Neuro-ophthalmology: Ocular Motor System

Heterophorias versus heterotropias

When no ocular misalignment of the eyes is present, the patient is said to have an “ortho” pattern of alignment. A “hetero” pattern indicates a misalignment. Two different terms are used, heterotropia or heterophoria , depending on whether binocular fusion must be disrupted for misalignment to be detected. With a tropia, there is a manifest deviation of one eye that can be readily seen. With a phoria, disruption of binocular fusion must occur to detect an ocular misalignment. Many individuals have a latent horizontal heterophoria, which may become manifest (heterotropia) under conditions of stress such as fatigue, exposure to bright sunlight, or ingestion of alcohol, anticonvulsants, or sedatives. Divergent eyes are said to be exotropic and convergent eyes esotropic . With vertical misalignment, when the nonfixating eye is higher, the patient is said to have a hypertropia , and when it is lower, a hypotropia —although by convention, right or left hypertropia is more often used than the term hypotropia .

Techniques to assess ocular alignment

Examination of ocular alignment should be performed for binocular diplopia. The alignment pattern of the eyes in primary position should be assessed first. Horizontal diplopia is accompanied by either an eso- or exo- deviation. Vertical diplopia is accompanied by either a left or right hyper-deviation. With diplopia from paralytic strabismus, the image from the nonfixating paretic eye is the false image and is displaced in the direction of action of the weak muscle. Thus, a patient with esotropia has uncrossed diplopia (see Fig. 18.11 , A ) and a patient with exotropia has crossed diplopia (see Fig. 18.11 , B ). After a variable period, a patient may learn to ignore or suppress the false image. If suppression occurs before visual maturity (approximately 6 years of age) and persists, central connections in the afferent visual system fail to develop fully, leading to permanent visual impairment in the deviated nonfixating eye (developmental amblyopia). Amblyopia is more likely to develop with esotropia than with exotropia because exotropia is commonly intermittent. After visual maturity, suppression and amblyopia do not occur; instead, the patient may learn to avoid diplopia by ignoring the false image.

Before determining ocular alignment, the examiner must neutralize a head tilt or turn by placing the head in the “controlled (forced) primary position”; otherwise, misalignment may go undetected because of the compensating head posture. Subjective tests of ocular alignment include the red glass, Maddox rod, Lancaster red-green, and Hess screen tests.

With the red glass test , the patient views a penlight while a red filter or glass is placed, by convention, over the right eye. This allows easier identification of the image seen by each eye; the right eye views a red light and the left a white light. The addition of a green filter over the left eye, using red-green glasses, further simplifies the test for younger or less reliable individuals. The target light is shown in the nine diagnostic positions of gaze (see Fig. 18.14 , A ). As the light moves into the field of action of a paretic muscle, the images separate. The individual is asked to signify where the images are most widely separated and to describe their relative positions. Interpretation of the results is summarized in Fig. 18.15 .

The Maddox rod test uses the same principle as the red glass test, but the images are completely dissociated. A point of light seen through the rod, which is a series of half cylinders, is changed to a straight line that is seen perpendicular to the cylinders ( Fig. 18.16 ). This dissociation of images (a point of light and a line) breaks fusion, enabling the detection of heterophorias as well as heterotropias. Cyclotorsion may be detected by asking if the image of the line is tilted ( Fig. 18.17 ). The Maddox rod can be positioned to produce a horizontal, vertical, or oblique line.

Similar tests include the Lancaster red-green test and the Hess screen test , which use the same principles, although they are unlikely to be used by a neurologist. Each eye views a different target (a red light through the red filter and a green light through the green filter). The relative positions of the targets are plotted on a grid screen and analyzed to identify the paretic muscle. These haploscopic tests are used mainly by ophthalmologists to quantitatively follow patients with motility disorders.

The Hirschberg test , an objective method of determining ocular deviation in young or uncooperative patients, is performed by observing the point of reflection of a penlight held approximately 30 cm from the eyes ( Fig. 18.18 ). The light should be centered on the cornea in one eye; if it is not also seen in the center of the other eye, an ocular misalignment is likely to be present. One millimeter of decentration is equal to 7 degrees of ocular deviation. One degree is equal to approximately 2 prism diopters. One prism diopter is the power required to deviate (diffract) a ray of light by 1 cm at a distance of 1 m ( Fig. 18.19 ).

The cover-uncover test is determined for both distance (tested at 6 m) and near (tested at 33 cm) vision. The patient is asked to fixate an object at the appropriate distance. The left eye is covered while the patient maintains fixation on the object. If the right eye is fixating, it remains on target, but if the left eye alone is fixating, the right eye moves onto the object. If the uncovered right eye moves in (adducts), the patient has a right exotropia; if it moves out (abducts), the patient has an esotropia; if it moves down, a right hypertropia; if it moves up, a right hypotropia (otherwise called a left hypertropia). The physician should always observe the uncovered eye. The test should be repeated by covering the other eye. Prisms are used—mainly by neuro-ophthalmologists, ophthalmologists, orthoptists, and optometrists—to measure the degree of any ocular deviation (see Fig. 18.19 ). If diplopia is due to breakdown of a long-standing (congenital) deviation, prism measurement can also be used to detect supranormal fusional amplitudes (large fusional reserves) to help confirm the long-standing nature. If no manifest deviation of the visual axes is found using the cover-uncover test, the patient is orthotropic. Then the physician may perform the cross-cover test.

During the cross-cover test (alternate-cover test), the patient is asked to fixate an object, and then one eye is covered for at least 4 seconds before the second eye is covered. The examiner should observe the uncovered eye. If the patient is orthotropic, the uncovered eye does not move but the covered eye loses fixation and assumes its position of rest—latent deviation (heterophoria or phoria). In that case, when the covered eye is uncovered, it refixates by moving back; the uncovered eye is immediately covered and loses fixation. The cross-cover test prevents binocular viewing, and thus foveal fusion, by always keeping one eye covered. Many normal subjects without a history of diplopia are exophoric because of the natural alignment of the orbits.

Fixation switch diplopia occurs in patients with long-standing strabismus who partially lose visual acuity in the fixating eye, usually because of a cataract or refractive error ( ). Such patients avoid double vision usually by ignoring the false image from the nonfixating eye, but a significant decrease in acuity in the “good” eye forces them to fixate with the weak eye. This causes misalignment of the previously good eye and results in diplopia. Fixation switch diplopia can usually be treated successfully with appropriate optical management.

Comitance versus incomitance

If a patient has an ocular misalignment (tropia or phoria), the physician must determine whether it is comitant or incomitant (i.e., noncomitant) by checking the degree of deviation in the nine diagnostic cardinal positions of gaze (see Fig. 18.14 , A ). When the pattern and degree of ocular misalignment—that is, the angle of deviation of the visual axes—is constant regardless of the direction of gaze, the patient has a comitant strabismus (heterotropia). For example, if a patient has an esotropia in primary position that does not change (and the degree of diplopia does not change) in right and left gaze compared with primary position, the misalignment is comitant. When the degree of misalignment varies with gaze direction, the patient has an incomitant (paralytic due to a weak eye muscle or restrictive due to a stiff eye muscle in the orbit) strabismus.

When a patient with incomitant strabismus fixates on an object with the nonparetic eye, the angle of misalignment is referred to as the primary deviation . When the patient fixates with the paretic eye, the angle of misalignment is referred to as the secondary deviation . Secondary deviation is always greater than primary deviation in incomitant strabismus because of the Hering law of dual innervation; it may mislead the examiner to believe that the eye with the greater deviation is the weak one ( Fig. 18.20 ).

Often, comitant strabismus is ophthalmological in origin. In contrast, incomitant strabismus is neurological (though a common exception to this generalization is skew deviation [discussed later]). As an example of incomitance, a right lateral rectus palsy will cause an esotropia that increases upon looking to the right, the side of the weak muscle, and decreases upon looking to the left, opposite side where the weak muscle is out of its plane of action (see Fig. 18.15 , A ). Similarly, with a right medial rectus weakness, an exotropia will be present that increases on looking left and decreases in right gaze (see Fig. 18.15 , B ). Of importance to accurate neurological localization and diagnosis is the concept of spread of comitance with a chronic lesion, which means that there is a tendency for a chronic ocular deviation to “spread” to all fields of gaze, thereby becoming comitant over time; thus, the usual localizing rules of comitance may not apply.

The Parks-Bielschowsky three-step test enables the examiner to assess the pattern of a vertical misalignment of the eyes to identify the paretic muscle. Eight muscles are involved in vertical eye movements: four elevators (two superior recti and two inferior obliques) and four depressors (two inferior recti and two superior obliques). The three-step test endeavors to determine whether a single paretic muscle is responsible for vertical diplopia (see Fig. 18.17 ). Using the cover-uncover test, which is objective, or one of the subjective tests such as the red glass test, the physician can perform the three-step test for vertical diplopia. When one of the subjective methods for test performance is used, it is important to remember that the hypertropic eye views the lower image. The examiner should also be aware of the pitfalls of the three-step test—namely, the conditions in which the rules break down. These include restrictive ocular myopathies ( Box 18.5 ), long-standing strabismus, skew deviation, and disorders involving more than one muscle. The test is most helpful for confirming the pattern of a fourth nerve palsy.

• Step 1 determines which eye is higher (hypertropic) in primary position. The patient’s head may have to be repositioned (controlled primary position) to neutralize any compensatory tilt. If the right eye is higher, the weak muscle is either one of the two depressors of the right eye (inferior rectus or superior oblique) or one of the two elevators of the left eye (superior rectus or inferior oblique).

• Step 2 determines whether the hypertropia increases on left or right gaze. If a right hypertropia increases on left gaze, the weak muscle is either the depressor in the right eye, which acts best in adduction (i.e., the superior oblique), or the elevator in the left eye, which acts best in abduction (i.e., the superior rectus).

• Step 3 determines whether the hypertropia changes when the head tilts to the left or the right. If a right hypertropia increases on head tilt right, the weak muscle must be an intortor of the right eye (superior oblique); if it increases on head tilt left, the weak muscle must be an intortor of the left eye (superior rectus).

Three additional optional steps have been described:

• Step 4 uses one of several techniques (e.g., double Maddox rod, visual field blind spots, indirect ophthalmoscopy, fundus photography) to determine whether ocular torsion is present. Establishing the degree and direction of ocular torsion, if any, can differentiate a skew deviation from a superior oblique palsy. Because the primary action of the superior oblique muscle is incyclotorsion (see Table 18.1 ), typically an acute palsy results in approximately 5 degrees of excyclotorsion of the affected eye due to unopposed action of the ipsilateral inferior oblique muscle; greater than 10 degrees suggests bilateral involvement. If either eye is intorted, a superior oblique palsy is not responsible and the patient may have a skew deviation ( ).

• Step 5 is helpful in the acute phase. If the deviation is greater on downgaze, the weak muscle is a depressor; if it is worse on upgaze, the weak muscle is likely to be an elevator. This fifth step is helpful only in the acute stage, because with time the deviation becomes more comitant.

• Step 6 involves assessing the size of the vertical deviation in a supine position. If the deviation improves in a supine position, a skew deviation is more likely than a superior oblique palsy ( ).

Head position, eyelids, and other exam techniques ( Video 18.1 )

Video 18.1 Forced Ductions. © Patrick J. M. Lavin, All rights reserved.

Patients with diplopia may compensate by tilting or turning the head in the direction of action of the weak muscle to move the eyes into a position where the weak muscle is not needed ( Fig. 18.21 ). For example, with right lateral rectus palsy, the head is turned slightly to the right; then, on attempted right gaze, the patient turns the head farther to the right (see Fig. 18.21 , A ). With a right superior oblique palsy, the head tilts forward and to the left (see Fig. 18.21 , B ). The rule is as follows: The head turns or tilts in the direction of action of the weak muscle.

Careful examination of the eyelids and external appearance of the eyes in the presence of diplopia can provide clues for accurate localization ( Box 18.6 ). Visual acuity, stereopsis, color vision, and confrontation visual fields should be checked carefully and separately in each eye, along with a complete neurological examination.

Nonfatigable limitation of eye movements may suggest a restrictive process such as a tethered extraocular muscle (entrapment) or an infiltrative process such as with thyroid eye disease (TED), idiopathic orbital inflammatory syndrome (IOIS), lymphoma, and so on. Assessment for such restriction is performed with forced duction testing under topical anesthesia. The use of phenylephrine hydrochloride eye drops beforehand reduces the risk of subconjunctival hemorrhage. Although this test is in the realm of the ophthalmologist, it may be performed in the office using topical anesthesia and a cotton-tipped applicator, but great care must be taken to avoid injuring the cornea. The causes of restrictive myopathy are listed in Box 18.5 ; however, any cause of prolonged extraocular muscle paresis can result in contracture of its antagonist muscle.

Extraocular muscles and orbit

Proptosis, eyelid retraction, lid lag (i.e., delayed lowering of the upper lid margin with depression of an eye), conjunctival injection, and periorbital swelling suggest an orbital/extraocular muscle process, such as an orbital mass lesion, thyroid eye disease (TED), or idiopathic orbital inflammatory syndrome (IOIS, also called orbital pseudotumor). Inflammation, infiltration, or fibrosis of an extraocular muscle often restricts the range of eye movement in the direction opposite that muscle’s field of action (for example, left medial rectus involvement leads to a left abduction defect) and occasionally may cause weakness and impair movement in the direction of action of the muscle.

The two most common conditions resulting in diplopia secondary to extraocular muscle disease are TED and IOIS. TED is typically painless except for a foreign body sensation (grittiness) and may present with unilateral or bilateral signs. IOIS is most often unilateral, with subacute painful onset. Classically, TED affects the inferior and medial rectus muscles early, leading to restriction of elevation and abduction of the eye. Both entities may cause vision loss from optic nerve involvement, by compression in TED, or inflammation with IOIS. Chronic progressive external ophthalmoplegia (CPEO) can also cause painless, slowly progressive loss of eye movements (usually without diplopia due to insidious progression and symmetry of the process). Unlike other causes of ophthalmoplegia, classic signs of orbital disease are not present; rather, unilateral or bilateral progressive ptosis is characteristic. Mitochondrial myopathy is the most common etiology of CPEO, either isolated or as part of a syndrome such as Kearns-Sayre.

An orbital CT scan may suffice to identify enlarged extraocular muscles ( Fig. 18.22 , A ) in TED and IOIS; however, orbital magnetic resonance imaging (MRI) with contrast is preferred and should include both axial and coronal images to assess for optic nerve compression; muscle enlargement may be underestimated with axial images alone. Involvement of the tendon of the enlarged extraocular muscle distinguishes IOIS from TED (see Fig. 18.22 , B ).

Serological thyroid function studies, including thyroid-stimulating hormone (TSH), tri-iodothyronine (T3) and thyroxine (T4), and TSH-receptor antibodies should be assessed if TED is suspected. Patients with TED may be serologically hyper-, hypo-, or euthyroid. Antithyroglobulin and antimicrosomal antibodies may be elevated with TED, whereas serum IgG subtyping may be helpful in identifying those patients with IOIS who have IgG4 disease, which can affect up to 50% ( ).

Neuromuscular junction

Myasthenia gravis (MG) is the most common disease of the neuromuscular junction. Ocular motor dysfunction can mimic virtually any pupil-sparing abnormal eye movement, from pupil-sparing third nerve palsies to fourth and sixth nerve palsies to brainstem supranuclear gaze palsies to internuclear ophthalmoplegia (INO). Diagnostic confusion often arises when the eye movements of MG mimic another disorder and ptosis is not present to raise suspicion of MG. It is always appropriate to keep MG in the differential diagnosis for any unexplained eye movement abnormality and to have a low threshold for pursuing diagnostic testing.

Botulism from Clostridium botulinum neurotoxin blockade also affects neuromuscular junction transmission. The eye movements are like those seen in MG, with variable patterns of ophthalmoplegia. However, unlike the lack of pupillary involvement in MG, tonic pupillary involvement (with slow tonic reaction and redilation to light and pupillary light-near dissociation manifested as better reaction to a near stimulus than to a light stimulus) is typical of botulism. A third disorder of the neuromuscular junction is the Lambert-Eaton myasthenic syndrome (LEMS), which is due to presynaptic neuromuscular junction failure (in contrast to MG, which is a postsynaptic disorder). The primary clinical manifestation is skeletal muscle weakness that may improve, rather than fatigue, with repetitive movement. Ptosis is common with LEMS; however, eye movements are affected less often ( ), and when affected are, rarely, the presenting clinical feature.

Historic features such as fatigability with diplopia more common toward the end of the day and/or variability in the pattern of diplopia among horizontal, vertical, and oblique patterns make MG more likely in a patient with diplopia. Signs of MG ( Video 18.2 ) include moment-to-moment or visit-to-visit variability in ocular misalignments, fatigability of eye movements or lids with prolonged upgaze, Cogan lid twitch, orbicularis oculi weakness, ptosis and curtaining or enhanced ptosis, and faster than normal “twitchy” saccades (i.e., lightning saccades). The finding of lid retraction should suggest coexisting TED, especially with proptosis. The incidence of thyroid dysfunction is higher in MG, particularly if seropositive ( ). Cogan lid twitch is an excessive twitch of the upper lid upon return of the eyes to central position after 10 seconds of sustained downgaze. The basis for eyelid curtaining is the Hering law of equal (dual) neural innervation to each eyelid: Manually elevating the more ptotic lid results in increased ptosis in the less ptotic or nonptotic eyelid. These signs are not pathognomonic for MG ( ); thus confirmatory laboratory testing is important.

Video 18.2 Eyelid Signs of Myasthenia Gravis.© Janet C. Rucker, All rights reserved.

Although diagnostic testing for MG is covered in more detail in Chapter 108 , it is important to note here that the edrophonium test must have an objective endpoint (e.g., ptosis, a tropia, limited ductions), and that the physician must observe an objective change. When forced ductions are positive, indicating a restrictive myopathy, the edrophonium test will be negative and therefore is not indicated. Myasthenic ptosis may be reversed temporarily with application of an ice pack over the affected lid for 1 to 2 minutes ( ) or after having the patient rest with closed eyes for 30 to 60 minutes. Acetylcholine receptor antibodies are elevated (abnormal) in about 80% of patients with generalized MG but in only 38% to 71% of those with ocular MG ( ). Anti-MuSK (anti–muscle specific receptor tyrosine kinase) antibodies are rarely associated with chronic ocular MG ( ), although ocular manifestations are a common presenting feature in disease that then generalizes ( ) and MuSK antibodies are more likely if there is significant bulbar involvement. A decremental response on repetitive electromyographic (EMG) stimulation is highly specific but has a low sensitivity in ocular MG ( ); single-fiber EMG of the orbicularis oculi has a high sensitivity and specificity ( ). A decremental response of the inferior oblique muscle on ocular vestibular evoked myogenic potential (oVEMP) stimulation is a novel and evolving ocular MG diagnostic test ( ). Conversion to generalized myasthenia will occur in up to 55% of patients presenting with isolated ocular symptoms ( ).

Ocular motor cranial nerves

See Chapter 103 for full coverage of the anatomy and clinical lesions of the third (III, oculomotor), fourth (IV, trochlear), and sixth (VI, abducens) cranial nerves. Supplementary comments are included here.