IVCM examination of a patient with corneal neuropathy and light sensitivity . At the beginning of the follow-up, IVCM showed an abnormal subbasal nerve plexus with a large neuroma, nerve tortuosity, and bleeding. Some dendritic cells are visible (a). At 9 months, IVCM showed an increase in the nerve density and persistence of bleeding and neuroma (b)
Nortriptyline 10 mg once a day at night was prescribed with a gradual increase to 50 mg, along with eight drops of autologous serum tears 20% a day, and loteprednol etabonate 0.5% drops four times a day for a week tapering to a drop each week. In addition, twice-a-week acupuncture and an increase in cardiovascular exercise were suggested to the patient. IVCM at 9 months showed a reduction of number of neuromas compared to the first visit, as well as an increase in nerve density (Fig. 8.1b ). Serum tears were maintained whereas nortriptyline was stopped according to the improvement of patient’s symptoms.
Case 2: Corneal Neuropathy After LASIK Surgery (Post-LASIK Neuralgia)
TB, a 35-year-old healthy male, was referred to our center for ocular pain and dry eye symptoms in both eyes. He had no past significant medical history. The ocular history was significant for LASIK surgery in both eyes performed 10 years ago. Two years post-LASIK, he started noticing ocular pain. He had been to several different ophthalmologists. A diagnosis of dry eye disease was made, and he was given artificial tears and steroid eye drops, both of which provided no relief. A different ophthalmologist diagnosed scleritis. He took prednisone 60 mg per day for 1 week, which reduced the pain. He then switched to naprosyn 250 mg twice daily, and the pain returned. An MRI of the brain and orbits was performed which was normal.
At the first visit to our clinic, the patient complained of an increase in pain duration and intensity over the past few months. He was on prednisolone acetate drops, vitamin C tablets, Omega-3, B complex vitamins, and calcium. His visual acuity was 20/20 in the both eyes. Slit-lamp examination revealed mild blepharitis, normal LASIK flaps, and no corneal staining. The rest of the ocular exam was also normal.
Which Patients Are Susceptible to Corneal Pain ?
Various inflammatory diseases, neurological diseases, or surgical interventions can be the underlying cause of corneal neuropathic pain (Table 8.1). Some of them include refractive surgery , dry eye disease [27, 28], Sjögren’s syndrome [29, 30], neuralgia associated with herpes virus , benzalkonium chloride (BAK) preserved eye drops, accutane, chemotherapy, and radiotherapy to mention a few . In addition to refractive surgery, particularly LASIK, we have also observed cataract surgery—clear cornea incision—to also trigger neuropathic corneal pain.
Causes of corneal neuropathic pain
Dry eye disease
Postsurgical (cataracts, refractive surgery, corneal transplantation)
Miscellaneous: ocular surface neoplasia, trauma, post-blepharoplasty, iatrogenic trigeminal neuralgia, chronic corneal pain with blepharospasm, fibromyalgia, small fiber neuropathy
What Is the Social Impact of Corneal Pain ?
Corneal nerve damage may be associated with symptoms of pain, light sensitivity, irritation, and sometimes a vague sensation of pressure. As a physician, one must understand that pain does not affect the patient alone, but it affects the entire social structure of the patient. Eye pain decreases work performance and can have huge impact on aspects of physical, social, and psychological functioning [32, 33]. Crucial daily activities like reading, driving, and computer work are affected giving a sense of handicap . Severe cases with photoallodynia may require dark glasses indoors affecting social quality of life. Many patients are unable to work and go on disability. Unfortunately, we have witnessed many patients with severe form of pain where anxiety and depression have forced them to contemplate and even seek ending their own life.
What Should We Do Next for This Patient?
As outlined earlier, after a complete ocular exam, IVCM should be done. In this patient, IVCM examination revealed an increase in the presence of dendritic cells, neuromas, and nerve tortuosity, while also revealing a reduction in nerve density (Fig. 8.2a). A diagnosis of corneal neuropathy was made. The pain was significantly reduced with proparacaine drops, confirming the theory of peripheral corneal neuropathy following LASIK surgery.
IVCM examination of a patient with corneal neuropathy and inflammation . At the beginning of the follow-up, IVCM showed a marked increase in dendritic cell density and a significant reduction in the nerve density (a). At 6 months, IVCM revealed a substantial decrease in dendritic cells and a moderate increase in the nerve density (b)
The patient was prescribed autologous serum tears (20%) eight times a day and loteprednol etabonate 0.5% drops four times a day for a week, tapering to a drop each week. After 6 months, the patient reported significant resolution of his symptoms and occasional flare-ups. Ocular examination was normal, and IVCM revealed no neuromas but persistent inflammation with a maintained reduction of nerve density (Fig. 8.2b ). The previous treatment was maintained.
Case 3: Ocular Pain and Centralized Pain
A 70-year-old female was referred to our center with a diagnosis of filamentary keratitis and photophobia. She was followed for 2 years elsewhere with partial response to removal of filaments with forceps and the use of bandage contact lenses. She had received punctal plugs and topical steroids with limited improvement.
At her first examination, she was taking cyclosporine 0.05% drops four times daily and non-preserved artificial tears on a very regular basis (more in her left eye than right eye). She was complaining of photophobia and ocular pain. The pain interfered with driving, watching TV, and sleeping. Her initial visual acuity was 20/40 in the right eye and 20/20 in the left eye. She had a tender posterior lid margin and telangiectasia, with trace fine vessel injection on her conjunctiva. She had mild blepharitis, with partial occlusion of meibomian gland ducts. The central cornea showed punctate epithelial keratitis and few central debris filaments. Tear breakup time was abnormally rapid, and tear meniscus was reduced. She was pseudophakic in both eyes with no signs of intraocular inflammation. Fundus examination was normal.
IVCM showed neuromas in both eyes, high corneal nerve tortuosity, and a reduction of corneal nerve density ( Fig. 8.3a ). Proparacaine drops did not provide relief from pain. A diagnosis of corneal neuropathy associated with central pain was made.
IVCM examination of a patient with ocular pain after LASIK surgery performed 10 years ago. IVCM examination at the beginning of the follow-up showed a large neuroma, dendritic cells with long dendrites, and a reduction in the nerve density (a). After 6 months, IVCM displayed reduced dendritic cells in number and size. Nerve density was still low (b)
The patient was started on autologous serum tears 20% eight drops a day, loteprednol etabonate 0.5% drops four drops a day for a week, tapering to a drop each week, and carbamazepine 400 mg orally twice daily. After 6 months of the treatment, the patient reported a substantial improvement of his symptoms, with only occasional discomfort. His visual acuity was stable. Slit-lamp examination was normal. IVCM at 6 months showed a reduction of dendritic cells compared to the first visit, as well as an increase in nerve density (Fig. 8.3b ). Serum tears were maintained. An additional month of loteprednol etabonate 0.5% drops was suggested, followed by one drop twice a week for 4 weeks.
Case 4: Corneal Neuropathy and Inflammation
RO, a 21-year-old male, was referred to our center with a diagnosis of systemic neuralgia, progressive ocular pain, and photophobia. He was undergoing treatment with high-dose duloxetine, 120 mg per day, but noticed worsening photophobia. The patient decided to reduce the treatment without any improvement in his ocular symptoms. He was not able to wear contact lenses but wore special sunglasses constantly. The patient denied having any other significant disease. His medical family history was negative for significant disease.
His corrected visual acuity was 20/25 in both eyes. Eyelid and slit-lamp examination, intraocular pressure, and fundus examination were all normal. The Schirmer’s test was normal (>10 mm in both eyes), and tear breakup time was >7 s. After the instillation of proparacaine drops, the patient reported an important reduction of the symptoms. The central component of the pain was minimal. IVCM revealed a significant increase of dendritic cells in the subbasal layer, associated with a clinically important reduction of the nerve density in both eyes ( Fig. 8.4a ).
IVCM examination of a patient with ocular pain with a central component . At the first visit, IVCM showed reduced nerve density and neuromas. After 6 months, a substantial improvement was observed with significant increase in nerve regeneration
Nortriptyline was prescribed (10 mg once a day at night) associated with autologous serum tears 20% eight drops a day, and fluorometholone 0.1% one drop a day for 4 weeks, and cyclosporine 0.05% drops. Doxycycline 100 mg two times per day was prescribed to improve meibomian gland disease. After 6 months, the patient reported an improvement of her symptoms. Her visual acuity was 20/20 in both eyes. Slit-lamp examination showed superficial punctate epitheliopathy. IVCM showed severe focal areas of inflammation but a reduction of neuromas with significant increase in nerve regeneration (Fig. 8.4b ). The patient was instructed to follow the same treatment and to consider acupuncture two times per week. An increase in cardiovascular exercise was also suggested to the patient.
Summary of the Management of Neuropathic Corneal Pain
Nerve injury results in the release of inflammatory cytokines from both the injured and healthy nerves [16, 29]. We always begin treatment with palliative care regardless of the underlying pathology of dry eyes or neuralgia. Lubricating the surface with modest frequency of non-preserved artificial tears or emulsion-based tears is our initial step. We have seen that adding punctal plugs to maintain a more generous tear lake benefits patients. The authors discourage placing punctal plugs in eyes with active allergies and inflammation, as this may increase the contact time of the allergens on the surface. Treating any concomitant posterior blepharitis and meibomian gland dysfunction with hot compresses and lid massage or medical therapy is always beneficial. For MGD cases refractory to medical management, procedures such as intraductal meibomian gland probing, thermal pulsation devices (Lipiflow), and intense pulse-lighted therapy may aid in the treatment of meibomian gland dysfunction and subsequent increase of TBUT .
In our experience, patients with corneal neuropathic pain typically require chronic use of anti-inflammatory agents (Table 8.2) to prevent recurrent episodes. Steroids are the main stay of treatment, especially for initial rapid relief. The authors prefer loteprednol 0.5% at an initial qid dose with biweekly taper to once or twice a week over a 6–8 week period. For severe refractory cases, we might add Anakinra (Kineret) human IL-1 receptor antagonist 2.5% at TID dosing for 3–6 months or Tacrolimus (calcineurin inhibitor) 0.03% at bid dosing for 3–6 months as they tend to be efficacious in reducing corneal surface inflammation and epitheliopathy [35, 36]. In addition, topical azithromycin 1% application at bedtime is a very effective and well-tolerated therapy of lid margin disease and meibomian gland dysfunction [37, 38]. It is both an anti-inflammatory, inhibiting pro-inflammatory cytokines, and an effective antibacterial agent. Likewise, oral doxycycline is an antimicrobial that also inhibits matrix metalloproteinases that degrade connective tissue . We use oral doxycycline at a dose of 100 mg once or twice a day for 2–3 months followed by daily dosing for another 3 months.
Evidence-based treatment of neuropathic corneal pain
A. Treatment of ocular surface disease
1. Increase tear production
– Use PFATs
2. Increase tear retention
– Punctal plugs, contact lenses, and moisture goggles
3. Treatment of lids and ocular surface disease
– Treat blepharitis with lid hygiene and warm compresses
– Refractory cases: meibomian gland probing, Lipiflow, intense pulse-lighted therapy
4. Managing comorbid conditions
– Treat allergies, conjunctival chalasis, lagophthalmos, and nocturnal exposure
B. Anti-inflammatory agents
1. Topical corticosteroids
2. Azithromycin ointment and oral doxycycline
C. Regenerative therapy
1. Autologous serum eye drops (20–100%)
2. Nerve growth factor
3. Platelet rich plasma
4. Umbilical cord serum eye drops
D. Protect ocular surface when required
1. Bandage contact lenses
2. Scleral contact lenses
3. Special scleral lenses like PROSE
E. Systemic pharmacotherapy for pain
1. TCAs like nortriptyline and amitriptyline
2. GABAergic drugs (gabapentin, pregabalin)
3. SNRI like duloxetine and venlafaxine
4. Opioids like oxycodone, methadone, morphine, and levorphanol
F. Complementary and alternative measures
2. Transcranial magnetic stimulation
3. Scrambler therapy
4. Cardio exercise
5. Omega-3-rich diet
Autologous serum tears (ASTs) are the mainstay of therapy for these patients. They contain a variety of pro-epithelial and pro-neural factors like epidermal growth factor (EGF), NGF, insulin-like growth factor (IGF-1), etc. [3, 40]. Concentrations from 20 to 100% have been shown to encourage epithelial healing, increase nerve density, and decrease nerve tortuosity . IVCM has demonstrated significantly improved nerve parameters including total length, number, reflectivity, and also reduction of beading and neuromas in patients treated with ASTs . Recent studies with the help of IVCM have shown a substantial correlation between the increase in dendritic cell numbers and decreased subbasal corneal nerves signifying a possible interaction between the immune and nervous system in the cornea . In our experience, the combination of steroids with ASTs is extremely synergistic as steroids decrease the initial inflammation on the ocular surface, providing an environment conducive to neuronal regeneration with the help of ASTs.