A patient comes to the ophthalmologist with extremely dry eyes and unrelenting, burning pain that is sensitive to light. The patient is diagnosed with keratoconjunctivitis sicca, otherwise known as dry eye, but remains symptomatic even after months of treatment. The patient’s objective indicators (tear osmolarity and inflammatory markers) and physical exam findings are entirely within normal ranges, leading the doctor to question the initial diagnosis.
Given that the patient’s primary complaint is unrelenting eye sensitivity with ocular pain and symptoms out of proportion with physical findings, neuropathic corneal pain (NCP) is high on the differential. In this condition, patients develop hypersensitivity to incidental stimuli which are normally non-painful. The mechanism driving this is believed to involve upregulated nociceptors and increased dysfunctional peripheral pain fiber excitability resulting in peripheral sensitization, or it can be driven by a central process that involves heightened sensitivity to normal stimuli.
Pathophysiology of Neuropathic Corneal Pain
The pathophysiology of peripheral sensitization is that recurrent damage and inflammation to the ocular surface can upregulate the release of pro-inflammatory mediators. As time progresses, this can result in central sensitization due to the neurons in the CNS becoming hypersensitive to similar magnitudes of pain and overall heightened awareness of pain.
Another theory behind neuropathic corneal pain is that dysfunctional pain-generation sites are discharging spontaneously and without stimulation.
A hallmark of central sensitization is pain that is detached from peripheral signals. Triggers of corneal neuropathic pain include chronic ocular surface disease, herpesvirus infections, post-surgical, radiation, trauma, trigeminal neuralgia, or fibromyalgia (4).
Classic Presentation and Clinical Exam of NCP
Patients classically present in great distress, with complaints of excruciating and incessant corneal pain that can sometimes be relieved by closing their eyes. They may present with dry eyes that are extremely sensitive to light, foreign body sensation, or reflex tearing (6). Often these patients do not find relief of their symptoms despite maximal dry eye therapy.
A thorough history can help differentiate the cause of NCP
Oftentimes, these patients’ symptoms can be dismissed by other physicians due to their ocular exam findings being normal. However, systemically patients may have a history of HSV infection, recent surgery, or a previous diagnosis of multiple sclerosis or fibromyalgia.
It is important to note patients that have other chronic pain syndromes or psychiatric disorders such as anxiety or depression as they may coincide with their pain and help determine the cause of their symptoms.
For example, fibromyalgia is a systemic disorder that can result in increased mortality from gastrointestinal, cardiovascular, and musculoskeletal diseases. Ocular manifestations of fibromyalgia include blurred vision, dry eye, and corneal sensitivity.
Studies have shown that patients with fibromyalgia may have irregular optic disc perfusion and decreased retinal nerve fiber layer thickness. In addition, patients with fibromyalgia have a higher threshold for detecting noxious chemical and thermal stimuli when it is applied to the cornea irrespective of age (8). This suggests that patients with fibromyalgia can have sensory deterioration that develops early in life.
On clinical examination, a slit-lamp exam with dyes such as fluorescein, lissamine green, and rose Bengal can be used to assess the patient’s corneal and conjunctival epithelial integrity to rule out possible corneal ulcers contributing to the pain.
Tear film volume can be assessed using Schirmer’s and phenol red thread to distinguish NCP from dry eye since neuropathic pain can be a component of dry eye (13). Furthermore, tear osmolarity and inflammatory markers can also be used to distinguish dry eyes although their efficacy remains controversial. If the patient does not have an underlying condition, their ocular surface will appear to be healthy; however, it is important to note that dry eye and neuropathic corneal pain may coexist, further making treatment and diagnosis more difficult.
Differential Diagnoses of NCP
Differential diagnoses to keep in mind when assessing a patient with neuropathic corneal pain include, but are not limited to, keratoconjunctivitis sicca (also known as dry eye), herpes simplex virus (HSV), fibromyalgia, radiation exposure, or limbal stem cell deficiency.
Keratoconjunctivitis sicca is a multifactorial disorder that is due to inflammation of the ocular surface, decrease in the production of tears, neurotrophic deficiency, and meibomian gland dysfunction (10). Herpetic keratopathy is due to HSV infection and it can result in denervation of the trigeminal nerve resulting in decreased corneal sensation. It can also stay dormant in the trigeminal nerve reemerging when the patient is ill or immunocompromised. Both severe dry eye and HSV keratopathy can damage the corneal nerves, resulting in neurotrophic keratitis. Due to the decreased corneal sensation, proper feedback provided by the cornea to generate tears is lost, causing the epithelium to break down, which prevents corneal healing and response to injury.
Systemic Approach to Diagnosis
A systematic approach that encompasses the patient’s history, symptoms, physical exam, and diagnostic tests can be to determine the underlying cause of a patient’s neuropathic corneal pain. Past medical history of surgery (e.g., LASIK) or infections such as HSV must be elicited along with radiation exposure, systemic disorders, or other ocular surface diseases.
The diagnosis of neuropathic corneal pain (NCP) can be challenging in part due to a lack of understanding of the disease, as well as the lack of predominant clinical signs that can conceal underlying health problems. Therefore, clinical history and symptoms are key for diagnosis along with the ophthalmologic exam.
To begin with, a validated questionnaire can be used to assess the patient’s symptoms and their quality of life. However, most questionnaires such as the Ocular Surface Disease Index (OSDI), McMonnies Dry Eye Questionnaire, and National Institute of Vision Function Questionnaires are aimed at the diagnosis of dry eye disease (13).
Therefore, It is important to use other tools to assess neuropathic corneal pain. The proparacaine challenge allows the physician to evaluate if the origin of the corneal pain is central or peripheral. Since proparacaine eliminates peripheral pain, patients that have relief after the proparacaine challenge likely suffer from peripheral or mixed NCP instead of central (7)
Esthesiometry such as Cochet-Bonnet contact esthesiometer can assess for nociceptive responses. As discussed earlier, clinical exams using a slit-lamp with dyes such as fluorescein can allow for assessment of the cornea to ensure corneal and conjunctival integrity. Laser in vivo confocal microscopy is a non-invasive, high-resolution device that allows visualization of corneal structures at a cellular level, providing biopsies at a histological level (2). In fact, confocal microscopy can be an incredibly valuable diagnostic tool as it may confirm abnormal collections of tortuous corneal nerves—and in this way, provide anatomical confirmation for symptoms ‘out of proportion’ to exam findings.
Treatment of Neuropathic Corneal Pain
Treatment of NCP involves determining the origin of the pain, whether it is central, peripheral, or mixed. Most of the proposed therapies are derived from evidence-based literature for ocular post-herpetic neuralgia and systemic neuropathic pain.
Peripheral NCP is initiated by injury to the nerve and subsequent inflammation. One mechanism to reduce this pain is the use of autologous serum tears (AST). This is derived from the fact that AST contains particular nerve growth factors that reduce allodynia (pain from stimuli that is normally not painful) through the reduction of reactive astrocytosis and glial modulation (1).
Topical corticosteroids can be used due to their inhibitory effect on cytokines, prostaglandins, and leukotriene synthesis along with leukotriene migration. Loteprednol 0.5% suspension gel with a slow taper is recommended for two weeks because it is associated with lower rates of increased intraocular pressure and risk of cataract formation.
Rehabilitation of the ocular surface
In patients that have concurrent dry eyes, lubrication can provide a bit of relief but it can also result in decreased tear osmolality and dilution of pro-inflammatory mediators. After treatment with anti-inflammatory medication, punctal plugs can be placed to increase the tear lake. Be aware that patients with concurrent ocular allergies can have greater contact time with the allergen due to the punctal plugs (5).
In patients with decreased tear break-up time and increased tear evaporation, treatment can be geared towards emulsion-based lubricants and treatment of concomitant meibomian gland disease. This can be done by a lid massage using hot compresses or thermal pulsation devices (14)
Here is a guide to using lipiflow to treat meibomian gland dysfunction: https://covalentcareers.com/resources/guide-to-using-lipiflow-to-treat-meibomian-gland-dysfunction/
Protective Contact Lens
Patients that have a peripheral source of pain (relief of pain after proparacaine challenge) that is refractory to topical meds can use extended wear soft bandage contact lens or scleral lens for relief. By guarding the corneal nociceptors from the external environment, patients may experience more relief and decreased light sensitivity (11).
When patients have NCP due to central sensitization, systemic pharmacotherapy is the best course of treatment. This is because the origin of the pain is from central neurons that are becoming highly responsive to the same magnitude of pain (9). Oftentimes, a combination of therapeutics is necessary to treat the patient's ailments.
First-line treatment is tricyclic antidepressants, which block the presynaptic reuptake of serotonin and norepinephrine along with cholinergic, histaminergic, and sodium channels (3). Carbamazepine, a sodium-channel blocker, is used in the treatment of trigeminal neuralgia.
Second-line treatments include opioid antagonists that block TLR-4 that has been associated with neuropathic pain, thereby reducing the release of pro-inflammatory cytokines. Tramadol is a weak μ-opioid agonist that also inhibits norepinephrine and serotonin. In the past, gabapentin, pregabalin, and carbamazepine have been used with some success.
Neuropathic corneal pain is a multifactorial disorder that can be challenging to diagnose and treat. It is important to keep NCP in the differential when a patient presents with dry eyes or intense pain not proportional to ocular findings. Treatment of NCP involves assessing the patient’s underlying medical problems, determining the root of the pain, and treating appropriately.
- Cirillo G, Cavaliere C, Bianco MR, et al. Intrathecal NGF administration reduces reactive astrocytosis and changes neurotrophin receptors expression pattern in a rat model of neuropathic pain. Cell Mol Neurobiol. 2010;30(1):51–62.
- Cruzat A, Qazi Y, Hamrah P. In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease. Ocul Surf. 2017;15(1):15–47.
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- Galor A, Zlotcavitch L, Walter SD, et al. Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain. Br J Ophthalmol. 2015;99(5):665-668.
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- Garcia-Martin E, Garcia-Campayo J, Puebla-Guedea M, Ascaso FJ, Roca M, Gutierrez-Ruiz F, et al. (2016) Fibromyalgia Is Correlated with Retinal Nerve Fiber Layer Thinning. PLoS ONE 11(9): e0161574. https://doi.org/10.1371/journal.pone.0161574
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- Spierer O, Felix ER, McClellan AL, et al. Corneal Mechanical Thresholds Negatively Associate With Dry Eye and Ocular Pain Symptoms. Invest Ophthalmol Vis Sci. 2016; 57(2):617–625. [PubMed: 26886896]
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