Ординатура / Офтальмология / Английские материалы / Ocular Periphery and Disorders_Dartt, Bex, Amore_2011

agonist-stimulated protein secretion since chelation of either the intracellular or the extracellular Ca2+ leads to complete inhibition of secretion. Ca2+ can stimulate secretion alone or do so by activating Ca2+ and calmodulindependent protein kinases to phosphorylate-specific substrates to cause secretion.

The DAG formed from the hydrolysis of PIP2 activates protein kinase C (PKC, Figure 5). PKC is a family of closely related isozymes that has been divided into three categories based on structural and functional criteria. A first group, termed conventional PKCs (cPKCs), includes PKCa, -bI, -bII, and -g isoforms, which have a Ca2+- and DAG-dependent kinase activity. A second group, termed novel PKCs (nPKCs), includes PKCE, -d, -y, and -Z isoforms, which are Ca2+-independent and DAG-stimulated kinases. A third group, termed atypical PKCs (aPKCs), includes PKCz and -i/l isoforms, which are Ca2+- and DAG-independent kinases.

Four isoforms of PKC are expressed in the rat lacrimal gland: one classical, PKCa; two novel, PKCd, and -E; and one atypical, PKCi/l. In an attempt to define the role that individual PKC isoforms might play in regulating lacrimal gland functions in response to cholinergic stimulation, isoform-specific peptide inhibitors of PKC were synthesized. These peptides were derived from the unique pseudosubstrate sequences of PKCa, -d, and -E, and were myristoylated at their N-terminus to make them cell permeant. Indeed, all PKC isoforms have a pseudosubstrate sequence in their N-terminal part, which interacts with the

catalytic domain to keep the enzyme inactive in resting cells. Using these peptides, it was shown that cholinergic agonists activate PKCa and -E to a larger extent and PKCd to a lesser extent, to induce protein secretion. It was also shown that PKCd and -E, but not -a, negatively modulate cholinergic-induced Ca2+ elevation in the lacrimal gland.

PLD-coupled signaling pathway

PLD catalyzes the hydrolysis of membrane phospholipids (preferably phosphatidylcholine), producing phosphatidic acid and the free polar head group. Phosphatidic acid, by itself or after its conversion to DAG by a phosphohydrolase, is an important second-messenger molecule. Besides its hydrolytic activity, PLD possesses the unique ability to catalyze a transphosphatidylation reaction, in the presence of a primary alcohol, in which the phosphatidyl moiety of the phospholipid substrate is transferred to the primary alcohol producing the corresponding phosphatidylalcohol. Accumulation of such unique transphosphatidylation products has been used to detect PLD activity unambiguously in diverse cell types.

Depending on the cell’s type, the receptor activation of PLD was shown to occur through mechanisms involving PKC activity, Ca2+, G proteins, or receptor-linked tyrosine kinases. Since PKC activation and Ca2+ mobilization are downstream to PLC stimulation, it has been suggested that PLD activation may be secondary to receptor activation of PLC.

Taking advantage of the transphosphatidyl reaction catalyzed by PLD, it was shown that the lacrimal gland contains a PLD activity. Cholinergic agonists, through the muscarinic receptor, stimulate both the hydrolytic activity of PLD to produce phopshatidic acid, as well as the transphosphatidyl reaction. However, if either Ca2+ is mobilized or PKC is activated, only the transphosphatidyl reaction is stimulated. This finding implied that cholinergic agonist activation of PLD in the lacrimal gland is not secondary to the activation of PLC by these agonists.

MAPK-coupled signaling pathway

MAPK, also known as ERK, is a dual serine/threonine and tyrosine protein kinase. It is activated through phosphorylation by an MAPK kinase (known as MEK). MEK is also activated through phosphorylation by its upstream MAPK kinase kinase (known as Raf). Raf is activated when the small GTP-binding protein, Ras, is in its GTP-bound form. Depending on the cell’s type, Ras can be activated by several mechanisms, including the nonreceptor tyrosine kinases Pyk2 and Src, growth factors receptors, and PKC.

In the lacrimal gland, the activation of MAPK attenuates protein secretion. The activation of MAPK by the M3 receptor was shown to involve the nonreceptor tyrosine kinases Pyk2 and Src, which in turn activate Ras and, ultimately, MAPK (Figure 5). Recent evidence showed that the activation of MAPK by cholinergic agonists is downstream of PLD activation. The mechanisms involved in PLD-mediated activation of MAPK in the lacrimal gland remain to be elucidated.

The termination of the cholinergic signaling pathway involves receptor desensitization, activation of protein

phosphatases to dephosphorylate ERK and other phosphorylated substrates, and the activation of ion channels/ pumps to return the concentration of cytosolic Ca2+ to its resting levels.

In summary, the activation of lacrimal gland cholinergic receptors in response to the parasympathetic neurotransmitter acetylcholine activates three main signaling pathways that either enhance (PKC, Ca2+) or attenuate (ERK) protein secretion (Figure 5). The net protein secretory output in response to acetylcholine stimulation will likely depend on the relative contribution of the stimulatory versus the inhibitory signal transduction pathways.

VIP-Activated Signal Transduction Pathways

VIP interacts with specific VIP receptors located on the basolateral membranes of lacrimal gland cells. Two types of VIP receptors have been identified, VIPRI and VIPRII, which are also known as VIPACR1 and VIPACR2, and both of them are expressed in the lacrimal gland, with VIPRI being the predominant type.

Adenylate cyclase-coupled signaling pathway

The VIP receptor uses the G protein Gas to activate the effector enzyme adenylyl cyclase (AC), which produces the second-messenger molecule, cyclic adenosine monophosphate (cAMP) (Figure 6). Molecular cloning has identified several isoforms of mammalian AC forming a family of at least 10 enzymes (ACI-X). There are at least three isoforms of AC (ACII, ACIII, and ACIV) present in the lacrimal gland, each having a unique localization.

Although the regulation of AC enzymatic activity is complex and isoform specific, all AC isoforms are activated

by Gas. Increases in the intracellular levels of cAMP lead to activation of protein kinase A (PKA), a ubiquitous serine and threonine protein kinase. In its inactive state, PKA consists of a complex of two catalytic (C) subunits and two regulatory (R) subunits (Figure 6). Binding of cAMP to the R subunit alleviates an autoinhibitory contact that releases the active C subunit (Figure 6). The active kinase is then free to phosphorylate specific protein substrates to stimulate lacrimal gland protein and fluid secretion.

MAPK-coupled signaling pathway

Recently, it has been shown that addition of VIP, exogenous cAMP, or analogs that increase cAMP levels inhibited both basal as well as cholinergic induced activation of MAPK in the lacrimal gland. One implication of these findings is that it could help explain the well-documented synergistic effect that addition of a cAMP along with a Ca2+-/ PKC-dependent agonist have on lacrimal gland protein secretion. Indeed, cholinergic agonists activate MAPK, which attenuates protein secretion. When the cAMP pathway is activated, MAPK activity is inhibited; this should alleviate the inhibitory effect that MAPK has on secretion and as a result, protein secretion will be potentiated if both the Ca2+/PKC and the cAMP pathways are activated simultaneously.

The termination of VIP-activated signaling pathways likely includes activation of the cAMP-phosphodiester- ase, which converts cAMP to the inactive 5’-AMP. Other

signal-terminating mechanisms include desensitization of the VIPR and AC, sequestration of the PKA C subunits by the naturally occurring protein kinase inhibitor (PKI), and activation of protein phosphatases.

a1-Adrenergic Agonist-Activated Signal

Transduction Pathways

Norepinephrine, released from the sympathetic nerves, binds to a1- and b-adrenergic receptors on lacrimal gland cells. b-Adrenergic receptors are coupled to activation of AC to activate a cAMP-dependent signal transduction pathway, as discussed for VIP. Of the three a1-adrenergic receptor subtypes (a1A, a1C, and a1D) identified, only the a1D subtype is expressed in the lacrimal gland.

Ca2+- and PKC-coupled signaling pathways

In most exocrine tissues, a1-adrenergic agonists activate the same pathway as cholinergic agonists (i.e., activation of PLC and PLD). Surprisingly, in the lacrimal gland, a1-adrenergic agonists do not activate PLC or PLD, although their activation leads to a slight increase in cytosolic Ca2+ and to activation of PKC isoforms (Figure 7). To date, the effector enzyme(s) activated by lacrimal gland a1D-adrenergic receptors to mobilize Ca2+ and activate PKC is still unknown.

Although Ca2+ mobilization in the lacrimal gland in response to adrenergic agonist stimulation is well

Ras

Raf

MEK

ERK

–

+

–

Exocytosis

documented, the mechanisms involved are poorly understood. A role for IP3 has been ruled out since adrenergic agonists do not increase its production as they fail to activate PLC. It has been proposed that cyclic ADP ribose, which activates ryanodine receptors to release Ca2+ into the cytosol, might be involved. Other investigators proposed that nitric oxide (NO)-induced generation of cyclic guanosine monophosphate (cGMP) is involved in a1- adrenergic agonist-induced mobilization of Ca2+.

The role of PKC in a1-adrenergic agonist-induced lacrimal gland protein secretion has been studied using the myristoylated pseudosubstrate-derived peptides. It was shown that a1-adrenergic agonists activate three PKC isoforms – PKCa, -d, and -E. Activation of PKCE enhances protein secretion, whereas activation of PKCa and -d attenuates protein secretion. This is in contrast to the stimulatory effect that PKCa and -d isoforms have on protein secretion when activated by cholinergic agonists. These findings imply that the effect (inhibitory or stimulatory) of a given isoform of PKC in the lacrimal gland is stimulus dependent and might be dictated by the cellular location of PKC isoforms.

MAPK-coupled signaling pathway

Similar to cholinergic agonists, a1-adrenergic agonists activate MAPK to attenuate lacrimal gland protein secretion. However, in contrast to the cholinergic pathway, activation of MAPK by the a1D-adrenergic receptor does not involve the nonreceptor tyrosine kinases Pyk2 and Src, but involves activation of the epidermal growth factor receptor (EGFR; Figure 7). The EGFR, also known as Erb1, is the prototypical member of the ErbB/EGFR family of receptors which consists of three additional members (ErbB2–4). EGFR is a type 1 transmembrane tyrosine kinase receptor consisting of an extracellular domain (ligand-binding site), a transmembrane domain, and the carboxy-terminal, an intracellular domain containing the tyrosine kinase motif. In addition, the carboxy-terminal domain contains tyrosine residues that become phosphorylated following ligand binding and receptor dimerization. Following receptor activation, several exogenous substrates that contain either Src homology 2 (SH2) or protein tyrosine binding (PTB) motifs are recruited to specific phosphorylated tyrosine residue.

In the lacrimal gland, the activation of the EGFR by a1-adrenergic agonists occurs through a process termed as transactivation and involves the activation of a metalloproteinase and shedding of EGF (Figure 7). Following activation, Shc (an SH2 motif-containing protein) is recruited to the EGFR, followed by recruitment of Grb2 and the guanine nucleotide exchange factor protein, SOS (Figure 7). SOS stimulates the exchange of GDP for GTP on Ras and hence leads to its activation. Activated Ras triggers the activation of the MAPK cascade, leading to activation of ERK (Figure 7). Similar to the cholinergic pathway, a1-adrenergic-activated ERK has been shown to attenuate lacrimal gland protein secretion.

NO-coupled signaling pathway

NO, along with L-citruline, is produced from L-arginine in the presence of O2- and NADPH-derived electrons. This reaction is catalyzed by the enzyme NO synthase (NOS). There are three well-characterized isoforms of NOS expressed by mammalian cells: neuronal NOS (nNOS also known as NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). Activation of nNOS and eNOS, but not iNOS, requires calmodulin and an increase in [Ca2+].

It has been shown recently that lacrimal gland a1-adrenergic receptors are coupled to the NO/cGMP pathway (Figure 7). Indeed, it was found that both nNOS and eNOS are expressed in the lacrimal gland. The addition of a1-adrenergic agonists led to generation of NO, presumably through activation of eNOS and not nNOS. NO, in turn, activates soluble guanylate cyclase to generate cGMP which enhances lacrimal gland protein secretion.

The termination of the a1-adrenergic signaling pathway is likely to involve receptor desensitization, activation of protein phosphatases to dephosphorylate ERK and other phosphorylated substrates, and the activation cGMP-phosphodiesterase, which converts cGMP to the inactive 5’-GMP.

In summary, the activation of lacrimal gland a1D- adrenergic receptors, in response to the sympathetic neurotransmitter norepinephrine, activates stimulatory pathways (including PKCE and cGMP) and inhibitory pathways (including PKCa, PKCd, and ERK; Figure 7). It is likely that the net lacrimal gland protein secretion in response to sympathetic stimulation is a balance between these stimulatory and inhibitory signal transduction pathways.

See also: Adaptive Immune System and the Eye: Mucosal Immunity; Lacrimal Gland Hormone Regulation; Lacrimal Gland Overview; Tear Film.

Further Reading

Botelho, S. Y., Hisada, M., and Fuenmayo, N. (1966). Functional innervation of the lacrimal gland in the cat. Archives of Ophthalmology 76: 581–588.

Broad, L., Braun, F., Lievremont, J., et al. (2001). Role of the phospholipase C-inositol 1,4,5-trisphosphate pathway in calcium release-activated calcium current and capacitative calcium entry.

Journal of Biological Chemistry 276: 15945–15952.

Chen, L., Hodges, R. R., Funaki, C., et al. (2006). The effects of a1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells. American Journal of Physiology. Cell Physiology 291: C946–C956.

Funaki, C., Hodges, R. R., and Dartt, D. A. (2007). Role of cAMP inhibition of p44/p42 mitogen-activated protein kinase in potentiation of protein secretion in rat lacrimal gland. American Journal of Physiology. Cell Physiology 293: C1551–C1560.

Hodges, R. R. and Dartt, D. A. (2003). Regulatory pathways

in lacrimal gland epithelium. International Review of Cytology

231: 129–196.

Hodges, R., Rios, J., Vrouvlianis, J., et al. (2006). Role of protein kinase C, Ca2+, Pyk2 and c-Src in agonist activation of rat lacrimal gland p42/p44 MAPK. Investigative Ophthalmology and Visual Sciences

47: 3352–3359.

Ota, I., Zoukhri, D., Hodges, R., et al. (2003). a1-Adrenergic and cholinergic agonists activate MAPK by separate mechanisms to

inhibit secretion in lacrimal gland. American Journal of Physiology. Cell Physiology 284: C168–C178.

Wu, K., Jerdeva, G., da Costa, S., et al. (2006). Molecular mechanisms of lacrimal acinar secretory vesicle exocytosis. Experimental Eye Research 83: 84–96.

T Wojno, The Emory Clinic, Atlanta, GA, USA

ã 2010 Elsevier Ltd. All rights reserved.

Glossary

Actinic lesion – Dry, scaly, rough-textured patches that form after years of exposure to ultraviolet light, such as sunlight.

Amblyopia – Disorder of the visual system that is characterized by poor or indistinct vision in an eye that is otherwise physically normal.

Anisometropia – Condition in which the two eyes have unequal refractive power.

Blepharitis – Chronic inflammation of the eyelids. Blepharoplasty – Surgical procedure intended to reshape the upper eyelid or lower eyelid by the removal or repositioning of excess tissue as well as by reinforcement of surrounding muscles and tendons.

Dermatochalasis – Redundant, baggy eyelids. Ectopion – Outward malposition of the eyelid. Entropion – Inward malposition of the eyelid.

Lagophthalmos – Inability to close the eye. Ptosis – Downward malposition of the upper eyelid. Strabismus – A condition in which the eyes are not properly aligned with each other.

Trichiasis – Misdirected eyelashes.

Anatomy

From a functional perspective, the upper lid can be divided into anterior, middle, and posterior lamellae (Figure 1). In the upper lid, the anterior lamella consists of the skin and orbicularis muscle while the posterior lamella consists of the conjunctiva, tarsus, levator, and Mu¨ller’s muscle. The middle lamella is the orbital septum and orbital fat. The thin eyelid skin covers the orbicularis muscle, which is functionally divided into the pretarsal, preseptal, and orbital parts. There is no discreet anatomic border to these components of the orbicularis. The levator muscle originates just superior to the annulus of Zinn at the orbital apex and changes from striated muscle to fibrous apponeurosis 15 mm above the superior border of tarsus. The levator inserts into the superior border and anterior surface of the tarsal plate. It is innervated by the third cranial nerve. Mu¨ller’s muscle is only 10–14 mm long and arises from the underbelly of the levator and inserts into the superior border of tarsus. It is composed of

smooth muscle fibers and is adrenergically innervated. The levator and Mu¨ller’s muscles function to open the upper lid while the orbicularis muscle closes it. The orbital septum is a thin, multilayered sheet of fibrous tissue separating the lid from the orbit. It arises from the superior orbital rim and inserts onto the levator aponeurosis 2–10 mm above the superior border of tarsus in Caucasians, 15 mm or more in blacks and at or below the superior border of tarsus in Asians. Small, fine, fibrous attachments extend from the levator to the subcutaneous tissue. These attachments and the insertion of the septum form the lid crease while the skin above the crease forms the lid fold. There are two fat pockets in the upper lid found nasally and centrally. The upper tarsus is a firm connective tissue usually 10–12 mm in height and 1 mm in thickness.

The lower lid is likewise divided into three functional lamellae: an anterior layer of skin and orbicularis, a posterior layer of conjunctiva and lower lid retractors, and a middle layer of septum and orbital fat (Figure 2). The lower lid retractors are composed of the capsulopalpebral fascia (the equivalent of the levator in the upper lid) and the inferior tarsal muscle (the equivalent of the Mu¨ller’s muscle in the upper lid). The capsulopalpebral fascia is a fibrous band originating from the underbelly of the inferior rectus muscle that courses anteriorly, enveloping the inferior oblique, and inserts onto the inferior border of tarsus. It is functionally controlled by its origin from the inferior rectus muscle to retract the lower lid inferiorly when the eye looks downward, preserving unobstructed vision. The inferior tarsal muscle is often just scattered smooth muscle fibers intermixed with the capsulopalpebral fascia. As in the upper lid, the septum arises from the orbital rim and inserts on the inferior border of tarsus, often blending with the lower lid retractors. A lower lid crease occasionally exists but is usually less obvious. There are three fat pockets in the lower lid: nasal, central, and temporal (or lateral). The lower tarsus is usually 4–5 mm in height.

The lid margin is the border between the anterior skin–muscle layer and the posterior tarsoconjunctival layer. There are two to three irregular rows of lashes, whose bulbs are embedded just below the skin surface within the orbicularis muscle. Posterior to the lash line are the meibomian gland orifices. These sebaceous glands are embedded within the tarsal plates and run the entire vertical length of the tarsus. There are about 25 of these glands in the upper lid and 20 in the lower lid. The mucocutaneous junction is just posterior to the meibomian

Superior rectus muscle

Levator muscle

Suspensory ligament of the upper fornix

Superior conjunctival fornix

Müller’s muscle

* = Whitnall’s

ligament

Figure 1 Cross-section of the upper eyelid.

Conjunctiva

Inferior fornix

Inferior rectus muscle

Fat pad

Inferior oblique muscle

Figure 2 Cross-section of the lower eyelid.

Skin

Subcutaneous tissue

Preseptal orbicularis

Orbital septum

Preaponeurotic fat pad

Levator aponeurosis

Fine attachment from levator aponeurosis to

Müller’s muscle

Conjunctiva

Tarsus

Pretarsal orbicularis

Skin

Pretarsal orbicularis

Tarsus

Suspensory ligament in the inferior fornix

Inferior tarsal muscle

Orbital septum

Preseptal orbicularis

Capsulo-palpebral fascia

gland orifices. The gray line is a variably visible section of pretarsal muscle (muscle of Riolan) just anterior to the tarsus. Embedded within the lid margin are the apocrine glands of Moll and the sebaceous glands of Zeiss associated with the lash follicles.

The upper and lower lids join laterally where the pretarsal heads of the orbicularis muscle form the lateral canthal tendon, which inserts into the orbital tubercle just posterior to the lateral orbital rim. Medially, the preseptal and pretarsal muscle form the medial canthal tendon,

whose anterior and posterior heads surround the lacrimal sac. The lacrimal puncta open on the lid margin 6 mm from the medial commissure of the lids.

Pathophysiology

Dermatochalasis

Dermatochalasis is the normal aging change in the upper and lower lids characterized by loose, redundant skin and

orbicularis muscle often with bulging of the orbital fat pockets (Figure 3). It may be associated with ptosis of the eyebrows and forehead relaxation. When severe in the upper lids, it can limit peripheral vision and obstruct the central visual axis. Lower lid dermatochalasis rarely affects the vision, but in rare cases, fat bulging can be so extreme so as to contact the patient’s glasses. Surgical treatment is aimed at removal of the excess skin, orbicularis, and fat.

Ptosis

Lid ptosis is a lower-than-normal position of the upper lid margin (Figure 4). When the lid margin is 2 mm or less from the center of the pupil, the superior visual field is usually significantly obstructed. Ptosis is either congenital or acquired. Congenital ptosis is usually the result of a malformed levator muscle often with a family history. It is unilateral in 75% of cases and bilateral (although often

Figure 3 Dermatochalasis of all four eyelids.

Figure 4 Ptosis of the right upper lid.

asymmetric) in 25% of cases. It is associated with anisometropia, amblyopia, or strabismus in 30% of cases. In general, the more severe the ptosis, the more dystrophic appears the muscle histologically. In cases of severe congenital ptosis, striated muscle fibers are usually completely absent, totally replaced by fibro-fatty connective tissue.

Treatment for mild-to-moderate congenital ptosis is to perform levator resection surgery, wherein 12–18 mm of the distal levator and the underlying Mu¨ller’s muscle is resected and the cut end resewn to the superior border of tarsus. This effectively shortens the muscle, resulting in a higher resting level of the lid on the globe but does not improve the overall movement of the lid. The most common problems post-operatively are undercorrection, overcorrection, or asymmetry of the lids often necessitating reoperation. Surgery induces lagophthalmos that increases with the amount of levator resected. Surprisingly, if done during childhood, lagophthalmos is usually well tolerated throughout the patient’s lifetime.

In severe congenital ptosis, the levator is usually so dystrophic that resection is ineffective. In such cases a sling must be performed. In this surgery, autogenous or banked fascia or some alloplastic material is sewn into the tarsus and then threaded under the skin to the frontalis muscle in the forehead. The patient then elevates the lid by contracting the frontalis muscle, which pulls up the lid margin. Most patients do so automatically, resulting in effective lid opening.

Acquired ptosis, usually seen with aging, results from thinning or dehiscence of the levator aponeurosis from the tarsal plate. Any condition, however, that causes lid swelling or stretching (cataract surgery, trauma, contact lens wear, etc.) can result in acquired ptosis. Much less frequently, acquired ptosis is due to actual deterioration of the levator muscle or true muscular dystrophy. The usual treatment of acquired ptosis is to shorten the levator aponeurosis but to a much smaller degree than done with congenital ptosis (usually 4–10 mm). In adults, ptosis repair, when performed bilaterally, is often combined with blepharoplasty surgery for optimal cosmesis. Like in congenital ptosis, undercorrection, overcorrection, and asymmetry are common problems. In adults, however, adjustments can often be accomplished in the office under local anesthesia. Lagophthalmos is generally to be avoided in adult surgery, since the cornea is usually very intolerant of any chronic exposure and can rapidly result in discomfort and even ulceration.

Retraction

The opposite of ptosis, retraction is abnormal elevation of the upper lid or downward positioning of the lower lid (Figure 5). Most cases of upper lid retraction are due to thyroid eye disease resulting from contracture of the upper and lower lid retractors secondary to inflammation.

The lower lids may also retract due to age, associated with poor support from the cheekbones. Retraction due to thyroid eye disease is often associated with exopthalmos or an abnormal anterior displacement of the globe, which further increases the stare – so characteristic of this disease. Patients with retraction often have lagophthalmos, resulting in corneal exposure and irritation. Lower lid retraction is often seen as a normal physiologic variant in people with shallow orbits, especially common in black patients. Retraction is occasionally seen with overexcessive skin excision in blepharoplasty surgery.

Treatment of upper lid retraction in thyroid eye disease consists of graded recession of the levator–Mu¨ller’s muscle complex superiorly so as to drop the upper lid margin down. Some surgeons insert spacers (autologous or banked tissues) between the recessed, cut edge of the levator–Mueller’s muscle complex and the superior border of the tarsus when performing this surgery. In the lower lid, retraction is treated with recession of the lower lid retractors very frequently combined with spacer grafts for additional support of the lower lid. In the upper lid, gravity works in favor of the correction while it works against it in the lower lid. If the retraction is due to skin shortage after blepharoplasty, then skin grafting may be necessary.

Entropion

Entropion is an inward turning of the upper or lower lid margin (Figure 6). This results in the lashes rubbing on the globe, causing irritation and even corneal ulceration. Senile or involutional lower lid entropion is common with age and is due to excess horizontal (canthal tendons) and vertical laxity (the lower lid retractors).

This may be intermittent at first but usually progresses to a chronic condition. The lid margin appears to have a

distinctive rolled-in appearance and can be reduced by pulling the lid against the lateral orbital rim, effectively tightening the lid. Surgical correction is aimed at correcting the horizontal laxity by resection of the redundant lid margin with resuspension at the lateral canthus. The vertical lid laxity may be corrected by plication of the lower lid retractors to the inferior border of tarsus. An effective repair is one which combines both of these procedures often performed through a lower lid blepharoplasty incision.

Involutional entropion usually does not occur in the upper lid. Such aging changes usually result in ptosis, as discussed above, or in lash ptosis – a downward angulation of the lashes due to relaxation of the anterior lamella of the eyelid in which the lash follicles are embedded. Lash ptosis is often corrected as part of an upper lid blepharoplasty procedure.

Cicatricial entropion may occur in both the upper and lower lids. It is due to vertical shortening of the posterior lamella of the eyelid, the tarsoconjunctival layer. It may be due to autoimmune disorders of the mucous membranes, inflammation, infection, surgery, trauma, or long-term use of glaucoma drops. Often, however, the cause is unclear. All surgeries for cicatricial entropion can be conceptualized as falling into three categories. The first are those that act by outward rotation of the lid margin (prototypical Weis procedure) usually involving a full-thickness, horizontal blepharotomy 4 mm from the lid margin. The second category involves expanding the shortened posterior lamella of the eyelid with grafts (usually buccal mucosa, amniotic membrane, or banked sclera). The third category involves procedures that split the lid margin at the gray line often with insertion of a spacer material, such as mucous membrane, to thicken the lid margin to the point that the lashes no longer rub against the globe. In some cases, the lash-bearing segment of the lid margin may simply be resected after splitting the lid margin.

Trichiasis

Often confused with entropion, trichiasis is inward misdirection of lashes against the globe in the presence of normal lid margin position. Trichiasis may, however, coexist with cicatricial entropion. Trichiasis is caused by the same factors that cause cicatricial entropion but is often idiopathic. Focal trichiasis is often treated by simple epilation of the offending lashes. If recurrent, electrolysis, cryotherapy, or laser may be used. Repeat treatment is often necessary since these modalities will kill the visible offending lashes but not the lashes that are about to bud. For large areas of the lid margin, surgery as outlined above for ciciatricial entropion may be needed. Alternatively, if focal, a segmental resection of the involved lid margin can be performed.

Distichiasis

Distichiasis is an additional row of lashes that grow from the meibomian orifices on the posterior lid margin. Such lashes will rub against the globe causing corneal irritation. Distichiasis may be congenital, often with a family history or acquired due to lid inflammation causing metaplasia of the cells in the posterior layer of the lid margin. It is treated with electrolysis or cryotherapy often after splitting the lid margin to prevent damage to the normal lashes. It may also be treated by direct surgical excision of the offending lashes.

Ectropion

Ectropion is outward rotation of the lower lid margin away from the globe (Figure 7). The exposure of the globe and the palpebral conjunctiva results in irritation, corneal damage, and keratinization of the conjunctiva. Epiphora, increased tear production, often results when the lower punctum stands off the globe and cannot adequately drain tears from the eye. Involutional ectropion occurs as an

Figure 7 Involutional ectropion of the lower lids, worse on the right.

aging change secondary to horizontal lid laxity, mainly in the medial and lateral canthal tendons. Repair is accomplished by horizontal shortening of the redundant lid margin, usually at the lateral canthus, sometimes combined with vertical shortening of the lower lid retractors. When the problem is mainly medial, punctual ectropion, a spindle of conjunctiva and lower lid retractors is resected immediately below the lower punctum. Lower lid ectropion may coexist with retraction, as was discussed above. Involutional ectropion usually does not occur in the upper lid.

Cicatricial ectropion is due to vertical shortening of the anterior, skin–muscle lamella of the upper or lower lid. It is usually secondary to trauma or skin disorders. In the upper lid, release of the scarred tissue is followed by skin grafting from the opposite upper lid, the retroauricular area, supraclavicular area, or forearm. In the lower lid, horizontal lid shortening is also often required since the chronically ectropic lid often has or develops a component of excess horizontal laxity. In the lower lid, a skin graft may be replaced by advancement of a skin–muscle flap from the surrounding area.

Paralytic ectropion is due to paralysis of the seventh nerve. There is also lagophthalmos due to inability of the upper and lower lids to close. Exposure can be severe and can lead to corneal ulceration. Conservative treatment consists of ocular lubrication, moist chamber devices and lid taping. Tarsorrhaphy may be needed if the cornea dries out in spite of conservative measures. For those cases in which seventh nerve function will not return a gold weight or spring may be placed in the upper lid to counter the lagophthalmos. The lower lid usually needs to be tightened horizontally and often lifted vertically with a posterior lamellar graft or suspension sling of fascia or silicone. Although such treatments are helpful, patients never have a normal blink with any of these procedures.

Floppy Lid Syndrome

This uncommon syndrome is most frequently seen in obese, middle-aged males (Figure 8). The upper lid is extremely lax and spontaneously everts often while the patient sleeps and rubs against the pillow. Those affected have a severe papillary conjunctivitis, ropey mucoid discharge, and irritation. Floppy lid syndrome is accompanied by sleep apnea and hypertension. Symptoms can sometimes be controlled by having the patient wear a Fox shield over the eye while sleeping to reduce nocturnal eversion of the lid. Most often, horizontal upper lid shortening is needed along with tightening of the lower lid for control of symptoms.

Common Malignant Eyelid Tumors

Basal cell carcinoma (BCC) is the most common eyelid malignancy accounting for 85–90% of such lesions.