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

46–128 and 30–90 in pig and camel, respectively. In both species, Golgi tendon organs are more frequent in the rectus EOMs than in the oblique EOMs.

Structure of Golgi Tendon Organs

Golgi tendon organs in EOMs of even-toed ungulates exhibit a fusiform shape and are enclosed by a capsule of perineural cells. The capsule space is filled with a viscous fluid containing acidic mucopolysaccharides. The main component of the Golgi tendon organs are collagen bundles that pass through the organ. At one end of the organ the collagen fascicles are attached to muscle fibers, and at the other end the fascicles merge with the tendon of the muscle. Many Golgi tendon organs contain only collagen bundles, but there are others which contain both collagen bundles and muscle fibers. Such intracapsular muscle fibers penetrate the Golgi tendon organ at one end and either terminate in collagen bundles or, more rarely, pass through the tendon organ. All Golgi tendon organs in the EOMs of even-toed ungulates exhibit a wide space in the central region that separates the collagen bundles and muscle fibers, if present, from the capsule (Figure 2(a)).

Each Golgi tendon organ is innervated by a single sensory nerve fiber. The nerve fiber penetrates the capsule at various points. Inside the organ, the axon divides into several preterminal branches which finally establish nerve terminals that contact the surrounding collagen fibrils. Nerve terminals are only partly covered with Schwann cells, and at the area of contact only a basal lamina lies between the nerve terminal and the neighboring collagen. Nerve terminals contain mitochondria and a few clear vesicles (Figure 2(b)).

With the exception of intracapsular muscle fibers and a more pronounced capsule space in the central region, Golgi tendon organs in even-toed ungulates share the structural features of Golgi tendon organs found in other mammalian skeletal muscles.

Function of Golgi Tendon Organs

Golgi tendon organs in mammalian skeletal muscle are sensitive to muscle contraction. During muscle fiber contraction collagen bundles are stretched, and the nerve terminals within the collagen are deformed, thereby generating a receptor potential. Golgi tendon organs in EOMs of ungulates are supposed to function analogously and register muscle fiber contraction. Muscle fibers passing through Golgi tendon organs are supposed to regulate the sensitivity of the organ.

Palisade Endings

Occurrence, Distribution, and Number of

Palisade Endings

Palisade endings (myotendinous cylinders) are sensory end organs that are unique to EOMs. So far, palisade endings have been found in the EOMs of almost all species investigated, including fellidae (cat), lagomorphs (rabbit), even-toed ungulates (sheep), rodentia (rat), and primates (monkey and man). These organs are located at the distal and proximal myotendinous junctions. Palisade endings are plentiful in the EOMs of monkey and cat (Table 1). In the distal myotendon of a monkey medial rectus 350 palisade endings have been counted, and in a

cat medial rectus 94. A smaller number of this EOMspecific organ have been found in the distal EOM myotendons of rat (27) and human (20–30).

Structure of Palisade Endings

Innervation for the palisade endings arises from nerve fibers that come from the muscle and extend into the tendon. Within the tendon, the nerve fibers make a 180 loop and return to the muscle. At the muscle–tendon junction, the returning axons divide into preterminal branches. Preterminal axons establish nerve terminals around the muscle fiber tips which have the appearance of a palisade fence (Figure 3), which is also the reason why this formation is called a palisade ending. The whole palisade complex is ensheathed by a capsule of fibroblasts.

Palisade ending is exclusively associated with the multiply innervated muscle fibers of the global (inner) layer of the EOMs. Such muscle fibers have several motor contacts along their length, and with respect to contraction they exhibit nontwitch characteristics. The multiply innervated muscle fibers have a unique innervation from small motoneurons located outside the borders of the main EOM nuclei.

The fine structure of palisade endings was initially analyzed in cat and monkey and later in sheep, rabbit, and man. It was observed that the majority of palisade nerve terminals contact the collagen fibrils of the tendon, and only a few of them contact the muscle fiber tip. Nerve terminals contacting the collagen fibrils are only partly enwrapped with Schwann cells, and at the area of contact with the collagen only a basal lamina covers the nerve terminals. Such neurotendinous contacts contain dense aggregations of clear vesicles and mitochondria. Palisade nerve terminals contacting the muscle fiber are free from a basal lamina in the synaptic cleft, thereby resembling sensory nerve terminals on intrafusal fibers of muscle spindles. Identical to neurotendinous contacts, neuromuscular contacts contain mitochondria and a large number of clear vesicles. Interestingly, in palisade endings of man and monkey, neuromuscular contacts have a basal lamina in the synaptic cleft which is a feature of motor terminals. Palisade

endings in rabbits and rats are an exception. In both species, the palisade endings lack neurotendinous contacts and neuromuscular contacts are present exclusively.

Molecular Characteristics of Palisade Endings

In cat and monkey, it has been recently demonstrated that palisade endings have a cholinergic phenotype. Utilizing immunohistochemistry, palisade endings have been labeled with all commercially available cholinergic markers, including antibodies against choline transporter (ChT), choline acetyltransferase (ChAT), and vesicular acetyl choline transporter (VAChT), as well as a-bungarotoxin. In the nervous system, ChT is used for the uptake of choline, ChAT is the synthesizing enzyme of acetylcholine, and VAChT is used to transport acetylcholine into the synaptic vesicles. a-Bungarotoxin is a snake venom that binds to nicotinic acetylcholine receptors, and this neurotoxin is widely used to detect motor terminals in skeletal muscle.

In cat and monkey, it has been shown that the nerve fibers supplying palisade endings are ChAT immunoreactive. The palisade complexes, including palisade nerve terminals, are ChAT positive as well. In monkey, it also has been demonstrated that palisade nerve terminals exhibit ChT/VAChT immunoreactivity, and neuromuscular contacts, when present, exhibit a-bungarotoxin binding. Finally, in some cases it has been detected that nerve fibers supplying palisade endings establish a-bungarotoxin-positive neuromuscular contacts outside the palisade complex (Figure 3(b)).

Function of Palisade Endings

So far, physiological studies on palisade ending are missing, and their function remains speculative. Indication that palisade endings are sensory organs comes from morphological studies and a single neuronal tracing experiment. Specifically, morphological studies show that palisade endings have nerve terminals contacting the tendon, and nerve terminals in apposition to collagen are arguably sensory. Palisade nerve terminals contacting

the muscle fibers lack a basal lamina in the synaptic cleft which is common with sensory nerve terminals in muscle spindles. Moreover, by injecting neuronal tracer into the sensory trigeminal ganglion, structures resembling palisade endings have been labeled. Palisade endings lie in series to the multiply innervated muscle fibers of the global (inner) EOM layer, and it is supposed that palisade endings register contraction of such muscle fibers.

Although a consensus exists that palisade endings are sensory, there are other findings which favor a motor role for palisade endings. In particular, immunohistochemical studies have demonstrated that palisade endings are cholinergic, a feature common with motor nerve terminals. Nerve fibers forming palisade endings also establish motor neuromuscular contacts outside the palisade complex. In a nerve degeneration experiment a lesion of the oculomotor nucleus was performed and, in addition to the expected loss of motor terminals, the palisade endings degenerate as well. The functional significance of palisade endings with a motor nature is difficult to predict. In particular, it is unclear what effect cholinergic neurotendinous contacts would have on the surrounding collagen. At the moment the function of palisade endings is still a matter of discussion, and for clarification physiological studies are highly warranted.

Further Reading

Billig, I., Buisseret, D. C., and Buisseret, P. (1997). Identification of nerve endings in cat extraocular muscles. The Anatomical Record 248: 566–575.

Blumer, R., Konakci, K. Z., Brugger, P. C., et al. (2003). Muscle spindles and Golgi tendon organs in bovine calf extraocular muscle studied by

means of double-fluorescent labeling, electron microscopy, and three-dimensional reconstruction. Experimental Eye Research 77: 447–462.

Blumer, R., Lukas, J. R., Aigner, M., et al. (1999). Fine structural analysis of extraocular muscle spindles of a two-year-old human infant.

Investigative Ophthalmology and Visual Science 40: 55–64. Blumer, R., Wasicky, R., Brugger, P. C., et al. (2001). Number, distribution and morphological particularities of encapsulated

proprioceptors in pig extraocular muscle. Investigative Ophthalmology and Visual Science 42: 3085–3094.

Blumer, R., Wasicky, R., and Lukas, J. R. (2001). Presence and structure of innervated myotendinous cylinders in rabbit extraocular muscle. Experimental Eye Research 73: 787–796.

Buisseret, P. (1995). Influence of extraocular muscle proprioception on vision. Physiological Reviews 75: 323–338.

Buttner, E. J. A., Konakci, K. Z., and Blumer, R. (2005). Sensory control of extraocular muscles. Progress in Brain Research 15(1): 81–93.

Donaldson, I. M. L. (2000). The functions of proprioceptors of the eye muscles. Philosophical Transactions of the Royal Society of London

355: 1685–1754.

Konakci, K. Z., Streicher, J., Hoetzenecker, W., et al. (2005). Molecular characteristics suggest an effector function of palisade endings. Investigative Ophthalmology and Visual Science 46: 155–165.

Konakci, K. Z., Streicher, J., Hoetzenecker, W., et al. (2005). Palisade endings in extraocular muscles of the monkey are immunoreactive for choline acetyltransferase and vesicular acetylcholine transporter. Investigative Ophthalmology and Visual Science 46: 4548–4554.

Lukas, J. R., Aigner, M., Blumer, R., Heinzl, H., and Mayr, R. (1994). Number and distribution of neuromuscular spindles in human extraocular muscles. Investigative Ophthalmology and Visual Science

35: 4317–4327.

Lukas, J. R., Blumer, R., Denk, M., et al. (2000). Innervated myotendinous cylinders in human extraocular muscle. Investigative Ophthalmology and Visual Science 41: 2422–2431.

Ruskell, G. L. (1989). The fine structure of human extraocular muscle spindles and their potential proprioceptive capacity. Journal of Anatomy 167: 199–214.

Ruskell, G. L. (1990). Golgi tendon organs in the proximal tendon of sheep extraocular muscle. The Anatomical Record 227: 25–31.

Ruskell, G. L. (1999). Extraocular muscle proprioceptors and proprioception. Progress in Retinal and Eye Research 18: 269–291.

Glossary

Amblyopia – Lazy eye with poor vision because of misalignment of the eyes during development.

Chronic progressive ophthalmoplegia (CPEO) –

This term describes a number of disorders affecting the extraocular muscles that lead to progressive limitation of eye motion.

Diplopia – Double vision.

Esotropia – Misalignment of the eyes, one of which turns in (toward the nose)–cross-eyed.

Exotropia – Misalignment of the eyes, one of which turns out (away from the nose)–wall-eyed.

Kearns–Sayre syndrome – One cause of CPEO (see above) that is inherited from the mother and affects other tissues, such as the heart.

Myasthenia gravis – A disorder causing muscle fatigue that is due to failure of the nerves to stimulate the muscles to contract.

Nystagmus – An oscillation of the eyes (shimmering or jumping eyes).

Optokinetic reflexes – Eye movements induced by moving a visual pattern in front of the eyes.

Ptosis – Droopy lids.

Saccades – Rapid eye movements that are used to move the point of visual fixation from one feature of interest to the next.

Smooth pursuit – Eye movements that smoothly follow a moving object, such as a bird in the sky.

Strabismus – Misalignment of the eyes; the eyes point in different directions.

Vestibulo-ocular reflexes – Eye movements induced by head movements, which stimulate the balance mechanism in the inner ear.

Introduction

In this article we apply current knowledge of the extraocular muscles (EOMs) and their brainstem innervation to develop working hypotheses to account for a range of abnormal eye movements. To be concise, we have mainly selected diseases with well-defined processes that affect

specific sites, from muscle to premotor neurons in the brainstem (Figures 1 and 2). This bottom-up approach is somewhat reductionist and simplified, but we hope that it will provide insights for readers with a broad range of interests. For more comprehensive reviews, readers can turn to sources listed at the end of this article.

A prerequisite for understanding disordered ocular motility is that eye movements can be systemically examined (Table 1). Thus, restricting attention to the most evident disturbance (e.g., strabismus) will impoverish interpretation of the underlying disorder. Conversely, considering the properties of saccades, pursuit, vestibular, and vergence eye movements, as well as the presence of any visual deficits, will enrich the understanding of the pathogenesis of the disorder.

Effects of Disorders of the EOMs on Eye Movements

The EOMs (Figure 1, site 1) possess unique properties that make them resistant to some diseases and susceptible to others. Thus, on the one hand, the EOMs are spared in Duchenne muscular dystrophy, even when the disease is well advanced, a finding that has prompted much research. On the other hand, EOMs are rich in mitochondria, which is appropriate for the sustained contraction required for precise gaze control, but which makes them susceptible to mitochondrial disorders. Although such disorders may arise in childhood along with involvement of other tissues, such as heart muscle (Kearns–Sayre syndrome), these may present throughout adulthood with the syndrome of chronic progressive ophthalmoplegia (CPEO). Such individuals have ptosis and a limited range of eye movements. The complaint of diplopia is rare in CPEO, and although this had been ascribed to equal involvement of each of the eye muscles, another explanation seems more likely. Thus, slow progression of CPEO allows time for the visual system to adapt, and suppress images from one eye. Another interesting finding is that such patients may also make relatively quick eye movements (saccades or vestibular eye movements), despite a limited range of movement. This anomaly may be due to sparing of fast type myosin heavy chain (MyHC) EOM-specific global EOM fibers, which have fewer mitochondria.

LR

Ach

CN III

Abducens nerve

3

PPRF 6 EBN

glu/asp

4

glu/asp IBN

Ach

8

NPH

1

MR

gly

Besides mitochondrial disorders, the EOM may be affected by other genetic diseases such as hereditary disorders of myosin, or acquired disorders that present as a restrictive ophthalmopathy, such as thyroid disease. Thyroid ophthalmopathy, which has been attributed to accumulation of glycosaminoglycans in the orbit, often presents with vertical diplopia that is worse on wakening. Associated lid retraction and exophthalmia are common manifestations.

Effects of Disorders of the Neuromuscular Junction on Eye Movements

Eye movements are especially susceptible to a disease affecting the neuromuscular junction (Figure 1, site 2), classical myasthenia gravis, which is due to an abnormal immune attack on the postsynaptic acetylcholine receptor. In half of all patients with myasthenia gravis, diplopia or ptosis is the presenting complaint and, in about 80%

of patients, movements of the eyes and lids are ultimately abnormal, with fluctuating weakness. Why are the EOMs so susceptible to diseases affecting the neuromuscular junction? One physiological reason arises from the demands made of eye movements to sustain the precise alignment of the eyes required for single binocular vision. It follows that fluctuating weakness due to myasthenia often causes ocular misalignment and diplopia. One morphological reason is that the postsynaptic junction of the EOM is poorly folded, thereby reducing the potential area for acetylcholine receptors. It follows that the EOM will be especially susceptible to loss of acetylcholine receptors. However, one subtype of EOM fibers, the MyHC EOMpositive myofibers (fast twitch/fatigable), which seems important for fast eye movements, does have substantial folding of its postjunctional membranes and, therefore, seems less susceptible to fatigue. Thus, it is interesting to note that patients with severe ocular myasthenia and little residual movement often retain the ability to make fast movements (quiver movements)-presumably due to preserved activity of their MyHC EOM-positive fast twitch myofibers.

Why is diplopia a common complaint in ocular myasthenia but rare in CPEO? The view that the eyes move conjugately in CPEO but not in myasthenia is not supported by measurements of eye movements. A more cogent reason is that the weakness in ocular myasthenia is highly variable (hence the characteristic symptom of fatigue), whereas in CPEO it evolves slowly and steadily. Thus, in CPEO the visual system has time to adapt to the loss of binocular correspondence, whereas in ocular myasthenia visual inputs are continually varying. This is not to state that adaptation of eye movements does not occur in myasthenia: the converse is the case, and is often evident by the occurrence of abnormally large eye movements immediately following pharmacological reversal of the neuromuscular failure by intravenous injection of the acetylcholine esterase inhibitor, edrophonium.

Although ocular myasthenia is the most common disease to affect the EOM neuromuscular junction, other disorders that can impair eye movements include systemic botulism, neuromuscular blocking agents, and the Lambert-Eaton myasthenic syndrome (LEMS), which is due to the impaired release of acetylcholine secondary to autoimmune

Table 1 Functional classes of human eye movements

Adapted from Leigh, R. J. and Zee, D. S. (2006). The Neurology of Eye Movements, 4th edn. New York: Oxford University Press.

attack on presynaptic P/Q voltage-gated calcium channels. As opposed to myasthenia, in LEMS, repetitive saccades may change from hypometric (under-shooting) to hypermetric (over-shooting) as a consequence of the characteristic facilitation of muscle strength.

Effects of Disorders of the Oculomotor, Trochlear, and Abducens Nerves on Eye Movements

Palsies of the nerves innervating EOMs are common in clinical practice and cause diplopia and selective patterns of weakness of the muscles they supply. Such paralytic strabismus (misalignment of the visual axes) is greatest when the affected patient attempts to look in the direction of the weak muscle. Thus, in the case of left abducens palsy (Figure 1, site 3), the patient cannot abduct (turn out) the affected eye to the left. However, such weakness and the attendant diplopia is a stimulus to adapt the neural signals that move the eyes. Such adaptive changes are evident if the strong eye is covered and the weak eye forced to view the world. A similar situation occurs naturally if the weak eye is also the visually dominant eye. In either case, the level of innervation is increased in motoneurons supplying muscles that induce corresponding movements in each eye. Thus, in our example, the left lateral rectus, which turns the left eye out, and the right medial rectus, which turns the right eye in, would

both receive increased innervation. One consequence of this adaptation is that movements of the weak eye may improve (unless paralysis is complete). A second consequence is that the strong eye, which also receives increased innervation, would, for example, make leftward saccades that overshoot the visual target. Such behavior is sustained for some time after adaptation even if the weak eye is covered and the strong eye views. This is a special example of plastic adaptation or motor learning, a property that depends heavily on the cerebellum, and which has been a subject of research interest for the past quartercentury. Because of the yoking mechanism by which eye movements are made conjugate in the brainstem circuitry (see the next section), there is a limitation to how much adaptive mechanisms can contribute to the recovery of the weakness due to nerve palsy. Nonetheless, such adaptive mechanisms undoubtedly contribute to the recovery from ocular motor nerve palsies. Paradoxically, in the case of trochlear nerve palsy, there is some recent evidence that such mechanisms may be maladaptive.

Effects of Disorders of the Brainstem Circuitry on Eye Movements

Horizontal Movements

The brainstem machinery whereby the eyes are coordinated to move together (conjugately) in the horizontal plane is summarized in Figure 1. The abducens nucleus, which lies in the pons, may be regarded as the horizontal gaze center (Figure 1, site 4). Thus, the abducens nucleus receives inputs for each functional class of eye movements, including saccades, smooth pursuit, vestibular and optokinetic reflexes. It follows that each of these classes of conjugate eye movement (Table 1) may be independently affected by disease. The abducens nucleus contains two main groups of neurons: abducens motoneurons and abducens internuclear neurons. Axons of abducens motoneurons project in the sixth (abducens) cranial nerve to innervate the lateral rectus muscle. Axons of abducens internuclear neurons cross the midline and ascend in the contralateral medial longitudinal fasciculus (MLF, Figure 1, site 5) to contact medial rectus motoneurons in the oculomotor nucleus, which lies in the midbrain. Axons of medial rectus motoneurons project in the third (oculomotor) cranial nerve to innervate the medial rectus muscle.

It follows that lesions affecting the abducens nucleus (Figure 1, site 4) will impair movements of both eyes to the side of the lesion (horizontal gaze palsy). It also follows that lesions of the MLF (Figure 1, site 5) will impair the ability of the ipsilateral eye to adduct; this is called internuclear ophthalmoplegia (INO), because the coordination of the abducens motoneurons and oculomotor medial rectus motoneurons is disrupted. Multiple sclerosis (MS) is the

most common etiology for an INO in young persons, especially when it is present bilaterally. Patients with INO due to demyelination of the MLF in MS show slowing or absent movements of the adducting eye because the MLF can no longer conduct high-frequency signals between the abducens and the oculomotor nuclei. However, vergence movements may be preserved either in abducens nucleus lesions or in INO, since vergence commands project directly to the oculomotor nucleus (Figure 1).

Horizontal saccades depend on premotor burst neurons, which lie in the paramedian pontine reticular formation (PPRF, Figure 1, site 6), and generate a high-frequency pulse of action potentials. Disorders affecting burst neurons of the PPRF selectively slow, or abolish, horizontal saccades. In contrast with abducens nucleus lesions, which cause complete horizontal gaze palsy, lesions of the PPRF usually spare ipsilateral smooth pursuit and vestibular eye movements.

The vestibulo-ocular reflex (VOR) for horizontal head rotations depends on vestibular afferents from the lateral semicircular canals, which relay their signal to the contralateral abducens nucleus via the medial vestibular nucleus (MVN, Figure 1, site 7). Wernicke’s encephalopathy, a disorder due to thiamine deficiency that occurs in alcoholics, involves the vestibular nuclei and may impair the horizontal VOR.

The nucleus prepositus hypoglossi (NPH , Figure 1, site 8), the adjacent MVN, and the cerebellum play an important role in holding the eyes in an eccentric position (e.g., far right gaze) against the elastic pull of the orbital tissues. This function depends on mathematical integration of premotor (visual, vestibular, saccadic) signals by the NPH/MVN–cerebellar network. Impaired function of this network (leaky integration) due, for example, to intoxication with alcohol, causes the eyes to drift back to the center, leading to gaze-evoked nystagmus. It has also been postulated that the ocular motor neural integrator network may also become unstable causing either increasing velocity drifts away from center position or quasisinusoidal eye oscillations (acquired pendular nystagmus).

Vertical Movements

The coordination of eye movements in the vertical plane depends heavily upon neural circuits in the midbrain. However, there is no single vertical gaze center similar to the abducens nucleus for horizontal gaze. The oculomotor and trochlear nuclei (Figure 2) house motoneurons that innervate EOMs that rotate the eyes mainly vertically (superior and inferior rectus muscles) or mainly torsionally (around the line of sight-the superior and inferior oblique muscles). These motoneurons receive their saccadic input from the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), which lies in the prerubral fields of the rostral midbrain. Bilateral lesions involving the riMLF (Figure 2, site 1) cause slow

or absent vertical saccades, such as in progressive supranuclear palsy (PSP), a Parkinsonian disorder. Unilateral lesions of riMLF, such as in rostral brainstem strokes, cause loss of torsional rapid movements that rotate the top pole of the eye toward the side of the lesion.

The signals for vertical vestibular and pursuit eye movements ascend from the medulla and pons to the midbrain in the MLF and other pathways. Thus, bilateral MLF lesions (Figure 2, site 2), which occur in MS, cause impaired vertical pursuit and vestibular responses (as well as bilateral adduction failure during horizontal saccades, as described in the previous section). The interstitial nucleus of Cajal plays an important role in holding vertical eccentric gaze steady (e.g., far upward gaze); lesions here (Figure 2, site 3) cause gaze-evoked nystagmus on upward or downward gaze, postulated to be due to a leaky ocular motor integrator. The superior colliculus is a midbrain tectal structure that receives inputs from the cortical eye fields, and is important for triggering both horizontal and vertical saccades. Functional imaging studies in humans have demonstrated activation of the superior colliculus during generation of short-latency (express) saccades.

Neural circuits important for the generation of vergence eye movements are also located in the pretectum and midbrain, but pontine nuclei and their projections to the cerebellum also contribute. Thus, disturbances of vergence eye movements are encountered with lesions, such as strokes, throughout the brainstem. However, abducens nucleus lesions and INO (Figure 1, sites 4 and 5) usually spare vergence movements.

Congenital Misalignment of the Eyes

(Infantile Strabismus) and Attendant

Nystagmus

Ocular misalignment from infancy may be due to disorders of the orbital tissues, the innervation of EOM, or as a consequence of failure to develop binocular vision. The failure to develop binocular vision usually presents as the fusional maldevelopment nystagmus syndrome (FMNS), which includes amblyopia of one eye, strabismus (commonly esotropia and dissociated vertical deviation, with upward deviation of the covered eye) and latent nystagmus. Latent nystagmus is a jerk nystagmus comprising slow drifts of the eyes off target and a rapid resetting component that is absent when both eyes are viewing but appears when one eye is covered. The quick components of latent nystagmus beat away from the covered eye, and the nystagmus reverses direction upon covering of either eye. In most patients, the nystagmus is present (but low amplitude) when both eyes are uncovered, and is termed manifest latent nystagmus. Thus, although binocular viewing is possible, affected individuals almost invariably choose to fix with one eye and suppress the image from the other. Latent nystagmus can be

induced experimentally in monkeys, either by depriving them of binocular vision early in life, or by surgically creating strabismus. In monkeys with latent nystagmus, the brainstem nucleus of the optic tract (NOT) shows abnormal electrophysiological properties. In normal monkeys, NOT neurons respond to visual stimuli presented to either eye. However, in monkeys with latent nystagmus, NOT neurons are driven mainly by the contralateral eye. Furthermore, inactivation of NOTwith muscimol abolishes latent nystagmus in monkeys who have been deprived of binocular vision. Since the NOT projects to vestibular circuits concerned with gaze control during head rotations, one current view of the pathogenesis of latent nystagmus is that it represents the consequences of imbalance of visual inputs to the vestibular system, as if the subject was being rotated toward the side of the viewing eye.

Effect of Visual System Disorders on Eye Movements

Patients with a broad range of retinal disorders causing blindness is often a familial disorder. Both show continuous jerk nystagmus, with components in all three planes, which changes in direction over the course of seconds or minutes. The drifting null point, the eye position at which nystagmus changes direction, probably reflects an inability to calibrate the ocular motor system. Animals raised in a strobe illuminated environment, which deprives them of retinal image motion while still providing position cues, also develop spontaneous ocular oscillations. Gene therapy used to restore vision to dogs blind due to an inherited retinal disease resulted in a decrease in their associated nystagmus. Nystagmus is also a feature of albinism, which is associated with abnormal development of visual pathways and optic nerve hypoplasia.

Infantile Forms of Nystagmus in Individual with Normal Visual Systems

Infantile nystagmus syndrome (INS), or congenital nystagmus, may be present at birth but usually develops during infancy. The nystagmus is almost always conjugate and horizontal, even on up or down gaze, with a small torsional component. It is usually accentuated by the attempt to fix upon an object and by attention or anxiety. Up to 30% of patients with INS have strabismus but, even in individuals lacking strabismus, stereovision is usually degraded, partly due to retinal image motion. Head turns are common in INS and are used to bring the eye in the orbit close to the null point or zone, at which nystagmus is minimized. Some patients with INS also show head oscillations; such head movements could not act as an adaptive strategy to improve vision unless the VOR was negated.

It seems possible that the head tremor and ocular oscillations in INS represent the output of a common neural mechanism. Measurements of nystagmus in INS demonstrate typical waveforms with increasing slow-phase velocity and the superimposed presence, during each cycle of oscillations (usually after a quick phase), of a brief period when the eye is still and is pointed at the object of regard. Such foveation periods are probably one reason why many individuals with INS have near-normal vision and why most do not complain of oscillopsia (illusory motion of the seen world), in spite of otherwise nearly continuous movement of their eyes.

INS, either with or without associated visual system abnormalities, is often a familial disorder. Both autosomal dominant and sex-linked recessive forms of inheritance have been reported. Although several hypotheses for the pathogenesis of INS have been offered, no animal models exist. At present, it seems possible that genetic studies will identify the underlying molecular mechanisms and point researchers to the neural disturbance causing INS.

Conclusions

Recent progress in understanding disorders of the EOMs and their innervation from the viewpoint of molecular biology and genetics is approaching the point where it can be combined with behavioral and electrophysiological studies. For example, recent evidence indicates that each functional class of eye movements (Table 1) is served by a separate population of ocular motoneurons that receive specific premotor inputs. It follows that each functional class of eye movements may depend on distinct molecular mechanisms or morphological characteristics, from premotor neurons to EOM. Human diseases provide many opportunities to study behavioral effects of a disease when the disease process affects a specific site-such as the acetylcholine receptor in myasthenia gravis. In this way, insights from basic science have a growing impact on clinical ophthalmology and neurology, and vice versa.

See also: Extraocular Muscles: Extraocular Muscle Anatomy; Extraocular Muscles: Extraocular Muscle Metabolism; Extraocular Muscles: Functional Assessment in the Clinic.

Further Reading

Kennard, C. and Leigh, R. J. (2008). Using eye movements as an experimental probe of brain function. A symposium in honor of Jean Bu¨ttner-Ennever. Progress in Brain Research 171: 1–603.

Leigh, R. J. and Zee, D. S. (2006). The Neurology of Eye Movements, 4th edn. New York: Oxford University Press.

Leigh, R. J. and Devereaux, M. W. (2008). Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus.

New York: Oxford University Press.

Glossary

Binocular vision – The simultaneous perception by both eyes of two slightly disparate images of the same target on corresponding retinal elements resulting in a single three-dimensional image. Cover test – The use of an ocular occluder over one eye or alternately occluding the eyes, either alone or in conjunction with prisms, to detect the presence of an ocular deviation and to measure its magnitude. Diplopia – Double vision caused by a misalignment of the eyes resulting from the same image stimulating noncorresponding retinal elements in the two eyes.

Esotropia – A form of strabismus where there is a nasal-ward deviation of the nonfixing eye. Exotropia – A form of strabismus where there is a temporal deviation of the nonfixing eye.

Phoria – This is a latent misalignment of the eyes kept under control by fusional mechanisms and is contrasted with a tropia which is a manifest constant or intermittent deviation of the eyes. A phoria can be seen only when fixation is interrupted, as during a cover test.

Recession surgery – In recession surgery, the overacting extraocular muscle is surgically removed from the sclera and resutured in a more posterior location on the globe. The goal is to decrease the rotational effect of muscle contraction.

Resection surgery – In resection surgery, the underacting extraocular muscle is surgically removed from the sclera, a portion of the insertional end is removed, and the remaining, now shorter, muscle is resutured to its original insertional site on the globe. The goal is to increase the rotational effect of muscle contraction.

Strabismus – A latent or manifest misalignment of the eyes.

Tropia – A manifest misalignment of the visual axes of both eyes.

Normal Eye Movements

There are six extraocular muscles responsible for eye movement within each orbit. These muscles are innervated by

cranial nerves III (superior rectus, medial rectus, inferior rectus, and inferior oblique), IV (superior oblique), and VI (lateral rectus). The medial rectus muscles are primarily responsible for adduction, pulling the eyes toward the nose. The lateral rectus muscles are responsible for abduction, pulling the eyes temporally. These horizontal movements are the most straightforward of the six extraocular muscles. The remaining four are cyclovertical muscles and have more complex function related to the fact that forwardoriented eyes are housed in laterally directed orbits. This means that the midline of these muscles does not consistently lie over the center of rotation of the globe in any position of gaze.

If examined from the superior view, the bony medial orbital walls are parallel to each other and are in the sagittal plane. The lateral walls, however, are at a 45 angle from the plane of the medial walls. Since all but the inferior oblique muscles take their origin from the orbital apex, contraction of the superior and inferior rectus and superior oblique muscles will have a rotational or torsional component. The same is true for the inferior oblique, which originates from the anterior and inferior nasal orbital wall and courses posteriorly and laterally to insert onto the globe inferior to the belly of the inferior rectus muscle. The direction of contraction of the inferior oblique muscle thus also results in both a torsional and vertical movement of the eye. The function of the individual extraocular muscles has been more extensively covered elsewhere in this encyclopedia. To summarize, however, the superior rectus muscle and the inferior oblique muscles are the principal elevators of the eye while the inferior rectus muscle and superior oblique muscle are the principal depressors of the eye. The incyclotorters of the eye are the superior oblique and the superior rectus while the excyclotorters are the inferior oblique and the inferior rectus muscles. Each of the cyclovertical muscles also has minor horizontal function. It is important to recognize that the vertical or torsional component of each of the cyclovertical muscles changes depending on whether the eye is held in adduction or abduction.

There are two basic kinds of eye movements: saccade and pursuit. Saccades are rapid and subserve fast changes in fixation. They are generated by a pulse-step pattern of innervation from the brainstem. An estimate of saccadic velocity can be gained by clinical observation alone, often with the use of an optokinetic nystagmus (OKN) drum or flag that the examiner uses to drive repeated changes in fixation, first in one direction and then in another.