Pain without stain poses diagnostic and therapeutic dilemma

Take-home message: Keratoneuralgia, also known as “pain without stain” is primarily a clinical diagnosis made for patients with corneal pain symptoms with minimal-to-no clinical signs and minimally, if at all, relieved by conventional dry eye treatments.

By Cheryl Guttman Krader; Reviewed by Stephen C. Pflugfelder, MD

Houston-Patients who complain bitterly about dry eye symptoms that are out of proportion to any disease signs and not ameliorated by usual dry eye treatments may be considered as hysterical or psychosomatic.

However, these “problem” patients may be suffering from keratoneuralgia, also known as “pain without stain,” said Stephen C. Pflugfelder, MD.

“Disconnect between the signs and symptoms in these patients may cause clinicians to discount or dismiss their complaints,” said Dr. Pflugfelder, professor and director, Ocular Surface Center, and holder of the James and Margaret Elkins Chair, Department of Ophthalmology, Baylor College of Medicine, Houston. “Because of their symptoms and inability to find relief, these patients are often depressed and they may also feel they are less productive.

“Unfortunately, keratoneuralgia is a tough condition to treat, and the outcome for many patients remains poor,” he said. “However, there are several options to try, including counseling to help patients cope with pain.”

Predisposing factors

The cornea is highly vulnerable to developing neuropathic pain as it is the most exposed mucosal tissue in the body, susceptible to trauma and environmental stress, and has the highest density of nociceptors of any tissue in the body, Dr. Pflugfelder explained.

Free nerve endings in the cornea can become more sensitive to normal environmental stimuli, perhaps as a result of the presence of increased inflammatory mediators or abnormal nerve regeneration resulting in increased density of sodium ion channels.

Thus, it may not be surprising that keratoneuralgia is most often seen after LASIK, where it can occur as a result of aberrant nerve regeneration. Tear dysfunction is another predisposing factor. In particular, the latter group of patients may include younger individuals with a history of some acute insult, such as blepharoplasty leading to ocular exposure or isotretinoin use causing meibomian gland loss.

Other risk factors for keratoneuralgia include excessive UV light exposure, chemical injury causing nerve damage, and trigeminal zoster.

Evaluation and management

The diagnosis of keratoneuralgia is primarily clinical and based on pain symptoms out of proportion to clinical signs.

“Patients with keratoneuralgia may report ocular burning, foreign body sensation, photophobia, and exquisite sensitivity to dry and drafty environments,” Dr. Pflugfelder said. “Their only objective sign may be a rapid tear break-up time and their chronic pain symptoms may lead to central sensitization.”

Central sensitization is an amplification of nerve signals within the central nervous system that elicit pain hypersensitivity from a loss of inhibitory neurons or from amplification of signals from low threshold innocuous stimuli, such as are drafts or temperature changes. It can be identified by failure to obtain symptomatic relief after instillation of a topical anesthetic or following placement of the PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem, Boston Foundation for Sight) device.

Confocal microscopy in patients with keratoneuralgia may show abnormal nerves. The findings can include decreased number, increased tortuosity, and beading of the subbasal nerve plexus along with presence of nerve stumps, excessive sprouting, or dendritic cell infiltration.

Strategies for management of keratoneuralgia include measures to shield the cornea from environmental stress, such as placement of a soft contact lens, use of wraparound or moisturizing glasses, or fitting with a PROSE device.

“The PROSE device shields the cornea from environmental stress and also bathes it with body temperature saline, and it may act to silence the corneal nociceptors,” Dr. Pflugfelder said.

Autologous serum or plasma drops may promote healing of damaged corneal nerves. Dr. Pflugfelder noted that he and colleagues reported on the use of autologous plasma to treat neurotrophic keratopathy in 11 eyes of 6 patients [Br J Ophthalmol. 2010;94:584-591]. The underlying etiologies for the group included LASIK, diabetes mellitus, herpes zoster, and trigeminal nerve ablation. The treatment promoted nerve regeneration and significant improvement in the mean symptom severity score.

“This was one of the more effective treatments we have used for pain without stain,” Dr. Pflugfelder said. “Recent evidence indicates that platelet-rich plasma may be even more effective. However, it is also more difficult to obtain.”

Systemic treatment with a GABA-mimetic agent, gabapentin or pregabalin, may also be helpful, but may require a high dose.

Dr. Pflugfelder described a patient he treated for keratoneuralgia postLASIK who had no relief with soft contact lenses or the PROSE device, some improvement using autologous plasma drops six times daily, and marked symptomatic improvement with gabapentin, but only after he self-titrated the dose to 1,200 mg, three times daily.

An oral tricyclic antidepressant, such as amitriptyline, can also provide symptomatic relief, particularly for patients with central sensitization.

Stephen C. Pflugfelder, MD

E: stevenp@bcm.edu

This article was adapted from Dr. Pflugfelder’s presentation during Cornea Subspecialty Day at the 2014 meeting of the American Academy of Ophthalmology. Dr. Pflugfelder is a speaker for Allergan, Bausch + Lomb, and GlaxoSmithKline and a consultant for Allergan and GlaxoSmithKline.