The extraocular muscles (EOM) are found within the bony orbit. They function in conjugate eye movements, maintenance of primary gaze position, and motor fusion – maintaining corresponding visual elements within the binocular field on corresponding retinal loci. In addition, the eyes must be able to follow moving objects (smooth pursuit) and accomplish rapid changes in fixation (saccades). This is accomplished by a very complex oculomotor control system, and the EOM are the final effector tissues. Understanding how the EOM adapt to changing visual demands is critical to the development of improved treatment strategies to realign the eyes when the system fails, as in strabismus or nystagmus.
The EOM have many distinct and complex properties that distinguish them from non-cranial skeletal muscles, many of which are normally associated with developing or regenerating muscle. This includes a population of multiply- and polyneuronally innervated myofibers, and retained expression of the immature subunit of the acetylcholine receptor, neural cell adhesion molecule, and “immature” myosin heavy chain isoforms. The EOM also have the capacity to continuously remodel throughout life. From a clinical perspective, the EOM have a distinct propensity for or sparing from a number of skeletal muscle diseases. EOM share some of their unusual characteristics with other craniofacial muscles, such as the laryngeal muscles, and the potential developmental basis for their unusual properties and disease profiles is presented.
The bony orbit
The eyes are protected in deep bony orbits that are roughly pyramidal in shape ( Fig. 7.1 ). The orbit is largest just inside the orbital margin at its anterior extent and smallest at its posterior extent, the apex. The orbital margins are composed of the frontal bone superiorly, the zygomatic process of the frontal bone and the frontal process of the zygomatic bone laterally, the zygoma and the maxillary bone inferiorly, and the frontal process of the maxillary bone, the lacrimal bone and the maxillary process of the frontal bone medially ( Fig. 7.1 ). However, direct impact to the bony margin can result in fracture (see Box 7.1 ). The orbit has a thick bony roof composed of frontal bone and a portion of the lesser wing of the sphenoid bone. The lateral wall is composed of the zygomatic bone and the greater wing of the sphenoid. A relatively thin floor is composed of the maxillary bone, a small and variable part of the palatine bone, and the zygomatic bone. The thin medial wall is composed of the maxillary, the lacrimal, ethmoid, and sphenoid bones. As a result of this bony configuration, the globe is somewhat protected from injury caused by direct impacts to the face, particularly if there are no bony fractures.
Bony fractures of the thin orbital walls can occur with blunt impact to the orbital margins. The increased force causes the bone to “blowout” into the sinuses, with the inferior and medial walls most susceptible to fracture. Sometimes the EOM become entrapped at the fracture site, as evidenced by restricted movements in the range of function of the entrapped muscle. These must be surgically repaired.
An understanding of the geometry of the bony anatomy relative to maintenance of eye position is critically important. The medial walls are parallel to each other, while the plane of the lateral wall in each orbit is 45° from the sagittal plane formed by the medial wall ( Figs 7.1 and 7.2 ). Additionally, the geometry of the orbital bones requires that both globes be partially adducted in primary gaze. Maintenance of eye position in primary gaze requires a constant steady-state resting level of tension in all the EOM, referred to as tonus.
The apex of the bony orbit has three major foramina: the optic foramen, and the superior and inferior orbital fissures. The nerves and blood vessels to the majority of structures within the orbit enter through these foramina. A number of small foramina also open into the orbit, allowing entry and exit of nerves and vasculature to a wide array of structures in the orbit and head.
Normal extraocular muscles
Gross anatomy
There are six EOM in each orbit whose function is to move the eyes: four rectus muscles, superior, medial, inferior, and lateral; and two oblique muscles, inferior and superior ( Fig. 7.3 ). In addition there is a seventh skeletal muscle in each orbit, the levator palpebrae superioris, which inserts into the upper eyelid and functions in elevating the palpebral fissure. While its cranial nerve innervation is similar to the EOM, functionally and metabolically it is distinct, and will not be discussed further in this chapter.
The four rectus muscles take their origin in part from the bones at the apex of the orbit, but also from the tendinous annulus. They course anteriorly to insert into the sclera anterior to the equator of the globe, a key factor when considering their functional effects on eye movements. Classically this insertion is described as external to the ora serrata; however, recent studies demonstrate that insertions of the rectus muscles range from 2.25 mm posterior to 2.25 mm anterior to the ora serrata, with 90 percent of the insertions within 1 mm. Generally considered to be tendinous at the insertion site, the medial and lateral rectus muscles in humans may contain myofibers that extend directly to the sclera, an important consideration for incisional strabismus surgery. The insertions of the four rectus muscles increase in distance from the corneal limbus circumferentially, with the medial rectus closest and the superior rectus furthest. The distances were originally determined on cadaveric material; however, recent analyses on living adult patients during strabismus surgery show that the average distances from the corneal limbus to the rectus muscle insertions have large inter-individual variations. In part, this explains the disparate measurements seen in the literature. One typical study measured the distances from the limbus to muscle insertion as 6.2 ± 0.6 mm for the medial rectus, 7.0 ± 0.6 mm, for the inferior rectus, 7.7 ± 0.7 mm for the lateral rectus, and 8.5 ± 0.7 mm for the superior rectus. Distances can vary up to 4 mm, even between the same muscles in both eyes of one patient, and does not correlate with primary position of the eye or surgical success for strabismus patients. Thus, there is a significant amount of variation in rectus muscle insertions, and this variability has important consequences for incisional surgery of the EOM.
The superior and inferior oblique muscles have distinct paths compared to the rectus muscles. The superior oblique takes its origin from the dense connective tissue periosteum lining the orbit just superior and medial to the attachment of the tendinous annulus, and courses anteriorly along the border between the orbital roof and the medial orbital wall. Approximately 10–15 mm posterior to the orbital margin it becomes tendinous and enters the trochlea, a cartilaginous and dense connective tissue structure attached to the orbital periosteum. Emerging from the trochlea, the superior oblique muscle passes posteriorly at a 51° angle to the axis of the eye in primary position and inserts into the sclera. The trochlea thus serves as the “de facto” origin, creating the vector of force that moves the globe. The insertion of the superior oblique is on the superior pole deep to the superior rectus muscle, but in contrast to the rectus muscles, posterior to the equator of the globe ( Fig. 7.3 ). The inferior oblique muscle is the only EOM that does not take its origin from the apex of the orbit; instead originating from the anteromedial orbital floor. The inferior oblique muscle courses posteriorly and inferior to the inferior rectus and inserts into the sclera posterior to the equator of the globe.
The shape, size, and orientation of the EOM from origin to insertion form the basis for the eye movements that result from their contraction ( Table 7.1 ). While the effect of contraction of each EOM will be described separately, it is important to remember that they work in a coordinated fashion, maintaining significant tension or “tonus” even when the eye is in primary position and thus presumably “at rest”.
| Muscle | Primary action | Secondary action | Motor innervation | Antagonists | Synergists |
|---|---|---|---|---|---|
| Lateral rectus | Abduction | None | Abducens n (CNVI) | Medial rectus | Superior and inferior oblique m |
| Medial rectus | Adduction | None | Oculomotor n (CNIII, inferior division) | Lateral rectus | Superior and inferior rectus m |
| Superior rectus | Elevation |
| Oculomotor n (CNIII, auperior division) | Inferior rectus |
|
| Inferior rectus | Depression |
| Oculomotor n (CNIII, inferior division) | Superior rectus |
|
| Superior oblique | Intorsion |
| Trochlear n (CNIV) | Inferior oblique |
|
| Inferior oblique | Extorsion |
| Oculomotor n (CNIII, inferior division) | Superior oblique |
|
Horizontal movements are controlled by the medial and lateral rectus muscles, agonist–antagonist pairs with opposing primary functions; the medial rectus adducts the eye, while the lateral rectus abducts the eye. Vertical movements are more complex. The superior and inferior rectus muscles have a more complex effect on the direction of eye movements because the bony orbits are not parallel to each other ( Fig. 7.2 ). In primary gaze, both the superior and inferior recti are angled laterally at approximately 22.5° from the sagittal plane. The primary action of the superior rectus muscle is elevation, but it also adducts and intorts the eye ( Table 7.1 , Fig. 7.4 ). Intorsion is where the superior pole of the eye rotates medially. Thus, if the superior rectus muscle was acting alone, the direction of gaze would be superior and medial, that is, up and in towards the nose. The inferior rectus is parallel to the superior rectus, but inserts on the inferior surface of the globe. Thus, it primarily depresses the eye, but also adducts and extorts ( Fig. 7.4 ); extorsion is rotation of the superior pole of the eye laterally.
Due to its insertion posterior to the equator of the globe, as well as the vector of force directed by the position of the trochlea in the superior and medial orbit, the superior oblique mainly intorts the eye ( Table 7.1 , Fig. 7.4 ). It also depresses and abducts. Thus, working unilaterally, gaze would be directed down and out. As the inferior oblique muscle parallels the superior oblique, but inserts on the inferior surface of the globe, its primary function is extorsion of the eye ( Table 7.1 , Fig. 7.4 ); it also elevates and abducts. In order for accurate positioning of the visual world on the fovea, activity of all the EOM must be tightly coordinated.
Cranial motor nerve innervation
The optic foramen is found within the lesser wing of the sphenoid bone at the orbital apex, through which runs the optic nerve (cranial nerve II, CNII) and ophthalmic artery. Between the greater and lesser wings of the sphenoid is the superior orbital fissure. The structures entering the orbit through this fissure are divided by the tendinous annulus (formerly the annulus of Zinn). Structures that enter the orbit superior to the annulus are the lacrimal and frontal nerves, both sensory branches of the ophthalmic division of the trigeminal nerve (CNV); the trochlear nerve (CNIV), motor nerve to the superior oblique muscle; and the superior ophthalmic veins ( Fig. 7.5 ). Once through the annulus, structures enter what is referred to as the muscle cone, and are surrounded by the EOM and their connective tissue ensheathments. Within the annulus, the superior orbital fissure admits the superior and inferior divisions of the oculomotor nerve (CNIII) the motor nerve to the inferior rectus, inferior oblique, medial rectus, superior rectus and levator palpebrae superioris muscles; the nasociliary nerve which is a sensory branch of the ophthalmic division of the trigeminal nerve (CNV), and the abducens nerve (CNVI), the motor nerve to the lateral rectus muscle. On the floor of the orbit is the inferior orbital fissure, which admits the zygomatic nerve, a sensory nerve innervating the lateral mid-face; communications of the inferior ophthalmic vein with the pterygoid plexus of veins inferiorly; and the lacrimal rami, carrying parasympathetic innervation from the facial nerve (CNVII) to the lacrimal gland.
Once inside the bony orbit, the motor nerve branches of CNIII, CNIV and CNVI course anteriorly towards the muscles they innervate. The superior division of CNIII innervates the superior rectus muscle and continues superiorly to innervate the levator palpebrae superioris. The inferior division of CNIII innervates the medial and inferior rectus muscles, and the latter branch continues inferiorly to innervate the inferior oblique. All nerve branches enter the muscles on their deep surfaces within the muscle cone. CNVI also enters the lateral rectus muscle on its deep surface. Of the motor nerves, only the trochlear nerve, CNIV, enters the orbit outside the tendinous annulus innervating the superior oblique muscle on its superior or lateral surface ( Fig. 7.5 ). All motor nerves that innervate the EOM enter the body of the muscles at their posterior third ( Fig. 7.5 ).
Neuromuscular junctions (NMJ) are the specialized sites of communication between a nerve and the myofibers it innervates. In non-cranial skeletal muscle, NMJs usually form in the middle one-third of each myofiber. The NMJs formed by the cranial motor nerves with individual EOM myofibers display some distinct differences compared to those in non-cranial skeletal muscle. Similar to body muscles, the EOM have singly innervated myofibers with NMJs referred to as “en plaque” endings ( Fig. 7.6 ). However, the “en plaque” NMJs in EOM are smaller and less complicated structurally than those in non-cranial skeletal muscles. In addition, the EOM have multiply innervated myofibers with neuromuscular junctions referred to as “en grappe” endings ( Fig. 7.6 ). These are a linear array of small synaptic contacts often found towards the ends of individual myofibers, but can be continuous along the length of individual myofibers. The “en grappe” NMJ contacts are structurally simple. Thus, in EOM a single myofiber can have an “en plaque” NMJ somewhere along the middle one-third and also have multiple “en grappe” endings along the tapered ends ( Fig. 7.6 ). Some myofibers in EOM that express the slow tonic myosin heavy chain isoform (MYH14) have “en grappe” endings along their entire myofiber length and do not have an “en plaque” ending.
The acetylcholine receptor found within NMJs is composed of 5 subunits, similar to skeletal muscle generally. In developing non-cranial muscle there are two alpha, 1 beta, 1 gamma, and 1 delta subunits (α2βγδ), and in the adult the γ subunit is replaced with the epsilon (ε) subunit. In contrast, in adult EOM the majority of the “en grappe” endings express the “immature” gamma subunit, rather than the epsilon subunit of mature endings. Both the “en plaque” and “en grappe” endings in the EOM can co-express both the epsilon and gamma subunits; this appears to be unique to EOM. Due to the nature of EOM myofiber length, as discussed in a following section, NMJs can be seen throughout the origin-to-insertional length of EOM in most species where this has been examined. This is in contrast to most limb skeletal muscles, which have a motor endplate zone, an NMJ band that is fairly contained within a defined area in the midbelly region of the muscle.
It has generally been assumed that the multiply innervated myofibers are innervated by a single motor neuron, but polyneuronally innervated myofibers are also present. This means that more than one motor neuron can innervate a single myofiber. This has important implications for EOM physiology and will be discussed in that section.
Orbital connective tissue
A complex framework of connective tissue exists throughout the orbit, and this network has a clear structural organization and constant pattern ( Fig. 7.7 ). These connective tissue septa contain nerves, vessels and smooth muscle, and are postulated to play a role in supporting eye movements. Recent studies have confirmed and extended these initial detailed analyses of orbital connective tissue septa to include thickenings around individual EOM called orbital pulleys ( Fig. 7.7 ). These connective and smooth muscle septa and bands constrain the paths of the EOM, changing the vector of force as the EOM contract and stabilize muscle position during movement.
Histological anatomy and physiologic implications
The EOM have a complex anatomy at the microscopic level. The overall cross-sectional areas of their myofibers are extremely small compared to non-cranial skeletal muscle. Each EOM is composed of two layers: an outer orbital layer composed of myofibers of extremely small cross-sectional area and an inner global layer with myofibers larger than in the orbital layer but still extremely small compared to non-cranial skeletal muscle ( Fig. 7.8 ). Further descriptions will concentrate on human muscle, but the EOM of other mammals have the same general features despite some variations in detail.
In non-cranial skeletal muscles, two general fiber types are described, fast and slow, referring mainly to the myosin heavy chain isoforms (MyHC) they express, which in turn determines their shortening velocity. Whether a fiber is “fast” or “slow” is due, in part, to their complement of contractile proteins. Non-cranial skeletal muscles that are largely fast MyHC-positive, such as the extensor digitorum longus, have an oxidative metabolism, rapid shortening velocities, and rapid fatigue with activation. Slow MyHC-positive myofibers in non-cranial skeletal muscle have a glycolytic metabolism, slower shortening velocities, larger force generation, and are fatigue-resistant. The EOM also have the two basic myofiber types. About 85 percent of the myofibers in both layers in adult EOM are fast MyHC-positive ( Fig. 7.8 ). The other 15 percent of the EOM myofibers immunostain for the slow MyHC. In contrast to non-cranial skeletal muscle, the EOM have extremely fast contractile characteristics yet are also extremely fatigue-resistant. Several factors support these apparently contradictory characteristics. While the vast majority of non-cranial skeletal muscles express one of four MyHCs, fast fiber types IIa, IIx, or IIb or slow type 1, EOM myofibers can contain up to nine MyHCs.
The MyHC expressed in EOM include: fast types IIa (MYH2), IIx (MYH1), or IIb (MYH4); MyHCs associated with immaturity – embryonic (developmental) (MYH3) and neonatal or fetal (MYH8); slow or type 1 (which is the same as beta-cardiac myosin) (MYH7); alpha-cardiac (MYH6); EOM-specific (MYH13); and the slow tonic myosin (MYH14). This large array of expressed MyHC within the EOM helps explain why its dynamic physiologic properties are significantly different than those in limb muscles. It should be noted that patterns of MyHC composition vary between each EOM, with lateral rectus being the most different. Support for the idea that the MyHC composition may be critical for understanding control of force generation is the physiological demonstration that there are significant contractile differences between muscles. For example, in the medial and lateral rectus muscles, motor units in the medial rectus generate faster twitch contractions and those in lateral rectus generate greater tetanic tensions. This concept is critical in understanding the CNS control of eye movements as well as eye movement disorders like strabismus.
The expression patterns of EOM myofibers for these MyHC differ significantly between the global and orbital layers ( Fig. 7.8 ); for example, the vast majority of the orbital layer myofibers are positive for developmental myosin (MYH3), yet the global layer only has scattered fibers that immunostain for this isoform ( Fig. 7.8 ). Distinct patterns of differential staining are seen for all other MyHC present in EOM. From a physiological perspective, this issue becomes even more complex. Approximately 25 percent of cat single lateral rectus motor units examined had myofibers in both the orbital and global layers. These bilayer motor units are stronger and faster than motor units contained within single EOM layers, and tend to be fatigable. Approximately 54 percent of the global motor units examined were stronger and faster than orbital layer units, in part a reflection of the properties imbued upon the individual myofibers by their contractile proteins.
The expression of individual MyHC also varies along the origin-to-insertion length of each muscle. In part this is because many of the EOM myofibers do not run from origin to insertion in both the orbital and global layers; they can be arranged in parallel or in series, and many branched and/or split myofibers exist ( Fig. 7.9 ). These short myofiber lengths have functional consequences. For example, in a series of studies examining summation of motor forces, individual cat and monkey motor units were stimulated, and the forces each unit produced in the lateral rectus muscle were determined. Then, using simultaneous stimulation, the evoked unit force of other motor units was added to the single motor unit force. In about 25 percent of the cases in cat and about 85 percent of the cases in monkey, the forces did not add linearly. Thus, force is “lost” as multiple myofibers are activated, partly due to force dissipation laterally through myomyous junctions and myo-connective tissue connections formed by short myofibers.
In addition, the serial or parallel arrangement of myofibers with different myofibrillar isoforms would significantly affect contractile behavior. This was elegantly demonstrated using sets of single myofibers in vitro, one fast and one slow, that were tied together in series or in parallel. In any given combination of one fast and one slow myofiber, the paired fibers showed a range of forces with greater or lesser fast or slow characteristics. In a fast/slow combination, the fast fiber begins to contract prior to the slow fiber, which is then slack and therefore not at its optimal length to generate full force. Serial or parallel arrangements of myofibers with disparate MyHC isoform composition would be expected, based on these results, to result in a range, or continuum, of forces produced by their co-activation. This suggests that a distributed model of motor unit recruitment at the CNS level is needed to address the non-linearity of the effector arm of the system, the EOM themselves.
Individual EOM myofibers are polymorphic and also can express more than one MyHC. This has been shown for a wide variety of species, including human muscle. For example, in both singly and multiply innervated myofibers in the orbital layer in rats, the fiber ends express the neonatal MyHC (MYH8), but this isoform is completely eliminated at the position of the NMJ, where the fibers immunostained for fast MyHC. In the orbital layer, individual myofibers express the embryonic MyHC (MYH3) at their fiber ends and the EOM-specific MyHC (MYH13) in the NMJ region. Orbital multiply innervated myofibers were found that expressed slow MyHC (MYH7) along their entire length, but also expressed embryonic MyHC (MYH3) at the fiber ends. Single myofibers in the global layer were found that express EOM-specific MyHC (MYH13) at the NMJ region as well as fast myosins IIb and/or IIx. In human EOM, orbital layer myofibers were found that expressed type 1 (MYH7), and of these ( Fig. 7.10 ) some also expressed slow tonic (MYH14), alpha-cardiac (MYH6), and/or embryonic (MYH3) or EOM-specific (MYH13). Physiologic examination of individual multiply innervated myofibers from the orbital layer of rats showed that electrical activity varied along the length of the fiber, with tonic characteristics at the fiber end and twitch characteristics in the central region near the endplate, the only location where fast MyHC was expressed.
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