Why Early NK Treatment Matters

In neurotrophic keratitis (NK), damage to the ophthalmic branch of the trigeminal nerve can lead to persistent epithelial defects, stromal scarring, corneal melting, and even perforation, all of which carry significant long-term visual consequences.

In my experience, early recognition and escalation of treatment are the most important determinants of success when managing NK; however, one of the challenges with this condition is that it is widely underdiagnosed. Patients with early NK can be easy to overlook, often presenting with an otherwise unremarkable ocular exam and only subtle symptoms, like mildly fluctuating or blurry vision. But once a patient progresses to stage 2 or stage 3 disease, management becomes far more difficult and the risk of permanent visual impairment increases (1).

Therefore, my goal is simple: to restore corneal innervation and stabilize the ocular surface as quickly as possible, before any patient progresses beyond stage 1.

Staging and diagnosing NK

The most commonly used system for staging NK is the Mackie classification: according to this system, in its first stage NK is characterized by punctate keratopathy and corneal epithelial abnormality; in the second stage patients experience persistent epithelial defect and stromal damage; in the third stage patients experience corneal ulceration with stromal melting, in addition to possible perforation (1).

When seeing patients with known risk factors, such as diabetes, prior herpetic infection, systemic neurologic disease, or a history of ocular surgery, there should be a heightened awareness of the possibility of NK. Additionally, if a patient has visible keratitis but reports no discomfort, this discrepancy should prompt an immediate corneal sensitivity test. Patients with corneal nerve damage may be able to tolerate an ocular surface that would be extremely uncomfortable for those with normal sensitivity (1).

Managing NK

In my experience, the most impactful treatments for NK are those that aim to add growth factors to the corneal surface in order to promote epithelial healing and nerve regeneration (2). Conventional therapies for NK include topical steroids, immunomodulators, and punctal plugs (3), but I have found that these are often insufficient to prevent disease progression, as they do not address the underlying neurotrophic pathology.

To combat the pathologic process, my first-line therapy is almost always a cryopreserved amniotic membrane (CAM), as they are rich in neurotrophic factors that promote corneal nerve regeneration (4, 5). For stage 1 and 2 NK, I typically start with the ringless option (CAM360 AG; BioTissue, Inc.), which is thinner and generally more comfortable, making it well suited for early disease and patients for whom comfort is key to compliance; I also often pair it with a short-term tape tarsorrhaphy to enhance its efficacy.

If the response in stage 2 is inadequate or slower than expected, I escalate to a self-retained CAM; the self-retained option is thicker and more durable, making it more appropriate for advanced or refractory cases. In stage 3, the self-retained variety is my starting point. In addition to their utility at any stage of NK, the wide availability of these products enables same-day treatment.

In stage 2 and stage 3 NK, recombinant human nerve growth factor (cenegermin [OXERVATE; Dompé U.S. Inc]) is often introduced concomitantly with CAM for additional nerve growth support (2). Cenegermin offers a highly concentrated nerve growth factor, which can be extremely effective in restoring corneal innervation (6); however, in my experience insurance authorization for this product is often delayed. If there is an insurance delay with cenegermin, I would advise you not to wait for the approval to also initiate CAM therapy. It’s also important to note that patients beginning cenegermin therapy may experience a temporary worsening of symptoms while their nerves regenerate in the presence of active keratitis (6), although in my experience this may be somewhat mitigated by starting them on a CAM first.

In situations where neither CAM therapy nor cenegermin are covered under the patient’s insurance, autologous serum tears or plasma-rich growth factor drops are potential treatments that offer cash-pay options, which may be more accessible (5).

Overcoming real-world barriers and setting expectations

When managing NK, I consider adherence and follow-up as critical aspects of the care plan – this is a chronic disease and patients need to understand that improvement takes time. Education is especially important before starting therapies like cenegermin, so that the transient symptom worsening they may experience does not lead to premature discontinuation. Insurance logistics and financial considerations also play a significant role, and clinicians must be prepared to advocate for their patients and offer alternatives when first-line therapies are not readily available or affordable.

Even after successful initial treatment, long-term ocular surface management is essential to prevent recurrence. Setting realistic expectations around the length of treatment and the importance of adherence helps patients stay engaged and committed to the healing process.

Addressing unmet needs and knowing when to escalate

Looking ahead, there are clear unmet needs in NK management – we need therapies that are more accessible, act quicker, and are easier for patients to use. Several emerging therapies show promise, and new formulations of placental and umbilical cord tissue rich in growth factors are particularly exciting to me. Further research into topical insulin and insulin-like growth factor pathways may also expand our therapeutic armamentarium and provide more accessible treatments to our patients. Additionally, therapies that leverage trigeminal nerve stimulation, such as varenicline nasal spray, are intriguing adjunctive approaches that warrant further investigation (2).

Understanding why NK develops in each case should be the fundamental tenet that clinicians keep in mind when evaluating a patient with this disease, and identifying and addressing patients’ underlying systemic disease, prior infections, surgical history, chronic dry eye, and lid pathology are critical steps for their long-term success. Lid disease, in particular, is frequently overlooked and, if left untreated, can undermine even the most advanced corneal therapies (2). While advanced medical treatments should always be pursued aggressively, clinicians must also recognize when surgical options are necessary. Corneal neurotization, temporary or permanent tarsorrhaphy, and collaboration with cornea or oculoplastic specialists may be necessary in severe cases.

Conclusion

NK is a common, aggressive, and often underestimated disease. Successful management depends on early recognition, prompt escalation, and a willingness to employ advanced therapies without delay. By treating decisively, educating patients thoroughly, and addressing the entire ocular surface ecosystem, we can preserve vision, prevent progression, and significantly improve outcomes for this challenging patient population.