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Neuropathic dry eye: When serum defeats tears


Ophthalmology Times is pleased to announce Melina I. Morkin, MD, and Pedram Hamrah, MD, FACS, of New England Eye Center/Tufts Medical Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, as the third-place winner of the 2017 Resident Writer’s Award Program, sponsored by Allergan. Their entry is featured here.

By Melina I. Morkin, MD, and Pedram Hamrah, MD, FACS; Special to Ophthalmology Times

A 39-year-old otherwise healthy man presented to the New England Eye Center for evaluation of dry eye disease (DED). He had undergone LASIK in both eyes (OU) 5 years earlier, followed by refloating of the flap and scraping of epithelial downgrowth in the right eye (OD) 2 weeks later, and LASIK enhancement in OD 3 years later.

Symptoms of foreign body sensation started shortly after LASIK, being more intense in OD. The Ocular Surface Disease Index (OSDI)1 was 65 measured on a scale from 0 to 100. The Ocular Pain Assessment Survey (OPAS)2 measured 2.7 in a scale from 1 to 10 for both 24 hour- and 2 week-pain intensity, 2/10 for impact in quality of life (QoL), and 90% worsening in windy/dry conditions. He had been using different artificial tears (most recently Thera­Tears, Akorn) 12 times daily, without relief. Although dissolvable punctal plugs temporarily improved dryness in OD, symptoms persisted.



His uncorrected visual acuity (UCVA) was 20/25 in OD and 20/20 in the left eye (OS). Pupils, motility, and IOPs were unremarkable. He was noted to have bilateral low tear films and mild superficial punctate keratopathy (SPK) inferiorly. Schirmer’s I test measured 1 mm in OU. Tear break-up time was 7 seconds in OU. LASIK flaps were intact, except for inferotemporal subepithelial haze in OD. The remainder of the ophthalmic examination was unremarkable.

While the patient had minimal response to Schirmer’s I test, blood markers for Sjögren’s syndrome were negative. Corneal in vivo confocal microscopy (IVCM) provides noninvasive high-resolution images of the corneal nerve plexus at the cellular level (Heidelberg Retina Tomograph 3/Rostock Cornea Module, Heidelberg Engineering). This “optical corneal biopsy” revealed severely decreased nerve density and abnormal morphology of the central subbasal nerve plexus in OD, while OS appeared intact (Figure 1A/B, Page 30).



Discussion, Diagnosis

The new Definition and Classification Subcommittee of the Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) recently reformulated the definition of the disease.3 Given mounting evidence of the role of local nerve damage in eliciting and potentiating ocular pain, neurosensory abnormalities have been introduced as part of its pathophysiology.

Furthermore, a new categorization algorithm that primarily focuses on the assessment of ocular surface symptoms and signs was introduced. Therefore, when symptoms are disproportionate to clinical signs, neurosensory abnormalities should be suspected. To incorporate this group of patients into the clinical decision-making algorithm, a new subcategory named “neuropathic dry eye” was proposed. 

Neuropathic dry eye can be due to diverse ocular conditions (e.g., DED, infectious/herpetic keratitis, radiation keratopathy), as well as surgical interventions (e.g., cataract and refractive surgery).4,5,6 Systemic conditions, such as fibromyalgia and Sjögren’s disease, also cause neuropathic dry eye.4 Symptoms can be potentiated by comorbidities like anxiety and depression.

As a result of the causes mentioned, nociceptors can undergo a plasticity process called “peripheral sensitization,” in which nerve injury and inflammatory mediators result in pathological structural changes of corneal nerves, lowering the threshold for pain and causing ectopic discharge of the nociceptors even with non-noxious stimuli.7 Over time, peripheral sensitization leads to a similar process in the central nervous system (CNS), called central sensitization, in which the CNS neurons’ responses are disproportionate to peripheral pain signaling, resulting in inappropriate amplification and prolongation of pain duration.8

Differentiating peripheral from central pain is crucial to guide appropriate treatment. This can be done through an in-office test, the instillation of topical 0.5% proparacaine hydrochloride.4 If pain resolves or partially improves after instillation, the patient likely suffers from a peripheral or mixed etiology. If pain remains unchanged, the patient likely has a central component.

For both central and peripheral neuropathies, treatment often involves a combined multistep strategy,4,5 starting with the treatment of associated conditions (such as DED, conjunctivochalasis, blepharitis/MGD, or predisposing systemic conditions).

Neuro-regenerative therapies intended to restore neuronal integrity and functionality (20% autologous serum eye drops, topical nerve growth factor) and anti-inflammatory agents that minimize nerve injury and sensitization from uncontrolled inflammation (e.g., corticosteroids) are more effective if peripheral neuropathy is present. Systemic pharmacotherapies (such as first-line agents, nortriptyline [tricyclic antidepressant] and carbamazepine [anticonvulsant], or second-line agents, low-dose naltrexone and tramadol), and even alternative medicine, are more favorable in central neuropathic patients.4

Given the compelling outcomes with the concurrent use of low-dose steroids and serum tears in corneal nerve regeneration,9 20% autologous serum tears (AST) eight times daily and loteprednol 0.5% two times weekly were started (an initial regimen of loteprednol 0.5% QID, followed by a bi-weekly taper is usually recommended).

By the 6-week follow-up, symptoms had begun to decrease and IVCM demonstrated increased nerve density with improved morphology in the affected eye (Figure 1C/D.

At his last appointment 18 months after his first visit, the patient reported an 80% to 90% subjective improvement of symptoms. OSDI decreased to 8 (from 65 initially). OPAS indicated a 0/10 pain intensity in the prior 24 hours and 2 weeks, a 0.1/10 impact in QoL, and 20% worsening only in windy/dry conditions. UCVA improved to 20/20 in OD. Ocular surface examination revealed trace SPK in OD only. IVCM showed near complete regeneration of subbasal nerves in OD, and normal density in OS (Figure 1E/F). The patient was tapered off AST.




As a result of international evidence-based efforts of the TFOS DEWS II to redefine DED understanding, a novel category labeled “neuropathic dry eye” has risen. Neurosensory dysfunction is not routinely contemplated or assessed in practice, and should be suspected in the presence of sign-symptom disparity or persistence of complaints despite treatment adherence.

In this case, tear replacement/conservation therapies alone would have been futile, leading to perceived treatment failure. Instead, the identification of corneal nerve damage caused by the refractive procedures led to effective and long-standing symptomatic control with AST.




1.  Friedman NJ. Impact of dry eye disease and treatment on quality of life. Curr Opin Ophthalmol 2010;21(4):310-6.

2.  Qazi Y, Hurwitz S, Khan S, Jurkunas UV, Dana R, Hamrah P. Validity and Reliability of a Novel Ocular Pain Assessment Survey (OPAS) in Quantifying and Monitoring Corneal and Ocular Surface Pain. Ophthalmology 2016;123(7):1458-68.

3.  Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols JJ, Tsubota K, Stapleton F. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15(3):276-283.

4.  Dieckmann G, Goyal S, Hamrah P. Neuropathic corneal pain: approaches for management. Ophthalmology 2017 (in press).

5.  Goyal S, Hamrah P. Understanding Neuropathic Corneal Pain--Gaps and Current Therapeutic Approaches. Semin Ophthalmol 2016;31(1-2):59-70.

6.  Theophanous C, Jacobs DS, Hamrah P. Corneal Neuralgia after LASIK. Optom Vis Sci 2015;92(9):233-240.

7.  Understanding Neuropathic Corneal Pain--Gaps and Current Therapeutic Approaches. Goyal S, Hamrah P. 2016, Semin Ophthalmol, Vols. 31(1-2):59-70.

8.  Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. 2004, J Neurosci, Vols. 24(20):4832–14389.

9.  Aggarwal S, Kheirkhah A, Cavalcanti BM, Cruzat A, Colon C, Brown E, et al. Autologous Serum Tears for Treatment of Photoallodynia in Patients with Corneal Neuropathy: Efficacy and Evaluation with In Vivo Confocal Microscopy. Ocul Surf 2015;13(3):250-62.

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