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

A decrease in saccadic velocity can be seen in patients with extraocular muscle palsy. Pursuit movements are slower, and are driven by smooth following movements in response to a target moved slowly before the patient. There should be no lag or saccadic interlude during pursuit movements.

Gaze refers to movement of both eyes together. Gaze is conjugate if both eyes move the same amount, at the same speed, and in the same direction. Thus, in right gaze, both eyes look to the right and reach the intended target at the same time. Gaze is disconjugate if both eyes move in opposite directions or there is substantial failure of one eye to reach the target. Therefore, convergence and divergence movements are disconjugate. Ductions are movements of one eye examined under monocular viewing conditions. For example, we refer to adduction as a nasalward movement of an eye when the other eye is covered, eliminating any binocular adjustment in eye position. In contrast, versions are movements of both eyes examined under binocular viewing conditions. Dextroversion is movement of both eyes to the right; levoversion is movement of the eyes to the left. Version testing is helpful for assessing overor under-action of a muscle compared to its yoked muscle in the other eye.

As conjugate gaze position shifts, yoked muscles contract in response to gaze-evoked increases in innervational frequency (Figures 1(a) and 1(b)). However, innervation to the antagonist muscles is inhibited. Therefore, for gaze right, the right lateral and the left medial muscles

contract, but the right medial and left lateral rectus muscles are innervationally inactive. Because the eyes must move in an accurate, balanced, and coordinated fashion when gaze position is changed, complex central nervous system control mechanisms are required. Input from the frontal and parietal cortex and from the cerebellum is routed through a neural integrator in the brainstem whose function and control is still being investigated. Feedback from the afferent visual system and from proprioceptive input from the extraocular muscles modulates innervational tone to all the extraocular muscles and is important for long-term calibration of eye movements.

Ocular Motility Assessment in the Clinic

When an individual is looking straight ahead, in what is called primary gaze, a light falling on the eyes from a distance will be perceived by an examiner as a corneal reflex or reflection in approximately the same position in the pupil of each eye (Figure 1(a), central photograph). If the eyes are not aligned, there will be a nasal, temporal, or vertical offset of the corneal reflex in one eye compared to the other eye. The amount of offset of the reflex can be estimated subjectively by the examiner or measured with prisms. Care must be taken in the patient who has a very small degree of misalignment as these tests are not sensitive enough to detect it.

To confirm normal alignment of the eyes, a cover test is performed. If there is no refixation movement of either eye

when the other eye is covered, the alignment of the eyes is considered orthotropic. This does not imply, however, that the eyes are normally aligned since latent misalignment of the eyes may be controlled by fusional mechanisms that can be remarkably robust. To determine if an individual’s eyes are normally aligned, an alternate cover test is performed. Here, the eyes are alternately occluded. If no refixation movement of the eye under cover occurs when the cover is moved to the other eye, then the individual is considered to have normal eye alignment and is deemed orthophoric. The alternate cover test can be used in all the cardinal positions of gaze to determine if changes in gaze position result in any misalignment. If refixation movement is detected with alternate cover testing, then prisms may be used with the cover test to measure the magnitude of the misalignment. A convergent misalignment of the eyes is called esotropia; divergent misalignment is called exotropia; and vertical misalignment is called hypertropia.

In addition to alignment testing, an examiner performs certain sensory tests to determine the quality of binocular function. These tests detect the presence of normal or abnormal retinal correspondence, the presence of suppression or diplopia, even if not subjectively present, the quality of stereoacuity if present, and the presence of torsion. The nature of this text does not allow an indepth review of such testing, but it is useful to document, as binocular function is an important aspect of normal visual experience, and is critical to the assessment of outcomes after treatment for strabismus.

Children with strabismus typically do not experience diplopia unless the onset of misalignment has been rapid as might be seen in an acute CN VI palsy due to increased intracranial pressure or due to a brain tumor. More often, children with strabismus suppress the nonfixing eye, an adaptive mechanism that obviates diplopia, but places the child at risk for the development of amblyopia, a nonorganic loss of vision that may be permanent if not treated during the child’s period of visual plasticity. Therefore, during the examination of children being evaluated for strabismus, careful assessment of visual acuity is essential.

During a motility examination, all patients should be carefully observed for the presence of nystagmus (rhythmic to and-fro movements of the eyes), muscle weakness (paresis), muscle restriction, or binocular-gaze deficits along with abnormal head posturing, head nodding, or other adaptive mechanisms that may arise as a result of an abnormal ocular motor condition.

Clinical Treatment for Primary Eye Motility Disorders

Once strabismus has been diagnosed, then a decision must be made regarding how to treat it. In children, glasses are an important consideration. Children with esotropia who

are hyperopic (far-sighted) will often have an accommodative component to their strabismus. Control of accommodation by correcting the hyperopia may eliminate or reduce the angle of esotropia. Glasses are occasionally used in children with exotropia as well. Certainly, if a child has a significant refractive error, glasses will be required to optimize acuity.

A child with strabismus and amblyopia will likely be given treatment for the amblyopia which may include occlusion therapy or optical penalization with atropine drops. Treatment of amblyopia is usually recommended before more definitive treatment of the strabismus is undertaken. Other nonsurgical treatments for strabismus include prisms, if the angle of misalignment is small or, in less common scenarios, exercises such as convergence training.

When a decision has been made to proceed with surgery, there are several available options. Typical incisional surgery addresses the misalignment mechanically. If a muscle is overacting, then it is weakened. This is usually done by recession surgery in which the muscle insertion on the sclera is transected and then attached with sutures more posteriorly on the globe. This decreases the mechanical advantage of the muscle by reducing the arc of contact of the muscle on the globe. By contrast, if a muscle is underacting relative to its antagonist, then the muscle insertion is resected. In this surgery, a portion of the insertion is removed and the shortened muscle is reattached to the original muscle insertion on the sclera. This surgery works by shortening the tether length of the muscle and increasing its mechanical advantage relative to its antagonist. The amount of recession or resection is titrated to the angle of the strabismus with larger amounts of surgery for larger angles of misalignment. There are numerous variations on this theme, and the literature is full of unique means of weakening or strengthening muscles. In certain situations, such as when a muscle is significantly paralyzed, healthy muscle insertions may be transposed to approximate the insertion of the paralyzed muscle to assist its function. Sometimes, this is done in conjunction with botulinum toxin injection into the antagonist muscle to weaken it and to improve the rotation of the globe in the direction of the paralyzed muscle.

Botulinum toxin A has heralded the beginning of a new era in strabismus surgery. First introduced into clinical use in the early 1980s by Dr. Alan Scott at SmithKettlewell in San Francisco, botulinum toxin weakens muscle by chemical denervation of the muscle. Release of the neurotransmitter, acetylcholine, into the synaptic cleft of neuromuscular junctions (NMJs) of treated skeletal muscle (including extraocular muscle) is blocked. This temporary paralysis of the synapses of the NMJs results in a spread of NMJ sites across the surface of the muscle. Treatment effect is maximal for approximately 6 weeks and then begins to diminish as the terminal nerves regrow and form new NMJs. Ultimately, there is a return of

function at the sites of the original NMJs and retraction of the sprouted nerves. Treatment effect is essentially void by 3 months postinjection.

Botulinum injection has been used by some clinicians for the treatment of infantile and childhood forms of strabismus, especially esotropia, but its use has not been widely adopted because of the frequent need for reinjections, especially for larger angles of misalignment. However, pharmacologic treatment of strabismus is attractive because of decreased operative times required for injection compared with typical incisional surgery, decreased scarring, and preserved biomechanical relationships of the muscle, and orbital soft tissues. In the recent literature, there have been a number of reports of the use of new candidate drugs for both weakening and strengthening extraocular muscle in experimental animals. Although much research is still needed, the era of drug treatment for strabismus is dawning, and heralds the possibility of both reducing the short-term risks of strabismus surgery and improving the long-term outcomes of our interventions.

Acknowledgments

This work was supported by EY15313 and EY11375 from the National Eye Institute, the Minnesota Medical

Foundation, the Minnesota Lions and Lionesses, Research to Prevent Blindness (RPB) Lew Wasserman Mid-Career Development Award (LKM), and an unrestricted grant to the Department of Ophthalmology from RPB.

See also: Abnormal Eye Movements due to Disease of the Extraocular Muscles and Their Innervation; Extraocular Muscles: Extraocular Muscle Anatomy; Extraocular Muscles: Extraocular Muscle Metabolism.

Further Reading

Anderson, B., Christiansen, S. P., and McLoon, L. K. (2008). Myogenic growth factors can decrease extraocular muscle force generation: A potential biological approach to the treatment of strabismus.

Investigative Ophthalmology and Visual Science 49: 221–229. Leigh, R. J. and Zee, D. S. (1999). The Neurology of Eye Movements,

3rd edn. New York: Oxford University Press.

McLoon, L. K., Anderson, B., and Christiansen, S. P. (2006). Sustained release of insulin growth factor-I results in stronger extraocular muscle. Journal of the American Association of Pediatric Ophthalmology and Strabismus 10: 424–429.

McLoon, L. K. and Christiansen, S. P. (2005). Pharmacological approaches for the treatment of strabismus. Drugs of the Future 30: 319–327.

Wong, A. (2008). Eye Movement Disorders. New York: Oxford University Press.

Glossary

Fluorescein sodium – A topical agent used extensively as a diagnostic tool in ophthalmology to enhance tear film visibility or to highlight epithelial cell loss. The molecule is highly fluorescent, with excitation and emission occurring at 494 and 521 nm, respectively. Interference bandpass filters are commonly combined with the observation systems used in ophthalmology to optimize visualization of the fluorescence alone.

Lacrimal gland – The lacrimal gland is a compound tubuloalveolar gland, similar to the salivary gland, situated superotemporally in the orbit, which secretes aqueous tear fluid.

Lacrimal sac – The lacrimal sac forms part of the tear drainage system, collecting tear fluid from the ocular surface via the puncta and canaliculi. Blinking controls the pumping action of the lacrimal sac into the nasolacrimal duct for drainage into the nasal cavity.

Meibomian gland – Vertically oriented tubulo-acinar glands, embedded in the upper and lower tarsal plates, which release meibum (lipid). Videokeratoscopy – A computerized, dynamic technique, based on the principle of keratoscopy, used traditionally to assess the shape of the anterior surface of the cornea (corneal topography) from the reflection of a series of projected concentric rings.

The tear film is a thin film of fluid, which covers the exposed ocular surface. Essential for the health and normal function of the eye and visual system, any abnormality in quantity or quality of the tear film can lead to signs and symptoms of dry eye disease and ultimately to a loss of vision.

The Role of the Tear Film

The tear film has a number of important functions, the first of which, as the most anterior element of the visual system, is maintenance of high-quality vision. Alterations in the stability of the tear film due to abnormal tear evaporation, production, and/or drainage can cause optical aberrations and adversely affect retinal image quality.

Secondly, the tear film plays an important role in ocular surface defence. Environmental challenges such as extremes of temperature or humidity, and exposure to irritants such as pollutants and allergens, can have a detrimental effect on the tear film. The tear film must be sufficiently robust to be able to withstand these challenges and be capable of responding rapidly with reflex tearing to help flush out irritants when required. External and adnexal infectious agents pose an additional risk to the exposed ocular surface. Antimicrobial components of the tear film, which include lysozyme, lactoferrin, and immunoglobulin A, help to protect the ocular surface from microbial infection.

Lubrication is another important tear film function. The non-Newtonian rheological properties of the tear film mucins enable the tear film to lubricate the corneal and mucosal surfaces. The normal blinking mechanism draws the tear film across the ocular surface, enhancing comfort and cushioning the ocular surfaces from the shearing forces present during the blink, while the mucins that trap and coat foreign particles in the tear film for removal at the caruncle, confer further epithelial surface protection.

Finally, the tear film plays a vital nutritive role in the transport of substances necessary for corneal metabolism and regeneration. Uniquely avascular for transparency, the cornea requires a nonvascular route for the supply of oxygen, electrolytes, growth factors, and nutrients to, and for the removal of metabolic by-products such as carbon dioxide from the ocular surface. While glucose diffuses primarily from, the aqueous humor, oxygen must be transported to the tissue through the tear film, either from the air in the open eye state or via the palpebral conjunctival vessels in the closed eye state.

Structure and Thickness of the Tear Film

Initial reports described the tear film as trilaminar in structure, consisting of a thin superficial lipid layer, an intermediate aqueous layer, and an underlying mucous layer. Each of these layers has the potential to be affected by different conditions resulting in qualitative and quantitative changes. Almost half a century later, it was proposed that interfaces existed between the layers, giving rise to a six-layer model, with an oily layer, a polar lipid monolayer, an absorbed mucoid layer, an aqueous layer, and a mucoid layer on a glycocalyx base. The carbohydrate-rich

glycocalyx, produced by the surface cells of the corneal epithelium and subsurface vesicles of the conjunctival epithelium, is believed to attach the tear film to the surface of the epithelial cells. The most recent studies do not differentiate this number of distinct layers, but instead suggest the existence of an aqueous-mucin continuum that contains a decreasing concentration of dissolved mucus toward the superficial lipid layer, and is anchored to the epithelium by glycocalyx (Figure 1).

The thickness of the precorneal tear film has proven to be a subject of great debate. Early estimates placed the thickness of the tear film in the region of between 4 and 8 mm. Later, on the basis of noninvasive techniques such as interferometry, it was proposed that due to a previously underestimated contribution from the mucous layer, the tear film thickness was closer to 40 mm in thickness. However, the most recent findings using techniques such as tomography and reflectance spectra propose values closer to the original measurements, suggesting that the tear film thickness is approximately 3 mm.

The Lipid Layer

The superficial lipid layer of the tear film forms the initial barrier between the ocular surface and the environment. This thin, oily layer approximates 100 nm in thickness, although values ranging between 10 and 600 nm have

been reported. It is derived primarily from the meibomian glands, with additional lipid secreted by the eyelid glands of Moll and Zeiss. The lipids are excreted as meibum onto the ocular surface through the gland orifices located at the mucocutaneous junction of the lid margins.

Between blinks, the lipid layer forms in two distinct phases. An inner, thin, polar layer spreads as a monolayer across the aqueous in the initial phase after the blink, then a thicker, outer, nonpolar layer follows, creating a final lipid structure with multiple layers. The lipid layer must be spread evenly by the blink to form a continuous layer without excessively thin or thick patches in order to inhibit evaporation and to prevent accelerated tear breakup from mucin contamination, respectively.

Table 1 describes the proportions of the major lipid components of meibum. The polar layer consists of phospholipids, free fatty acids, and cerebrosides, while the less surface-active, nonpolar layer comprises mainly wax esters and sterol esters. The lipid layer confers a number of important protective functions including the formation of a hydrophobic barrier to prevent tear overflow onto the lids and to provide a water-tight seal during overnight lid closure, and the prevention of tear film contamination by skin lipids. However, arguably one of the most critical roles of the superficial lipid layer is to retard evaporation from the ocular surface. The polar lipids of the ocular tear film in the normal eye are capable of reducing its rate of evaporation by about 80–90%.

Tear Evaporation

Numerous investigators have measured evaporation of fluid from the tear film, since it was established that the lipid layer retarded evaporation in a rabbit model, in 1961. Later work, also in a rabbit model, passed dry air over a cornea enclosed within a chamber. From the weight of water collected, the evaporative rate was measured as 10.1 10–7 g cm–2 s–1, and a fourfold increase in evaporation was found to occur with the removal of the rabbit tear film lipid layer. A similar increase in human tear film

Adapted from McCulley, J. P. and Shine, W. E. (2003). Meibomian gland function and the tear lipid layer. Ocular Surface 1(3): 97–106, with permission.

evaporation has since been confirmed in patients with incomplete or absent lipid layers (Figure 2).

The use of different techniques for measurement of tear film evaporation makes comparison of evaporation rates in different studies difficult because the absolute values recorded are technique-dependent. However, a pattern to the observations reported in the literature does exist, making evaporation rate a useful measurement in the differential diagnosis of dry eye. In most cases, significant increases from normal tear film evaporation are seen in patients with aqueous deficient dry eye (ADDE), evaporative dry eye (EDE), and meibomian gland dysfunction (MGD). The evaporation in normal eyes averages 13.57

6.52 10–7 g cm–2 s–1, while in ADDE the values average 17.91 10.49 10–7 g cm–2 s–1, and in EDE, 25.34 13.8 10–7 g cm–2 s–1.

The Aqueous Layer

The aqueous component of the tear film is a watery phase, bordering the lipid layer and comprising most of the tear film thickness. It is produced principally by the main lacrimal gland and accessory lacrimal glands of Krause and Wolfring although additional water and electrolytes are secreted by the epithelial cells of the ocular surface. The typical or basal level of tear flow present is believed to originate mainly from the accessory glands while the reflex tears, produced in response to mechanical, noxious, or emotional stimuli, arise from the main lacrimal gland.

During sleep, tear production is minimal but in the normal eye, in the open eye state, sensory stimulation of the exposed ocular surface induces tear production at a rate that varies according to the demands of the external environment. The secretion of electrolytes, protein, and water onto the ocular surface serves to nourish and protect the epithelia and convey messages between the structures bathed in aqueous.

Corneal innervation is denser than that of any other part of the body, resulting in extreme pain if the corneal epithelium is damaged. Sensory nerve supply to the ocular surface arises from the trigeminal nerve. Stimulation of these nerve endings causes the release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP), which, through initiation of the inflammatory cascade, is believed to be an important step in the pathogenesis of many cases of dry eye.

The lacrimal and meibomian glands are innervated by parasympathetic efferent nerve fibers (muscarinic and vaso-intestinal peptide (VIP)-ergic fibers) and to some extent they, and the blood vessels supplying them, are sympathetically innervated through tyrosine hydroxylase (TH) and neuropeptide Y fibers. Parasympathetic efferent nerve terminals surrounding the goblet cells suggest that conjunctival secretions are also under neurogenic control.

The aqueous phase has a number of important responsibilities. These include creating a nurturing environment for the epithelial cells of the ocular surface, carrying essential nutrients and oxygen to the cornea, allowing cell movement over the ocular surface, and washing away epithelial debris, toxic elements, and foreign bodies. The major electrolytes present in the tear film are sodium, potassium, bicarbonate, and chloride, with magnesium, calcium, nitrate phosphate, and sulfate present in smaller quantities. The electrolytes dictate the osmolarity of tears, besides acting as a buffer to maintain pH and playing a role in maintaining epithelial integrity. An increase in the electrolyte concentration, described as hyperosmolarity, can cause damage to the ocular surface.

The tear film protein concentration is approximately 10% that of plasma. The proportion of lacrimal gland versus serum-derived proteins and enzymes varies with tear flow rate, epithelial surface stimulation, blinking, and ocular surface disease. The tear proteins are involved in defense of the ocular surface and the maintenance of tear film stability. Electrophoresis has confirmed the presence of approximately 80 different components of human tear proteins. Around 30 proteins have been identified, half of which are enzymes. The principal tear proteins are lysozyme, lactoferrin, albumin, tear-specific pre-albumin, and globulins. Table 2 shows typical concentrations of the most significant tear proteins. The tear film also contains antioxidants such as vitamin C and tyrosine, which scavenge free radicals from within the tear film, while the

Table 2 Average concentration of the principal tear proteins

Adapted from Sariri R. and Ghafoori, H. (2008). Tear proteins in health, disease, and contact lens wear. Biochemistry (Moscow) 73(4): 381–392, with permission.

abundance of growth factors facilitates constant epithelial regeneration and promotes wound healing.

Alterations in tear composition or inflammatory changes within the conjunctival vascular endothelia can act as the stimulus to ocular surface inflammation in which both cellular and soluble mediators play a significant role. The numbers of T lymphocytes and the relative proportions of activated T cells are increased in dry eye. The ocular surface epithelial cells are directly involved in such ocular surface inflammation with the release of a number of pro-inflammatory cytokines such as interleukin (IL)-1a, IL-1b, IL6, IL8, transforming growth factor beta 1 (TGF-b1) and tumor necrosis factor alpha (TNFa), and increased expression of immune activation molecules such as CD54 and HLA-DR. Increased proteolytic enzyme levels and activity have been observed in dry eye with, in particular, high levels of matrix metalloproteinase 9 (MMP9), which are not present on the normal ocular surface. The inflammatory markers described as precipitating dry eye are also recognized to perpetuate ocular surface inflammation, triggering an escalating cycle of ocular irritation, inflammation, apoptosis, and tear film dysfunction and instability, epithelial cell disease, and disruption of corneal epithelial barrier function.

Tear Production

Traditional methods of measuring tear production rates are based on absorption of tears by Schirmer strips or cotton threads; however, both tests have been found to be poor quantifiers of tear production; the Schirmer test is marred by low specificity and sensitivity and the exact parameter measured with the cotton thread test has been questioned. As a result, a number of tests have been devised to measure the rate of disappearance of a dye marker placed in the tear film, as new tears are produced and the waste eliminated. In most studies in recent years, the rate of disappearance of instilled sodium fluorescein dye has been used to determine tear turnover (TTR) by the technique of fluorophotometry (Figure 3).

FCE (ng ml−1)

4.2

C0

4.0

3.8

3.6

3.4

3.2

3.0

Time (min)

The values reported for tear turnover (%min–1) and tear flow (ml min–1) in the major studies in the literature for normal and dry eye subjects of studies using the commercial fluorophotometer have recently been collated. The data reported for normals in the majority of studies ranges from 10% to 20% min–1, which equates to an average basal tear flow rate of 1.03 0.39 ml min–1 (16.19 5.10% min–1). For dry eye, in all its forms, it averages 0.58 0.28 ml min–1 (9.36 5.68% min–1) and, within the dry eye subtypes, averages 0.40 0.10 ml min–1 (7.71 1.02% min–1) and 0.71 0.25 ml min–1 (11.95 4.25% min–1) for ADDE and for EDE, respectively. These are the rates of tear production under nonstimulated conditions in normal and dry eyes. However, the eye is capable of producing copious reflex tears under provocative conditions, providing the lacrimal gland has the ability to function at the required capacity. Reflex rates have been quoted as approximately 100-fold those under basal conditions.

The Mucin Layer

The innermost, mucin layer of the tear film lies adjacent to the hydrophobic epithelial cells of the ocular surface. The layer consists of soluble, gel-forming mucins, which are capable of retaining large quantities of water, and corneal and conjunctival epithelial mucins (principally MUC1, 2, 4, and 16), which form the glycocalyx. The glycocalyx functions, through the membrane-spanning domain of MUC1, to anchor the soluble mucin layer to the plasma membrane of the corneal and conjunctival epithelial cells, while the soluble mucins interact with these transmembrane mucins and with the overlying aqueous layer, to form a water-retaining gel. The most significant soluble mucin for the ocular surface is MUC5AC, secreted by the goblet cells of the conjunctiva.

The high-molecular-weight glycoproteins, with additional proteins, electrolytes, and cellular material that

contribute to the mucous layer, enable fulfilment of several important functions in the maintenance of a healthy ocular surface. In addition to providing a hydrophilic surface upon which to support a stable aqueous layer, the mucous layer offers protection against the shear force of blinking and environmental insult, and facilitates maintenance of a smooth ocular surface for optical clarity. The constituents are also believed to protect the ocular surface by inhibiting inflammatory cell adhesion.

Tear Distribution and Stability

The distribution of tear fluid on the ocular surface is highly dependent on the blink. Lid closure during a blink progresses from the temporal to the nasal side of the eye spreading tears across the ocular surface and facilitating tear drainage through the lacrimal puncta. The inter-blink period in normal individuals averages 4.0 2.0 s and is significantly decreased in patients with dry eye (to 1.5 0.9 s); a high blink rate in dry eye patients maximizes the tear supply to the ocular surface. In detailed reading tasks, requiring concen-

tration, the blink rate drops to about a half (from 22.4 8.9 to 10.5 6.5 min–1).

In the clinical setting, tear film stability has traditionally been measured following the instillation of fluorescein sodium solution into the tear film, to improve visualization of the film. Tear breakup time has been defined as the time taken for the tear film to form a dark spot or streak, following a blink. However, subsequent awareness of the disruptive effect of fluorescein instillation on the tear film has encouraged use of noninvasive techniques where tear film stability is determined by observing mires reflected from the tear film surface, for signs of disruption or distortion following a blink. A tear breakup time of greater than 10 s is considered normal while values less than 5 s are suggestive of dry eye. Values between 5 and 10 s are