Ocular and periocular structures are innervated by fibers originating from the ophthalmic branch of the trigeminal nerve. Among the many functions of these fibers is maintaining the health of the ocular surface. Damage to these nerves can cause symptoms similar to dry eye (eg, blurred vision, photophobia, pain, redness, and foreign body sensation).1–4 This condition has been termed corneal neuralgia. These symptoms are produced by hypersensitive pacemakers in regenerating nociceptor fibers and dorsal root ganglia. Although most cases of corneal neuralgia resolve within several months, some patients experience pain that may intensify or become permanent.1,2
Corneal neuralgia has been reported as a rare complication of corneal and refractive surgeries, including laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), cataract surgery, lamellar keratoplasty, and corneal cross-linking for keratoconus.1 In a retrospective review done by Theophanous et al.,3 three male patients presented with intractable dry eye symptoms within 1 year of LASIK. Tear metrics and trials of dry eye therapy did not support a diagnosis of dry eye, which commonly occurs as a complication of LASIK and PRK. In vivo confocal microscopy revealed an abnormally reduced corneal nerve density and altered morphology that suggested a neuropathic process.3
A diagnostic finding that has been used to indicate the presence of a corneal neuropathic process is reduction of symptoms with topical corneal anesthesia. The reduction of pain with anesthetic indicates involvement of nociceptive afferent fibers, which comprise a central role in the pathogenesis of corneal neuralgia.2 Complete relief of pain with topical anesthetic indicates a peripheral neuropathic pain process, improved but persistent symptoms indicate mixed central and peripheral processes, and no relief of pain indicates a central neuropathic process.4 Although the pathogenesis of this condition has been described, therapeutic options have not been clearly delineated. We present a case of ocular neuralgia successfully treated with a combination of steroid and local anesthetic injections.
A 21-year-old man known to one of the authors (RWH) since the age of 10 years with a complex ophthalmic history of oculocutaneous albinism type 1A (OCA1A), nystagmus, strabismus, previous eye muscle surgery, iris transillumination, severe astigmatism, and optic nerve and foveal hypoplasia presented in pain in 2014, at 3 months following bilateral PRK surgery. Previous to his PRK surgery, he had no history of chronic periocular pain associated with previous eye muscle surgery, photophobia associated with albinism, dry eye, or contact lens use. Any ocular pain the patient experienced from previous eye muscle surgery was limited to his immediate (days) postoperative course. He had also been treated with spectacles and was wearing contact lenses at presentation. Within 3 to 4 weeks after his refractive surgery in 2014, he began complaining of chronic, moderate to severe, bilateral ocular and orbital pain that varied in frequency and was sometimes associated with eye movements. He noted mild relief with multiple forms of dry eye treatments, sleep, and eyelid closure, but no relief with topical steroidal or nonsteroidal medications. There were no physical residua nor any indication of other complications after PRK surgery. The PRK surgery was performed at an outside institution, and the operative report made no mention of special precautions given his nystagmus other than preoperative oral sedation with an intravenous dose of fentanyl.
To test the presence of a neuropathic process, a trial of topical anesthetic was done. He noted significant relief, with a 50% to 70% reduction in his pain (from 9 of 10 to 3 of 10). As the anesthetic effect diminished, his pain returned. Neurology, psychiatry, psychology, and pain clinic consultations were obtained. Over the next 2 years, trials of nonsteroidal anti-inflammatory drugs, nortriptyline, duloxetine, venlafaxine, pregabalin, gabapentin, acupuncture, meditation, and cognitive-behavioral therapy were unsuccessful, resulting in persistent, bilateral eye pain that was only inconsistently controlled with oral opioid medications. In May 2016 during a routine follow-up appointment, a “diagnostic/therapeutic” trial of a left orbital block with a retrobulbar injection of 0.25% bupivacaine was then done by one of the authors (RWH), which resulted in relief of pain for 2 to 3 weeks. A standard inferotemporal retrobulbar approach was used to ensure that the ciliary ganglion was included as a target of the injection. Three months later, the patient consented to a trial of 40 mg/cc triamcinolone acetonide and 0.25% bupivacaine injection of both orbits. A total of 3 to 4 cc of a 50:50 mixture of 40 mg/mL triamcinolone acetonide and 0.25% bupivacaine was injected into each orbit in standard retrobulbar fashion inferotemporally using a 27-gauge ¾” needle. Repeat injections have been regularly performed over the past 3.5 years (Table 1), allowing for improved symptoms lasting from 4 to 6 months. A change in the last two injections to a combination of orbital dexamethasone implant (Ozurdex; Allergan, Irvine, CA) and 0.25% bupivacaine has allowed relief of symptoms for up to 9 months each. There have been no complications associated with multiple injections over the past 3.5 years. Corrected distance visual acuity has remained stable in both eyes since 2014 at 20/80 in the right eye, 20/70 in the left eye, and 20/60 under binocular conditions. Although the tear film had a short break-up time, the ocular surface remained consistent during the entirety of follow-up with a clear, compact, nonstaining epithelium without any signs of edema, infiltration, or neovascularization.
Time Table of Orbital Injections, Type of Injection, and Subjective Measure of Pain Before and After Each Orbital Injection
Our case investigates the possibility of a novel therapeutic option for patients suffering from neuropathy after corneal refractive surgery. The pathogenesis of corneal neuralgia is similar to other peripheral neuropathic processes.1–4 However, treatment options effective for peripheral neuropathy have been minimally reported in the context of corneal neuralgia occurring as a complication of corneal and refractive surgeries.4–6 Many studies hypothesize that treatments used regularly for peripheral neuropathic processes may be helpful in corneal neuralgia. A study conducted by Obermann et al.7 evaluated the efficacy of pregabalin in trigeminal neuralgia, a severe, generalized facial pain caused by injury to the trigeminal somato-sensory system. Pregabalin was found to relieve 50% to 100% of pain in 74% of patients. Pregabalin works by binding to the alpha-2-delta subunit of calcium voltage-gated channels, which decreases central pain sensitization.8 It is endorsed as a first-line treatment for neuropathic pain secondary to diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain.9 However, a trial of pregabalin did not show efficacy in our case of ocular neuralgia, possibly due to the presence of both central and peripheral sensitization components.10 Although the pathogenesis of the many forms of trigeminal neuralgia involves injury to the trigeminal nerve, there may be unique factors contributing to the presentation of ocular neuralgia. These may include increased density of nociceptive fibers, concurrent inflammatory damage to multiple nerve plexuses within the ciliary ganglia and/or cornea, and varying return of function with nerve regeneration.10 According to St. John Smith,11 recent RNA-sequencing of sensory neurons showed that neuronal expression profiles vary in different tissues, possibly leading to varying neuropathic pain presentations. It has been found that distinct subunits of ion channels on nociceptors mediate excitation of corneal afferent fibers, leading to the clinical symptoms of ocular neuralgia.
Intrathecal delivery of bupivacaine and low-dose fentanyl in the upper cervical spine was shown to be effective in managing refractory corneal neuropathic pain after LASIK surgery in a case described by Hayek et al.5 The patient noted greater than 50% relief of pain after the intrathecal drug delivery system was implanted. In another case reported by Sayegh et al.,12 electrode implantation to stimulate the trigeminal ganglion resulted in complete resolution of corneal neuropathic pain symptoms. In a retrospective case series by Morkin and Hamrah,13 cryopreserved amniotic membranes were found to improve corneal neuropathic pain severity by 72.5% ± 8.4% after retention for approximately 6.4 days on average.13 Few studies have investigated the possibility of periocular injections of anesthetic and steroid combinations to treat ocular neuralgia. The combination of bupivacaine and triamcinolone acetonide was chosen based on combining our community standards for retrobulbar anesthesia and steroids for noninfectious intraocular inflammation. The mechanism underlying the success of bupivacaine injections in our case may be similar to that of intrathecal delivery of bupivacaine in the cases reported by Hayek et al.6 and Devor et al.14 Bupivacaine reversibly inhibits sodium channels, effectively preventing action potential generation and propagation, while also blocking N-methyl-D-aspartate (NMDA) receptor sensory nerve signaling in the dorsal horn of the spinal cord. The addition of triamcinolone acetonide served to decrease peripheral inflammation, while also suppressing neuronal signaling originating from injured nerves.6,14 We hypothesize that the 1:1 ratio of anesthetic and steroid used in our case worked synergistically to decrease pain sensitization in nociceptive fibers, as well as inflammation caused by damage to periorbital and corneal nerves. The rationale for adding the additional steroid component was to provide a lengthier effect of treatment due to the associated inflammatory components of the postoperative neuralgia syndrome.
The long-lasting pain reduction after the injections may be due to sustained reversal of abnormally created central pain pathways. Retrobulbar ciliary nerves are peripherally blocked, directly via anesthesia and indirectly via suppression of inflammation, which arises from injured corneal nerves. This suppresses abnormal cyclic and ectopic neuronal activity, thus decreasing nociceptive signaling to central pain pathways. The recurrence of the pain is associated with reestablishment of the anomalous ectopic signaling from corneal nerves.
The use of an Ozurdex implant in the orbit is a unique application of an extended release intraocular steroid implant. The Ozurdex implant was chosen due to its consistent, slow steroid release formulation. It was injected into the retrobulbar space through the inferotemporal forniceal conjunctiva. The injection catheter system was inserted around and near the globe until the end of the blue sleeve prior to releasing the implant. Although an off-label application has its own potential complications, we chose to minimize an adverse event by injecting the implant in the infero-temporal, extraconal orbit, which is a routine location for orbital injections. There have been no complications thus far in the patient's treatment course.
Our patient was affected by OCA1A, an autosomal recessive condition caused by a nonfunctional tyrosinase enzyme, which leads to lack of melanin production in melanocytes. Almost all individuals affected by OCA1A exhibit photophobia, a painful aversion to light.15 Few studies have investigated the outcomes of refractive surgery in these patients. Although it is possible that the photophobia associated with OCA1A may have developed after refractive surgery and been the cause of the ocular neuralgia, our patient's symptoms were not related to different levels of illumination and were not improved in darkness.
Our method of periocular injections is advantageous due to long-lasting effects, low cost (excepting the use of the Ozurdex implant), and accessibility to patients. Although risks may exist with this method of treatment, it serves as an effective option for patients suffering from refractory corneal neuralgia or severely impaired quality of life. Further studies in larger cohorts are needed to clearly delineate the efficacy of retrobulbar injections in the management of ocular neuralgia.
- Rosenthal P, Borsook D, Moulton EA. Oculofacial pain: corneal nerve damage leading to pain beyond the eye. Invest Ophthalmol Vis Sci. 2016;57:5285–5287. doi:10.1167/iovs.16-20557 [CrossRef]
- Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol. 2016;100:128–134. doi:10.1136/bjophthalmol-2014-306280 [CrossRef]
- Theophanous C, Jacobs DS, Hamrah P. Corneal neuralgia after LASIK. Optom Vis Sci. 2015;92:e233–e240. doi:10.1097/OPX.0000000000000652 [CrossRef]
- Dieckmann G, Goyal S, Hamrah P. Neuropathic corneal pain: approaches for management. Ophthalmology. 2017;124:S34–S47. doi:10.1016/j.ophtha.2017.08.004 [CrossRef]
- Hayek SM, Sweet JA, Miller JP, Sayegh RR. Successful management of corneal neuropathic pain with intrathecal targeted drug delivery. Pain Med. 2016;17:1302–1307. doi:10.1093/pm/pnv058 [CrossRef]
- Duerr ER, Chang A, Venkateswaran N, et al. Resolution of pain with periocular injections in a patient with a 7-year history of chronic ocular pain. Am J Ophthalmol Case Rep. 2019;14:35–38. doi:10.1016/j.ajoc.2019.02.001 [CrossRef]
- Obermann M, Yoon MS, Sensen K, Maschke M, Diener HC, Katsarava Z. Efficacy of pregabalin in the treatment of trigeminal neuralgia. Cephalalgia. 2008;28:174–181. doi:10.1111/j.1468-2982.2007.01483.x [CrossRef]
- Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Prim. 2017;3:17002. doi:10.1038/nrdp.2017.2 [CrossRef]
- Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17:1113. doi:10.1111/j.1468-1331.2010.02999.x [CrossRef]
- Shaheen BS, Bakir M, Jain S. Corneal nerves in health and disease. Surv Ophthalmol. 2014;59:263–285. doi:10.1016/j.survophthal.2013.09.002 [CrossRef]
- St John Smith E. Advances in understanding nociception and neuropathic pain. J Neurol. 2018;265:231–238. doi:10.1007/s00415-017-8641-6 [CrossRef]
- Sayegh RR, Sweet JA, Miller JP, Hayek SM. Electrical stimulation of the trigeminal ganglion and intrathecal drug delivery systems for the management of corneal neuropathic pain. Cornea. 2016;35:576–577. doi:10.1097/ICO.0000000000000751 [CrossRef]
- Morkin MI, Hamrah P. Efficacy of self-retained cryopreserved amniotic membrane for treatment of neuropathic corneal pain. Ocul Surf. 2018;16:132–138. doi:10.1016/j.jtos.2017.10.003 [CrossRef]
- Devor M, Govrin-Lippmann R, Raber P. Corticosteroids suppress ectopic neural discharge originating in experimental neuromas. Pain. 1985;22:127–137. doi:10.1016/0304-3959(85)90173-3 [CrossRef]
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Time Table of Orbital Injections, Type of Injection, and Subjective Measure of Pain Before and After Each Orbital Injection