Neuromodulation for Treatment of Dry Eye

Signs, Symptoms, and Diagnosis of Dry Eye

Dry eye, also known as keratoconjunctivitis sicca, is a multifactorial disease of the tears and ocular surface that is caused by reduced tear production and/or excessive tear evaporation. Common symptoms of dry eye include conjunctival redness, burning/stinging, itching, foreign body sensation, irritation, ocular fatigue, blurred vision, contact lens intolerance, excessive eye watering, and photophobia ( ). In addition to symptoms of ocular discomfort and visual disturbance, dry eye is associated with a loss of homeostasis of the tear film, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles ( ).

Dry eye is usually a symptomatic disorder, ranging in severity from mild ocular irritation or discomfort to significant vision loss ( ). In the majority of patients, the condition is characterized by episodic irritative symptoms that are often triggered or exacerbated by aggravating factors such as environmental conditions that increase evaporative tear loss (e.g., exposure to low humidity, air conditioning, or high winds) ( ). In other patients, dry eye disease may be chronic, marked by continuous symptoms of fluctuating severity and possible damage to the ocular surface. Inflammation associated with dry eye disease can lead to various ocular complications, including infection, ocular surface keratinization and vascularization, corneal ulceration and opacification, and conjunctival squamous metaplasia ( ).

The symptoms of dry eye disease can adversely affect the performance of everyday vision-related activities such as reading, driving, computer use, and watching TV ( ). Manifestations of ocular pain and irritation, and impairment of vision-related function associated with dry eye disease have significant negative impact on patients’ quality of life ( ). Dry eye disease is one of the leading causes of patient visits to ophthalmologists and optometrists ( ). There is currently no cure for dry eye. The most frequently used treatments are artificial tears and anti-inflammatory agents ( ). Artificial tears often contain polymers that lubricate the ocular surface, but lack the numerous biological factors found in natural tears that maintain ocular surface homeostasis ( ). In addition, preservatives in multidose formulations of artificial tears may irritate the ocular surface ( ). Thus, an opportunity exists for development of novel therapies with different mechanisms of action that can trigger production of natural tears in patients with dry eye.

Diagnosis of dry eye disease is based on the presence of symptoms in combination with one or more objective clinical signs of reduced tear flow, tear film instability, and ocular surface damage ( ). Supplementary diagnostic procedures that are used where available include measurement of tear film osmolarity, tear lactoferrin levels, and impression/brush cytology, and other more sophisticated laboratory tests such as fluorescein tear clearance measurements, lacrimal gland function tests, meibography, and tear fluid protein immunoassay ( ). However, diagnosis of dry eye disease is complicated by the poor correlation between clinical signs and reported symptoms, the absence of a single definitive diagnostic test, and the lack of consensus on which combination of tests should be used ( ). Because of these limitations, dry eye disease is presumed to be frequently misdiagnosed and under-reported.

Epidemiology of Dry Eye Disease

Estimates of the prevalence of dry eye symptoms in the general population vary widely, ranging from 5% to 50%, depending on the population studied, the geographic location, and how dry eye is defined ( ). In the United States, the prevalence of self-reported dry eye in the Beaver Dam (Wisconsin) Eye Study (n = 3722) varied from 8.4% in subjects under 60 years of age to 19.0% in those over 80 years of age; the overall prevalence was 14.4% ( ). The Men’s Health Study (n = 25,444) indicated that the prevalence of dry eye (defined as a reported clinical diagnosis or either frequent or constant symptoms of dryness and irritation) was 3.9% in men in the 50–54-year age group, rising to 7.7% in those over 80 years of age ( ). Using the same definition of dry eye, the Women’s Health Study (n = 39,876) reported a prevalence of 5.7% in women under 50 years of age, rising to 9.8% in those over 75 years of age ( ). In the United States, it had been estimated that 3.2 million women and 1.7 million men over the age of 50 years have moderate to severe dry eye ( ), and tens of millions more experience other forms of dry eye ( ).

Established risk factors for dry eye include advanced age and female gender ( ), postmenopausal estrogen therapy ( ), androgen deficiency ( ), a diet low in omega-3 essential fatty acids or with a high omega-6 to omega-3 fatty acid ratio ( ), vitamin A deficiency ( ), contact lens use ( ), prolonged computer use ( ), low humidity environments (e.g., air-conditioned offices, aircraft cabins) ( ), refractive surgery ( ), bone marrow transplantation ( ), hepatitis C ( ), and certain classes of systemic medications, including antidepressants, anxiolytics, and antihistamines ( ). The prevalence of dry eye is likely to continue to grow with the increase of risk factors such as an aging population, a greater number of refractive laser surgeries, and more frequent use of contact lenses, computers, smart phones, and tablets.

Physiology of the Ocular Surface

Tears

The ocular surface, which comprises the cornea and the bulbar and tarsal conjunctiva up to the mucocutaneous junctions of the lid margin, is continuously bathed by tears. Components of the tear are secreted by the lacrimal and meibomian glands, with additional contributions from the conjunctiva ( ) ( Fig. 102.1 ). The lacrimal glands are exocrine glands located beneath the superior temporal lid and orbital rim (main lacrimal gland) and on the inner surface of the lids and conjunctival fornices (accessory lacrimal glands of Krause and Wolfring) that secrete aqueous fluid into the upper and outer conjunctival fornices ( ). The lacrimal secretion, comprising water, electrolytes and proteins, including glycoproteins such as mucins (MUC1, MUC4, MUC7, MUC5AC) from the acinar cells of the lacrimal glands or tear duct ( ), is responsible for the bulk of the tear volume and flow ( ). Conjunctival goblet cells also produce the gel mucin component (MUC5AC), which acts as an eyelid lubricant ( ).

The meibomian glands are tubuloacinar sebaceous glands lying in parallel rows in the tarsal plates of the upper and lower eyelids, with duct orifices opening onto the eyelid margins ( ). The meibomian secretion (meibum) in its healthy form is a clear oily product, consisting of a complex mixture of lipids, that is expressed into a shallow, eyelid margin reservoir, from where it spreads onto the surface of the tear film with each blink ( ).

Meibum secretion is achieved by the coordinated activity of Riolan’s muscle, a sphincter muscle at the orifice of the meibomian glands on the surface of the eyelid, and the orbicularis oculi muscle that runs alongside the eyelids and provides pressure to the meibomian glands when contracted ( ). When the eyelids are open, Riolan’s muscle is contracted, which closes the orifice of each meibomian gland, thereby minimizing environmental influences such as bacterial entry into the meibomian gland; at the same time, the orbicularis oculi muscle is relaxed and thus exerts minimal pressure on the meibomian glands. During blinking or when meibum needs to be expressed, orbicularis oculi muscle action increases the pressure and temperature inside the meibomian glands, while relaxation of Riolan’s muscle allows the meibum to exit the gland onto the eyelid margin. Subsequent blinking helps to mix and distribute the meibum with the tear film across the eye.