocular surface hydration
• Discontinuation of toxic medications, such as preserved eye drops, glaucoma drugs, and long-term corticosteroids, helps prevent epithelial toxicity
• Use of contact lenses (bandage, scleral, and amniotic membrane lenses) supports healing in persistent epithelial defects^1,2,3

Biological and pharmacologic treatments

• Recombinant nerve growth factor (NGF) stimulates corneal nerve regeneration and enhances epithelial healing
• Platelet-rich plasma and autologous serum drops, which contain epithelial growth factors and anti-inflammatory cytokines, help reduce inflammation and support ocular surface repair^1,2,3

Additionally, new more advanced therapies are becoming more and more widely developed. Mesenchymal stem cell therapy, bioengineered corneal substitutes, and gene-based neurotrophic factor delivery are emerging therapies that effectively promote corneal nerve regeneration, epithelial healing, and ocular surface restoration.^1,2,3

Surgical approaches

Surgical options are considered in severe or refractory cases of NK. These include:

• Tarsorrhaphy reduces corneal exposure and promotes healing
• Amniotic membrane transplantation, promotes epithelial healing through its growth factors and anti-inflammatory properties
• Corneal neurotisation transplants the supraorbital or infraorbital nerve to restore corneal sensation
• Conjunctival flaps and keratoplasty address corneal perforation

Prognosis and complications

The early stages (stage 1 or 2) of NK can be challenging to diagnose. Degeneration of the trigeminal nerve happens gradually over time, additionally, damage to the eye can accumulate, and be hard to identify because of the reduced corneal sensation associated with NK. 

Despite this, we know that timely treatment interventions improves health outcomes. Whereas in advanced cases, when diagnosis occurs at stage 3, prognosis is worsened and you are at higher risk of developing secondary infections, corneal scarring, and sometimes even complete blindness. Therefore, early diagnosis and prompt intervention might reduce the risk of further impairment or vision loss. Improper management might result in complications such as delayed corneal wound healing, scarring, and complete vision loss.^1,2,3

Prevention and monitoring

• Early identification of people with diabetes, prior infection with either herpes simplex virus or varicella-zoster virus, or a history of neurosurgical procedures reduces the risk
• Regular monitoring of corneal healing in patients with reduced corneal sensitivity, along with treatment adherence, helps detect early signs of disease progression and complications, allowing for timely interventions
• Educating people on proper eye drop instillation helps prevent ocular trauma, improves adherence, and supports effective disease management^1,2,3

FAQs

What is the most common cause of neurotrophic keratoconjunctivitis?

Ocular conditions such as herpetic simplex/zoster infections, prolonged topical anesthetic use, chemical and thermal burns, prolonged contact lens use, topical drug toxicity, irradiation to the eye or adnexa, and corneal surgery are the most common causes of neurotrophic keratoconjunctivitis.

Is neurotrophic keratoconjunctivitis the same as dry eye?

No. Stage 1 symptoms of neurotrophic keratoconjunctivitis are quite similar to those of patients with dry eye disease, such as eye pain, irritation, foreign body sensation, or constant blurred vision. However, the discomfort decreases as the severity of the condition increases.

Summary

Neurotrophic keratoconjunctivitis is a rare, degenerative eye disease that damages the corneal nerves and decreases corneal sensitivity. The condition is asymptomatic in its early stages; however, a few individuals may experience eye pain, redness, blurred vision, and scarring. This condition impairs the cornea’s protective reflexes and healing ability, increasing the risk of epithelial defects, ulcers, thinning, and in severe cases, perforation and vision loss. 

The most common causes include infections (like herpes simplex/zoster), systemic diseases (such as diabetes), prolonged contact lens use, trauma, surgeries, and certain congenital syndromes. The condition progresses gradually from mild epithelial changes (stage 1) to severe corneal ulceration and complete vision loss (stage 3). Patients diagnosed in stage 1 or 2 achieve favorable visual outcomes, while those progressing to stage 3 increase the risk of complete vision loss. Diagnosis often requires careful clinical examinations and specialised imaging techniques. 

Treatment varies based on severity and includes lubricants, therapeutic contact lenses, biological agents like recombinant nerve growth factor, and surgery in advanced cases. Emerging therapies, such as stem cell and gene-based treatments, have shown improved outcomes. Regular monitoring and educating patients on self-care techniques enhance patient treatment adherence and help manage their condition.