When patients present with ocular pain, we will search for the underlying cause to determine our management pathways. When a cause is identifiable as in the case of trauma, infection, or inflammation, this is managed using topical steroids, topical or systemic nonsteroidal anti-inflammatory drugs (NSAIDs), lubricants, and so on. And, with careful follow up, the presenting symptoms typically resolve.

However, when a patient presents with ocular pain in the absence of the expected clinical signs, the clinical management becomes more challenging (Galor et al, 2018; Galor et al, 2015). This is most commonly and frustratingly encountered in practice when a patient presents with symptoms of dry eye and ocular pain without the expected signs relating to aqueous deficiency or evaporative dry eye disease (DED) (Craig et al, 2017). The Tear Film and Ocular Surface Society’s (TFOS) Dry Eye Workshop II (DEWS II) report identified this presentation as “neuropathic pain” (Craig et al, 2017). The report placed particular emphasis on neurosensory abnormalities, acknowledging that these may play a role in the presentation of DED (Craig et al, 2017).

Importantly, neuropathic pain is considered a separate entity from DED, and so a separate line of management is required (Belmonte et al, 2017). Some of our patients presenting with dry eye symptoms and pain may, therefore, not have DED at all. Rather, it may just be a perturbance of pain and sensation, which could possibly explain why treatment is ineffective in many cases.

What Is Neuropathic Pain?

According to the International Association for the Study of Pain, pain can be either nociceptive or neuropathic. Nociceptive pain is a result of damage to non-neural tissue, which then activates the nociceptors, hence manifesting in transient pain as a result of normal functioning nociceptors. DED would be expected to contribute to nociceptive pain.

With neuropathic pain, there is a lesion in the somatosensory nervous system in the absence of signs, although the original cause may be a result of systemic conditions such as diabetic peripheral neuropathy or post-herpetic neuralgia. In many cases, there is no clear underlying pathology.

At the ocular surface, nociceptors respond to mechanical, chemical, and thermal stimuli. Corneal nociceptors are responsible for detecting evaporation at the ocular surface and are linked to the blink reflex as well as to lacrimal and meibomian gland secretion through the autonomic nervous system. The development of neuropathic ocular pain is hypothesized to result from recurrent injury—such as prolonged inflammation—that sensitizes the peripheral and central somatosensory pathways (Galor et al, 2018).

Centralized Versus Peripheral Neuropathic Pain

Peripheral pain refers to pain that is localized to the peripheral sensory nerves and tends to be acute and short-lived, while centralized pain refers to pain that is at the level of the central nervous system and tends to be chronic. The abnormal signaling in peripheral nerve pain may convert to centralized pain due to chronic stimulation. We can differentiate pain that is centrally mediated from that which is peripherally mediated by using topical anesthetic; the elimination of symptoms indicates that the pain is peripherally mediated, while pain that remains is centrally mediated (Crane, Feuer et al, 2017).

How Can We Assess Neuropathic Pain in Practice?

Neuropathic pain and DED share many features, for example, discordance between signs and symptoms and non-response to therapies (Galor et al, 2018). Unlike DED, there is no consensus as to the diagnostic protocols for neuropathic ocular pain. Evidence of damage to the somatosensory nervous system is required, but can be difficult to ascertain.

Diagnosis is ultimately questionnaire-based, with a significant overlap in the questions asked for DED (Galor et al, 2018). The Ocular Surface Disease Index (OSDI) (Schiffman et al, 2000), Dry Eye Questionnaire (DEQ) (Begley et al, 2001), and the Ocular Pain Assessment Survey (OPAS) (Qazi et al, 2016) can all be used. Allodynia (central pain sensitization following normally non-painful, often repetitive stimulation) and hyperalgesia (a disproportionate pain response to an innocuous stimulus) are two symptoms associated with centralized neuropathic pain. However, there is no clinical grading scale for these.

Testing corneal sensitivity may also help determine the presence of neuropathic pain in cases in which sensitivity is reduced in the presence of ocular pain (Jacobs, 2017). For example, using nerve conduction testing, quantitative sensory testing, or nerve excitability may help identify the presence of a systemic neuropathy (Galor, Levitt et al, 2016). This may then require a more systemic approach to the management of the ocular pain. To start, determine the cause of this peripheral neuropathy, such as post-herpetic neuralgia.

The structure of corneal nerves can be assessed using in vivo corneal confocal microscopy (Oliveira-Soto and Efron, 2001). However, their relationship with symptoms of neuropathic ocular pain are equivocal (Belmonte et al, 2017).

It is important to determine whether there is a history of ocular surgery or a history of pain elsewhere that could suggest a systemic neuropathy; patients who have ocular neuropathic pain tend to report more frequent and severe non-ocular functional comorbid pain disorders (Crane, Levitt et al, 2017; Galor, Covington et al, 2016). A recent study has suggested that a vitamin B12 deficiency may be linked with neuropathic pain, which suggests the need to measure serum levels of B12 in the presence of resistant ocular pain (Ozen et al, 2017).

What Can We Do About It?

Management of neuropathic pain differs from that for DED given the differing etiologies. Therefore, the differential diagnosis of neuropathic pain from physiologic nociception is critical to allow for suitable management. The focus is on symptoms, which is how the disease manifests. Additionally, the goal of treatment is to reduce signaling, which is the underlying cause of neuropathic pain. Management needs to be multimodal and includes both local and systemic therapies to address peripheral and centralized pain:

1. Peripheral Pain Reduce the potential for local subclinical inflammation that can promote pathological signaling and further damaging. The use of topical steroids, immunomodulators, autologous serum, and NSAIDs have been suggested to target this (Jacobs, 2017). It is important to weigh the benefits against the risks of each drug type.

2. Systemic Treatment for Peripheral or Centralized Pain Gabapentin and pregabalin (calcium channel alpha 2 delta ligands) have been used in painful neuropathic pain such as severe diabetic neuropathy, fibromyalgia, and post-herpetic neuralgia (Wiffen et al, 2017). Galor, Batawi et al (2016) report the use of these medications for neuropathic pain and cite side effects of drowsiness, dizziness, headache, and loss of balance.

Alternate approaches such as stimulation therapies have shown very little evidence to support their use in neuropathic pain. In addition, non-pharmacological approaches—such as exercise, massage, and acupuncture—have similarly been recommended with little evidence supporting their use.

Conclusion

Patients presenting with ocular pain—such as dry eye symptoms in the absence of associated dry eye signs—may in fact be experiencing neuropathic pain. Given the differing etiologies, the latter needs to be differentially diagnosed to allow appropriate management.

Patients who have neuropathic pain need to be carefully monitored and educated because no single cure will necessarily work. They may also need to be co-managed with colleagues in another field (such as neurology) in the case of underlying systemic neuropathies. CLS

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