Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

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Figure 1 Dysfunction of the integrated lacrimal functional unit, diagrammed in the uppermost triangle, can manifest as altered tear composition, ocular surface inflammation, or secretory dysfunction. Primary dysfunction in one part of the lacrimal functional unit, in the tear film, the ocular surface, or the secretory glands, can lead to secondary dysfunction in the others, as indicated by the arrows connecting them. All forms of lacrimal functional unit dysfunction can result in tear film instability, with ocular discomfort and ocular surface disease, including apoptosis of glandular and ocular surface epithelial cells, as important consequences. The overall disorder, previously called dry eye syndrome, is more appropriately termed in this book lacrimal keratoconjunctivitis (LKC).

functional unit, can destabilize the tear film and lead to lacrimal keratoconjunctivitis (LKC), previously known as keratoconjunctivitis sicca (KCS). Conditions affecting each of these components are reviewed in this chapter.

II.AFFERENT DISRUPTION

Clinical and experimental evidence indicates that decreased trigeminal afferent sensory input from the ocular surface and adnexal tissues results in decreased tear secretion by the lacrimal glands and mucin production by the ocular surface

ophthalmicus who develop neurotrophic keratopathy had significantly lower aqueous tear production and greater loss of the nasal-lacrimal reflex compared with patients who did not develop corneal changes [2]. This suggests that aqueous tear deficiency is a risk factor for neurotrophic keratopathy, a theory supported by a report that 87% of neurotrophic ulcers healed following punctual occlusion [3]. Experimental trigeminal nerve ablation resulted in decreased conjunctival goblet cell density, decreased corneal epithelial glycogen, and morphological changes in the ocular surface epithelium similar to those seen in KCS [4].

When all emotional and afferent sensory stimulus for tear secretion is removed by general anesthesia, tear production falls to below detectable levels [5]. Topical anesthesia of the ocular surface caused a 66% decrease in aqueous tear production [6], and anesthesia of the nasal mucosa decreased tear secretion in the ipsilateral eye by about 34% [7]. A reduced blink rate may accompany ocular surface anesthesia because one trigger of involuntary blinking is the sensation of tear film breakup. This concept is supported by the observation that the rate of involuntary blinking in normal subjects decreases after topical corneal anesthesia [8]. The combination of reduced aqueous tear production and increased tear evaporation that accompanies a reduced blink rate may explain the abnormally elevated tear-film osmolarity observed in rabbits after instillation of 0.5% proparacaine [9].

In addition to their stimulatory effect on tear production, the trigeminal nerves exert trophic influences on the ocular surface epithelium. For example, increased corneal epithelial permeability was reported after experimental corneal denervation in rabbits [10]. Also, a significantly decreased mitotic rate in the corneal epithelium of rats was observed after sensory denervation [11]. This may be due to reduced release of mitogenic neuropeptides, such as substance P, from the sensory nerve endings, or to decreased intracellular levels of acetylcholine in the corneal epithelium associated with corneal denervation [12,13]. Taken together, these findings indicate that secretion, spread, and clearance of tears is driven by afferent neural stimulation in a reflexive manner.

Afferent stimulation of aqueous tear production may be disrupted by congenital or acquired diseases of the trigeminal nerves that innervate the ocular surface. Familial dysautonomia (also known as Riley-Day syndrome) is a hereditary sensory and autonomic neuropathy that causes corneal anesthesia, decreased tear secretion, and severe LKC [14]. Patients with this condition produce a reduced amount of tears when crying. Reflex lacrimation in response to irritants, such as the odor of onions or scratching of the middle nasal turbinate, is absent [15]. However, children with this syndrome produce abundant tears after parenteral administration of the cholinergic agonist methacholine, indicating parasympathetic denervation supersensitivity of the lacrimal gland [15,16]. Lacrimal gland histology appears normal in this condition [17]. In addition to reduced tear secretion, corneal anesthesia renders patients with Riley-Day syndrome even more susceptible to developing corneal ulceration and perforation [14].

A number of acquired ocular and systemic diseases cause trigeminal dysfunction and decreased tear secretion. Herpes zoster ophthalmicus often resolves with reduction or loss of corneal and cutaneous sensation in the distribution of the first division of the trigeminal nerve [2,18,19]. Herpes simplex keratitis can produce sectoral or diffuse reduction of corneal sensation [20,21]. Corneal sensation decreases with long-term hard or soft contact lenses wear [22–24]. Diabetes mellitus can cause a polyneuropathy that reduces corneal sensation and causes a secondary aqueous tear deficiency and LKC. Reduced corneal sensation and aqueous tear deficiency have been identified as risk factors for development of diabetic keratoepitheliopathy [25–27]. Lattice corneal dystrophy has been reported to decrease corneal sensation [28]. Corneal sensation can also be affected by severe microbial keratitis and conjunctival inflammatory conditions, such as Stevens-Johnson syndrome and ocular cicatricial pemphigoid.

Corneal and external ocular sensation can also be disrupted by injuries to the ocular surface, orbit, or central nervous system. Surgical damage or amputation of trigeminal afferent nerves is one of the most common causes of reduced corneal sensation [2]. Ocular surgical procedures that decrease corneal sensation include scleral buckling for retinal detachment repair, penetrating keratoplasty, photorefractive keratectomy, and laser-assisted intrastromal keratomileusis (LASIK) [29–33].

III.EFFERENT DISRUPTION

Diseases of the efferent component of the functional unit can affect the autonomic nerves stimulating tear secretion (secretory fibers), those regulating eyelid blinking and the tear drainage pump (motor fibers), or both. Tear spread and renewal can also be compromised by eyelid alterations (e.g., ectropion, lid margin irregularity) and lagophthalmos (e.g., thyroid eye disease, postblepharoplasty), which disrupt normal blinking, even when efferent neural connections are intact.

Disruption of the parasympathetic and sympathetic secretory nerves can result from a number of causes, including degenerative and inflammatory diseases, tumors, and injuries (Fig. 2). A common cause is the use of systemic medications with anticholinergic effects. Included among the ever-increasing number of these medications are antihistamines, antispasmotics, antiemetics and antidepressants [34–36]. One of the mechanisms of secretory dysfunction in Sjögren’s syndrome mimics the anticholinergic side effects of these medications: circulating autoreactive antibodies disrupt function of M3 acetylcholine receptors located on the basolateral cell membranes of lacrimal gland secretory acinar cells [37]. Age-related generalized degeneration of the parasympathetic nervous system also results in decreased secretory drive [38]. Damage to the lacrimal secretory fibers of the seventh (facial) nerve in the nervus intermedius or the greater superficial petrosal nerve may result in dry eye [39].

Tear spread and clearance can be disrupted by disease or injury of the motor fibers of the seventh cranial nerve. Bell’s palsy is a common facial neuropathy that is associated with lagophthalmos and partial or complete blink paralysis. Bell’s palsy may result from injury, viral infection, inflammation, ischemia, or idiopathic causes. Besides experiencing corneal exposure secondary to inadequate lid closure, approximately 10% of patients with Bell’s palsy have been observed to have decreased or absent corneal sensation, presumably resulting from exposure hypesthesia, adaptation, or inflammation [40]. Parkinson’s disease is a neurodegenerative disease that is associated with reduced blink rate, increased tear evaporation, and ocular surface desiccation [41]. The tear film instability in this condition may be further compromised by some of the medications with anticholinergic side effects that are used to treat it.

IV. DISRUPTION OF TEAR SECRETORY GLANDS

Malformation, disease, or damage of the tear-secreting apparatus (consisting of the lacrimal glands, ocular surface epithelia, conjunctival goblet cells, and meibomian glands) is the third mechanism for disrupting the functional unit (Fig. 2).

V.LACRIMAL GLAND

Age-related degeneration may be the most common cause of lacrimal dysfunction [42,43]. Age-related pathological changes of the lacrimal gland include lobular and diffuse fibrosis and atrophy, as well as periductual fibrosis. An age-related shift from fluid/protein-secreting to mucus-secreting acini was observed in a histopathological study of 80 human lacrimal glands from patients with a mean age of 59 years [42,44]. Although age-related lacrimal dysfunction can be differentiated from Sjögren’s-associated dry eye by its lack of circulating autoantibodies, an immune mechanism for lacrimal gland destruction cannot be excluded because age-related lymphocytic infiltration of the lacrimal gland has been correlated with acinar loss and ductal pathology [43,45].

Tear flow and tear volume have been reported to decrease with age [46]. Furthermore, lacrimal secretion of supportive and protective factors, such as epidermal growth factor (EGF) and lactoferrin, decreases with age [47].

VI. OBSTRUCTIVE LACRIMAL DISEASES

Infectious and inflammatory diseases of the conjunctiva may cause secondary aqueous tear deficiency by scarring the excretory ducts of the main and accessory

lacrimal glands. Trachoma is a chronic infectious conjunctivitis caused by Chlamydia trachomatis. A cell-mediated immune response to this organism develops in the conjunctiva [48] that causes scarring and secondary occlusion of lacrimal gland ductules, aqueous tear deficiency, and KCS [49].

Ocular cicatricial pemphigoid (OCP) is a chronic autoimmune disorder characterized by recurrent blisters or bullae of the mucous membranes and skin with secondary cicatrization [50]. Aqueous tear deficiency follows fibrotic occlusion of the lacrimal gland ducts. Instability in the tear film also results from conjunctival squamous metaplasia and decreased goblet cell density [51]. Conjunctival scarring may also develop from chronic use of certain topically applied medications (drug-induced pseudopemphigoid), including ecothiophate iodine, pilocarpine, idoxuridine, and epinephrine [52].

Erythema multiforme minor is an acute, self-limited inflammatory condition that primarily involves the skin and can be precipitated by drugs or infections, most commonly herpes simplex [53]. The acute phase of this disease includes a conjunctivitis of variable severity, which can be pseudo-membranous and lead to scarring and fibrotic obliteration of the lacrimal ducts. StevensJohnson syndrome (also known as erythema multiforme major) characteristically involves two or more mucous membranes, including the conjunctiva. It also occurs after administration of many different drugs and systemic infectious diseases [53]. After the acute episode has subsided, squamous metaplasia with keratinization and goblet cell loss may develop in the conjunctival epithelium [50,54]. Recurrent or prolonged inflammation may worsen LKC in this condition [55].

Chemical trauma to the ocular surface with either alkaline or acidic substances may cause dry eye by damage to or destruction of the ocular surface epithelia and the lacrimal and meibomian gland ductules [56].

VII. ENDOCRINE IMBALANCE

As reviewed in Chapter 8, androgenic hormones play an important role in supporting the secretory immune function of the lacrimal glands [57,58]. The meibomain glands are also androgen target organs [59]. Relative androgen deficiency might explain the greater prevalence of dry eye in women. Consistent with this, Sjögren’s syndrome KCS occurs almost exclusively in women [60]. Androgen levels decrease with age in both sexes and may be responsible in part for the age-related deterioration in tear secretion. Hormone replacement therapy in postmenopausal women may also be associated with dry eye. Women taking estrogen replacement therapy are at a greater risk for developing dry eye than women taking a combination of estrogen and progesterone [61]. It has not been established whether oral contraceptives lower aqueous tear production [62].