Woman experiences photophobia while undergoing chemotherapy for breast cancer
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A 59-year-old woman presented to Lahey Hospital & Medical Center in June 2021 with a several months’ history of bilateral light sensitivity, intermittent watery eyes and blurred vision.
The photophobia was severe enough that the patient had to drive early to work before sunrise to avoid the sun.
The patient was seen by an outside optometrist 2 months before presentation, and treatment with fluorometholone four times daily in both eyes and Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) twice daily in both eyes did not improve her symptoms. She did not have redness of the eyes, mucopurulent discharge, or a history of contact lens wear or trauma.
Her medical history was significant for breast cancer, migraine, hypothyroidism, localized skin cancer status post excision, and vitamins B12 and D deficiency. Medications included sumatriptan, levothyroxine and vitamin D3. Allergies included latex (contact dermatitis) and penicillin V (rash). She did not smoke, drink alcohol or use illicit drugs.
In 2015, the patient was diagnosed with stage 1 HER2-positive infiltrating ductal carcinoma of the right breast and underwent partial mastectomy with adjuvant chemotherapy and local radiation therapy. Five years later, she developed recurrence, with lung metastasis, and in April 2020, she started Herceptin (trastuzumab, Genentech), Taxotere (docetaxel, Sanofi) and Perjeta (pertuzumab, Genentech), a combination of chemotherapy and monoclonal antibodies used for the treatment of metastatic HER2-positive breast cancer. Taxotere was discontinued in August 2020 due to neurotoxicity and nail bed changes, and both Herceptin and Perjeta were stopped in February 2021 after the patient developed photophobia.
Examination
On examination, visual acuity was 20/40 (pinhole to 20/25) in the right eye and 20/60 (pinhole to 20/40) in the left eye. Pupils were round and reactive with no afferent pupillary defect. IOPs were within normal limits. Motility was full and orthophoric.
The anterior segment slit lamp examination was notable for corneal changes in both eyes. In the right eye (Figure 1), there were raised epithelial lesions in the temporal periphery, extending into the midperiphery with subtle subepithelial deposits. Lesions negatively stained with fluorescein in a linear pseudodendritic pattern. Corneal neovascularization and pannus were noted at the limbus at 8 o’clock, suggesting a chronic process. The left eye (Figure 2) showed similar and more obvious corneal changes with fluorescein uptake and raised epithelial lesions that formed a semicircular ridge nasally. Corneal neovascularization was noted at the limbus nasally. The anterior chambers were deep and quiet bilaterally, and there were no iris nodules in either eye.
Source: Omar Abu-Qamar, MD, Naveen Rao, MD, and Sarkis Soukiasian, MD
The posterior segment exam was within normal limits without notable pathology.
What is your diagnosis?
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Severe photophobia
The patient wassu treated with prednisolone acetate four times daily and continued on preservative-free artificial tears four times daily and Restasis twice daily. She developed elevated IOP while being treated with prednisolone, which was stopped, and fluorometholone was added at night. Corneal cultures were taken to assess for herpes simplex virus and were negative by PCR. LipiScan (Johnson & Johnson Vision) was used to better characterize the extent and quality of dry eye, which revealed significant meibomian atrophy. She started doxycycline 50 mg daily.
Despite multiple interventions including topical steroids, a trial of bandage contact lens and Polytrim (polymyxin B sulfate and trimethoprim ophthalmic solution, Allergan), serum tears, artificial tears and Restasis, the photophobia did not significantly improve. Of note, Herceptin was restarted by the treating oncologist soon after the patient’s presentation to ophthalmology in June 2021.
Please see Figure 3 for the clinical course.
Discussion
The differential diagnosis for this patient who presented with severe photophobia, pseudodendritic keratitis and raised peripheral/midperipheral epithelial lesions is wide and includes infectious causes including herpetic keratitis (herpes simplex virus, varicella zoster virus), bacterial keratitis, infectious crystalline keratopathy, fungal keratitis, Thygeson’s superficial punctate keratitis, Salzmann’s nodular degeneration, filamentary keratopathy, and neuropathic corneal pain from chronic dry eye disease and toxic keratopathy due to monoclonal antibody cancer therapy.
Neuropathic corneal pain is an entity that has been gaining more attention in recent years, but the pathophysiology and management strategies remain limited. Often, patients are misdiagnosed as having dry eye or are underdiagnosed due to the limited findings on slit lamp examination. The underlying etiologies thought to precipitate neuropathic corneal pain include toxic keratopathy, dry eye disease, surgical interventions and infectious keratitis, which cause dysregulation of the peripheral nociceptive input, ultimately resulting in a malfunction of the pain signaling pathway. This dysregulation of the pain signaling pathway manifests as allodynia, in which an innocuous stimulus such as light touch can result in extreme pain, or photoallodynia, in which an innocuous light stimulus can be perceived as extreme pain. This pathway and subsequent symptomatology were described by Goyal and Hamrah.
Proposed treatment strategies for corneal neuropathy are aimed at decreasing inflammation and promoting nerve regeneration. This is done in a stepwise approach that includes, but is not limited to, treating ocular surface disease with artificial tears and punctal plugs; anti-inflammatory agents such as topical steroids and oral doxycycline; regenerative therapy via autologous serum eye drops; bandage and scleral contact lenses; systemic pain medications such as tricyclic antidepressants and GABAergic agents; and other holistic interventions such as acupuncture or cardiovascular exercises.
The cause of corneal neuropathic pain in our patient was most likely a combination of dry eye disease, evidenced by absent meibomian glands on LipiScan, and toxic keratopathy due to Herceptin. Herceptin is a humanized monoclonal antibody that binds to human epidermal growth factor receptor type 2 (HER2) and is used in HER2-dependent tumors such as breast cancer and advanced gastric cancer. It was shown by Güler and colleagues to inhibit corneal neovascularization in animal models, and Orlandi and colleagues authored a case report of a patient treated with Herceptin who developed bilateral corneal marginal infiltrates resistant to topical steroids and antibiotics that resolved with autologous serum tears. Studies of a related compound, trastuzumab emtansine, an antibody-drug conjugate, reported corneal adverse events in up to 30% of cases.
Given our patient’s immunocompromised status, infectious etiologies remained in the differential but were less likely due to her lack of worsening, especially after chronic steroid therapy. We were reassured based on the HSV PCR that this was not likely herpetic; however, bacterial and fungal etiologies could not be excluded. A case report by Sridhar and colleagues reported a patient treated with a similar chemotherapy and monoclonal antibody regimen who developed bilateral corneal changes with a projecting crystalline process. Corneal scrapings grew Streptococcus anginosus and Staphylococcus aureus, and the patient was diagnosed with infectious crystalline keratopathy and treated with topical fortified cefazolin and fortified tobramycin every hour with good response. Therefore, corneal scraping to rule out infection was a reasonable next step for our patient in her follow-up appointment.
Given the patient’s clinical course and lack of clinical improvement, the etiology was presumed to be neuropathic corneal pain secondary to dry eye disease from meibomian gland atrophy and corneal toxicity from Herceptin; therefore, Herceptin was discontinued in September 2021. This case exemplifies the importance of interdisciplinary communication among ophthalmologists and oncologists, as this ocular condition may warrant modification of systemic therapy.
Corneal neuropathic pain is an entity that warrants more attention and is likely underdiagnosed. Patients’ quality of life can be severely impaired, and one should keep a high index of suspicion for this diagnosis, especially in patients with symptoms out of proportion to examination findings.
- References:
- Eaton JS, et al. J Ocul Pharmacol Ther. 2015;10.1089/jop.2015.0064.
- Goyal S, et al. Semin Ophthalmol. 2016;doi:10.3109/08820538.2015.1114853.
- Güler M, et al. Am J Ophthalmol. 2009;doi:10.1016/j.ajo.2008.09.022.
- Orlandi A, et al. BMC Cancer. 2015;doi:10.1186/s12885-015-1969-3.
- Raizman MB, et al. Surv Ophthalmol. 2017;doi:10.1016/j.survophthal.2016.11.008.
- Sridhar MS, et al. CLAO J. 2001;27(2):108-110.
- For more information:
- Omar Abu-Qamar, MD, Naveen Rao, MD, and Sarkis Soukiasian, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Allison V. Coombs, DO, MS, and Nisha S. Dhawlikar, MD, MPH. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.