Chapter 11: Extraocular Movements and Approach to Diplopia: Cranial nerves 3, 4, and 6

Each eye is moved by six muscles: four rectus muscles and two oblique muscles. These muscles are controlled by three nerves: cranial nerves (CNs) 3, 4, and 6. These cranial nerves all originate from brainstem nuclei that communicate with one another through the medial longitudinal fasciculus (MLF) to coordinate movements between the left and right eyes. These nuclei are controlled by brainstem gaze centers that coordinate the eyes to move together horizontally or vertically, and these gaze centers are stimulated by cortical eye fields. From the top down, the cortical eye fields stimulate the gaze centers in the brainstem, the brainstem gaze centers communicate with the cranial nerve nuclei of CN 3, CN 4, and CN 6, and CN3, CN 4, and CN 6 activate the extraocular muscles.

The vestibular system also interacts with the eyes to coordinate eye movements with head movements. This pathway involves CN 8 and the cerebellum, and is discussed further in Chapter 12.

The six muscles that control each eye are the four rectus muscles (superior, inferior, medial, lateral) and the two oblique muscles (superior and inferior) (Fig. 11–1 and Table 11–1). CN 4 controls the superior oblique, CN 6 controls the lateral rectus, and CN 3 controls the rest (superior, inferior, and medial recti and inferior oblique). The principal eye movements performed by the rectus muscles are easy to understand:

• Lateral rectus (CN 6) moves the eye laterally (abducts)

• Medial rectus (CN 3) moves the eye medially (adducts)

• Superior rectus (CN 3) primarily moves the eye superiorly (elevates)

• Inferior rectus (CN 3) primarily moves the eye inferiorly (depresses)

The principal eye movements performed by the oblique muscles are slightly more complicated. In addition to moving up, down, left, and right, the eyes can also rotate when the head is tilted to either side. Rotation of the eye toward the nose/midline is called intorsion and rotation toward the ear is called extorsion. As the head is tilted to the left and the eyes attempt to maintain fixation straight ahead, the left eye must intort (turn toward the nose) and the right eye must extort (turn toward the ear). As the head is tilted to the right, the right eye intorts and the left eye extorts. In sum, when the head tilts to one side, the eye on the side to which the head is tilted (bottom eye) intorts and the other eye (top eye) extorts (Fig 11–2). This is important in understanding the symptoms and signs of a CN 4 palsy, which is discussed further below.

Intorsion of the eye is the main role of the superior oblique muscle. However, when the eye is fully adducted, the superior oblique depresses the eye. To understand the actions of the superior oblique, take your left hand and place it on the crown of your head with your elbow sticking out to the left. Look straight ahead. Your head now represents the right eye and your arm represents the right superior oblique muscle, bent at the elbow to represent the bend of the superior oblique muscle as it passes through the pulley (trochlea) for which CN 4 is named (i.e., trochlear nerve). If you pull with your hand, this will tilt the head inward— this is intorsion. If you turn your head all the way to the left so you are looking at your elbow crease (adducting the right eye), now pulling with your hand causes the head to look down (depressing the eye). The angle of the superior oblique allows for it to intort the eye when the eye is midline or abducted, and to depress the eye when the eye is adducted (Fig 11-1B). The inferior oblique performs an equal but opposite function: extorsion of the eye when the eye is midline or abducted, and elevation of the eye when the eye is adducted.

The primary actions of the superior rectus and inferior rectus are what would be expected based on their names: superior rectus elevates the eye, inferior depresses it. However, these two muscles also perform rotatory functions. Just as the superior oblique intorts the eye, the superior rectus also contributes to intorsion; just as the inferior oblique extorts the eye, the inferior rectus also contributes to extorsion (mnemonic to recall that inferior muscles extort and superior muscles intort: InfEXions will leave you SupINe). Just as the superior and inferior oblique perform their secondary actions (depression and elevation) in the adducted position, the superior and inferior recti also perform their secondary actions (intorsion and extorsion) in the adducted position.

All of the ocular motor nerves originate in brainstem nuclei (CN 3 and CN 4 in the midbrain; CN 6 in the pons), and travel in the subarachnoid space, through the cavernous sinus, and then into the orbit. Lesions causing dysfunction of these cranial nerves can occur at one of four locations:

1. Nucleus or fascicle of CNs 3, 4, or 6 in the brainstem. The term fascicle refers to the portion of a cranial nerve that is still in the brainstem. Potential pathology in the brainstem includes stroke, tumor, and demyelination.

2. CNs 3, 4, or 6. Trauma and nerve infarct are the most common causes of isolated 3, 4, or 6 palsy. Trauma can affect CNs 3, 4, and 6 because their length and course render them susceptible to trauma. Nerve infarct of CN 3, 4, or 6 is most commonly caused by diabetes. CNs 3, 4, and 6 can also be affected by skull base tumors, aneurysms, subarachnoid hemorrhage, meningitis, and Guillain-Barré syndrome (especially the Miller Fisher variant; see “Guillain-Barré syndrome” in Ch. 27).

3. Cavernous sinus. CNs 3, 4, and 6 pass through the cavernous sinus along with the V₁ and V₂ branches of the trigeminal nerve (Fig. 11–3). Potential pathology here includes cavernous sinus thrombosis, carotid-cavernous fistula, pituitary tumors or pituitary apoplexy, and Tolosa-Hunt syndrome (an idiopathic inflammatory condition of the cavernous sinus).

4. Orbit. When CNs 3, 4, and/or 6 are affected in the orbit, the optic nerve is also often affected (this is not the case with cavernous sinus pathology since the optic nerve does not pass through the cavernous sinus). Potential orbital pathology includes tumors, infections (orbital cellulitis), and orbital pseudotumor (an idiopathic inflammatory condition of the orbit).

Cranial Nerve 3: The Oculomotor Nerve

CN 3 originates in the medial dorsal midbrain and exits the midbrain anteriorly. It travels along the medial skull base, passing adjacent to the medial temporal lobe, through the cavernous sinus, and into the orbit. CN 3 innervates:

• Superior rectus, medial rectus, inferior rectus, and inferior oblique (all extraocular muscles except superior oblique [innervated by CN 4] and lateral rectus [innervated by CN 6])

• Levator palpebrae, which elevates the eyelid

• Parasympathetic fibers to the pupil, which constrict it (see Ch. 10)

A complete third nerve palsy (Fig. 11–4) causes:

• Weakness of the four supplied muscles, leaving the eye down and out: down due to the unopposed action of the superior oblique (CN 4) and out due to the unopposed action of the lateral rectus (CN 6)

• Weakness of the levator palpebrae, causing ptosis

• Decreased parasympathetic input to the pupil, leading to pupillary dilation (mydriasis)

Due to the way the different fibers run in the third nerve, partial lesions of the third nerve can affect the pupillary fibers in isolation or the ocular motor fibers in isolation. The pupillary fibers run on the medial exterior part of the nerve, whereas the oculomotor fibers run on the inside of the nerve. A lesion compressing the third nerve affects the outermost fibers first, which can lead to impaired pupillary constriction with no extraocular muscle dysfunction (or preceding the development of extraocular muscle dysfunction). On the other hand, an ischemic insult to the nerve will affect the innermost fibers supplied by small penetrating vessels, and can cause extraocular dysfunction with sparing of pupillary reactivity. This is called a pupil-sparing third nerve palsy (Fig. 11-4).

Compressive lesions that can affect CN 3 causing isolated (or initially isolated) pupillary dilatation without eye movement abnormalities include posterior communicating artery aneurysms, skull base tumors, and uncal herniation. Pupil-sparing third nerve palsy is most commonly due to nerve infarct caused by diabetes, which usually resolves over months. Pupil-involving third nerve palsy requires urgent neuroimaging to evaluate for aneurysm or other intracranial mass lesion. When the pupil is not involved in an otherwise complete CN 3 palsy, neuroimaging can be deferred, although in practice it is often obtained in this scenario as well.

Each CN 3 nuclear complex in the dorsal midbrain has several subnuclei: one for each extraocular muscle (superior rectus, inferior rectus, medial rectus, inferior oblique). The Edinger-Westphal nuclei provide parasympathetic input for pupillary constriction. The levator palpebrae muscles (which elevate the eyelid) are supplied bilaterally by a single nucleus called the central caudal nucleus. The central caudal nucleus projects bilaterally to allow for symmetric eyelid elevation. The superior rectus subnucleus of each third nerve nucleus projects contralaterally, and the crossing fibers pass in close proximity to the contralateral CN 3 nucleus. Therefore, a very small focal lesion of the entire third nerve nuclear complex on one side will cause ipsilateral impairment of all third nerve functions and bilateral involvement of the superior rectus. Lesions of the third nerve nucleus cause bilateral superior rectus weakness because the affected superior rectus subnucleus projects contralaterally (causing contralateral impairment of upgaze), and the crossing fibers projecting from the unaffected contralateral superior rectus subnucleus pass in close proximity to the affected nucleus, causing involvement of the eye ipsilateral to the side of the nuclear lesion. If the adjacent central caudal nucleus in the dorsal midbrain is also involved, this will cause bilateral ptosis.

The fascicle of each CN 3 travels anteriorly in the midbrain in proximity to the red nucleus, substantia nigra, and descending (not-yet-crossed) corticospinal tract before exiting as the third nerve itself. Fascicular lesions cause the same ocular findings as nerve lesions (without any contralateral/bilateral findings as can occur with lesions of the nucleus), and may be associated with contralateral motor symptoms/signs (Weber’s syndrome) due to the not-yet-crossed corticospinal tract, contralateral movement disorder (Benedikt’s syndrome) due to involvement of the substantia nigra, and/or contralateral tremor and/or contralateral ataxia (Claude’s syndrome) due to involvement of the red nucleus and crossed superior cerebellar peduncle (coming from the contralateral cerebellar hemisphere; see Ch. 8).

Cranial Nerve 4: The Trochlear Nerve

CN 4 originates in the dorsal midbrain and is the only cranial nerve to exit posteriorly and the only cranial nerve that crosses to project contralaterally. It innervates one muscle, the superior oblique. Like CN 3 and CN 6, it is susceptible to trauma and diabetic nerve infarct (although diabetic nerve infarct occurs less commonly in CN 4 than in CN 3 or CN 6). CN 4 can also be compressed by dorsal midbrain pathology (e.g., pineal mass).

When the head is tilted to one side, the eye that intorts is the one on the side of the head to which the patient is tilting the head (for example, if the patient tilts the head to the left, the left eye must intort, rotating equal and opposite to the direction that the head is tilting). When intorsion is impaired due to a CN 4 palsy, double vision (diplopia) occurs when the head is tilted toward the affected side since that eye cannot intort to maintain fixation. Therefore, the patient’s preferred head position is to tilt the head away from the affected side to keep the eyes aligned. In a left CN 4 palsy, a patient’s double vision will worsen when tilting the head to the left, and so the patient will prefer to keep the head tilted to the right. In a right CN 4 palsy, a patient’s double vision will worsen when tilting the head to the right, and so the patient will prefer to keep the head tilted to the left.

Patients with CN 4 palsy have vertical double vision that is worst in downgaze when looking away from the side of the affected eye (e.g., looking left if the right eye affected). This is because looking away from the side of the affected eye puts the affected eye in adduction, the position in which the superior oblique functions to depress the eye. When placed in the position that most needs the superior oblique (down and in), CN 4 dysfunction will be most evident, leading to double vision that is worst in this position (Fig. 11–5).

In summary for superior oblique palsies, the patient tilts the head away from the side of the palsy, and the diplopia worsens with downgaze away from the side of the affected eye (i.e., affected eye in adducted position). The trochlear nerve is the only cranial nerve that crosses, and as a mnemonic, its deficits can also be thought of as “crossed”: The head tilts away from the side of the superior oblique palsy, and diplopia worsens when looking away from the side of the superior oblique palsy (i.e., adducting the affected eye).

Cranial Nerve 6: The Abducens Nerve

The abducens nuclei reside in the dorsomedial pons, and the bilateral CN 6 run from their nuclei through the anterior pons, exit anteriorly, and then pass over the clivus, through the cavernous sinus, to the orbits.

An abducens palsy leads to failure to abduct the affected eye (Fig. 11–6). Abduction weakness causes horizontal diplopia that worsens when looking toward the side of the abduction deficit (e.g., a right-sided CN 6 palsy will cause diplopia when looking to the right, which requires right eye abduction). If there are no other cranial nerve or extraocular muscle deficits, looking away from the side of the deficit should lead to complete resolution of double vision, since adduction and contralateral eye abduction are spared. If a CN 6 palsy causes complete paralysis of the lateral rectus, the affected eye may be misaligned medially at rest with no lateral movement of the eye on attempted gaze toward the affected side. With partial weakness, the eye may be able to abduct only partially, allowing some of the lateral sclera to remain visible on attempted lateral gaze (called inability to “bury the sclera”).

CN 6 has a long and tortuous intracranial course that takes it over the clivus. Like CNs 3 and 4, the length of CN 6 makes it susceptible to trauma. CN 6 infarct, most commonly due to diabetes, is another common cause of unilateral CN 6 palsy. Unilateral or bilateral CN 6 palsy can also occur when intracranial pressure is elevated since this pressure leads to stretching of the nerve(s) (see Ch. 25). This is sometimes referred to as a “false localizing” sign since it is a focal deficit that may not necessarily be caused by a focal lesion.

If CN 6 and CN 7 are affected on the same side, this suggests pontine localization since the CN 6 and CN 7 nuclei are adjacent in the pons. With a larger unilateral pontine lesion, contralateral hemiparesis may accompany CN 6 and CN 7 lesions (due to involvement of the not-yet-crossed corticospinal tract). If CN 6 is affected with CN 3 and/or CN 4 without involvement of CN 2, localization of the lesion in the cavernous sinus should be considered. Involvement of CNs 3, 4, and/or 6 and CN 2 suggests localization in the orbit.

The ocular motor nuclei of CNs 3, 4, and 6 for the two eyes must be coordinated for conjugate binocular movements such as horizontal gaze, vertical gaze, convergence, and divergence. These conjugate movements are under the control of gaze centers in the brainstem, which in turn are under the control of higher cortical centers.

Rapid conjugate eye movements to a target are called saccades, which are tested by having the patient look rapidly from one place to another (for example, from the examiner’s nose to the examiner’s finger held out to one side or above or below the eyes). Conjugate eye movements that track an object are called smooth pursuit movements, which are tested by asking the patient to follow the examiner’s finger. Saccades may occur voluntarily (a conscious decision to look at something), or can occur involuntarily (e.g., eyes move reflexively in the direction of a loud noise). The frontal eye fields initiate intentional saccades, and the parietal eye fields are involved in reflex saccades and smooth pursuit. This is logical if one recalls that intentional actions originate in the frontal lobes, whereas spatial attention is supported by the parietal lobes (see Ch. 7).

Optokinetic Reflex

The saccadic (frontal) and smooth pursuit (parietal) systems can be tested by evaluating the optokinetic reflex (Fig. 11–7). An optokinetic nystagmus (OKN) strip typically has vertical alternating white and red stripes, and an OKN drum typically has vertical alternating white and black stripes. When an OKN strip is moved across the visual field in one direction (or an OKN drum is rotated in one direction), the eyes follow it in the direction it is moving. However, in order for the patient to continue following it, the patient must make saccades in the direction opposite the direction of movement of the strip/drum (like when watching trees pass by out of the window of a train). For example, when moving the OKN strip from left to right (or spinning the OKN drum from left to right), the eyes follow smoothly to the right with interrupting saccades back to the left. The pursuit in the direction that the OKN strip is moving/drum is turning is supported by the parietal lobe ipsilateral to the direction that the strip is moving/drum is turning (in this example, the right parietal lobe supports rightward smooth pursuit when the OKN strip is moving to the right). The saccades in the opposite direction from the direction of motion of the OKN strip/drum (left in this example) are supported by the frontal lobe ipsilateral to the direction of movement of the OKN strip/drum (in this example, the right frontal lobe generates leftward saccades when the OKN strip is moving to the right).

In addition to utilizing optokinetic nystagmus to localize frontal versus parietal lesions, the optokinetic reflex is very hard to inhibit and, therefore, may be used to distinguish psychogenic blindness from true visual loss.

Horizontal Gaze

The signal to voluntarily move the eyes comes from the frontal eye fields (Fig 11–8). Just as each hemisphere controls the contralateral side of the body and sees the contralateral visual field, the frontal eye fields send the eyes to the contralateral side: The left frontal eye field sends the eyes to the right, and the right frontal eye field sends the eyes to the left.

Horizontal gaze requires synchronizing the eyes for conjugate movements. For example, to look to the left, the left eye must abduct (left lateral rectus controlled by left CN 6) and the right eye must adduct (right medial rectus controlled by right CN 3). To achieve conjugate horizontal gaze, there must be a communication between the CN 6 nucleus on one side and the CN 3 nucleus on the other. This communication is the medial longitudinal fasciculus (MLF), a tract that connects each CN 6 nucleus with the contralateral CN 3 nucleus.

The MLF crosses from the CN 6 nucleus en route to the contralateral CN 3 nucleus almost immediately, spending most of its course contralateral to its point of origin. For this reason, the MLF is named for the side of the CN 3 nucleus with which it connects rather than the CN 6 nucleus from which it originates: The left MLF travels from the right CN 6 nucleus to the left CN 3 nucleus, and the right MLF travels from the left CN 6 nucleus to the right CN 3 nucleus.

The frontal eye fields do not communicate directly with the cranial nerve nuclei but rather through horizontal and vertical gaze centers. These are the centers that communicate with the cranial nerve nuclei, which in turn communicate with each other to synchronize conjugate eye movements. The horizontal gaze center is the paramedian pontine reticular formation (PPRF). There is a left PPRF in the left pons for leftward gaze and a right PPRF in the right pons for rightward gaze. The flow of information for horizontal gaze is from frontal eye fields→contralateral PPRF→CN 6 nucleus→contralateral CN 3 nucleus (via MLF).

For example, to look to the left, the left eye must abduct (left lateral rectus controlled by left CN 6) and the right eye must adduct (right medial rectus controlled by right CN 3). The initial signal to intentionally move the eyes comes from the right frontal eye field and crosses to connect with the left PPRF, which is adjacent to the left CN 6 nucleus. The left PPRF signals the left CN 6 nucleus to activate the left lateral rectus. The left CN 6 nucleus simultaneously communicates to the contralateral (right) CN 3 nucleus by way of the right MLF to signal the right CN 3 to activate the right medial rectus. A lesion of the right frontal eye field, the left PPRF, or the left CN 6 nucleus would, therefore, all lead to impaired left gaze in both eyes. Both eyes are affected because the problem is with gaze in a particular direction rather than a problem with an individual nerve or muscle. In contrast, a lesion of the abducens nerve (CN 6) itself would preclude lateral movement of that eye, but on attempted lateral gaze, the contralateral eye would still be able to adduct.

Conjugate Horizontal Gaze Abnormalities

A patient with a large middle cerebral artery (MCA) stroke that affects the frontal eye field will have gaze deviation toward the hemisphere of the stroke, which is away from the side of the hemiparesis (Fig. 11–9 and Table 11–2). For example, a large right MCA stroke can cause left hemiparesis and right gaze deviation with inability to look to the left. In contrast, patients with unilateral pontine stroke affecting the not-yet-crossed corticospinal tract and the lateral gaze center on one side will be unable to look toward the side of the lesion, which can produce gaze deviation toward the side of the hemiparesis, which is away from the side of the lesion. For example, a right pontine stroke can cause left hemiparesis with gaze deviation to the left and inability to look right. Gaze deviation may also be toward the side of the hemiparesis (and away from the lesion) in thalamic hemorrhage, a phenomenon called “wrong way eyes.”

If seizure activity reaches a frontal eye field and activates it, this will cause the eyes to look contralaterally (i.e., deviate away from the seizure focus and toward the shaking limb if the seizure is focal). When the seizure is over and the seizure focus is in a refractory state, the eyes may deviate toward the focus in the postictal period (which would be away from the side of a Todd’s paralysis, if present).

Dysconconjugate Horizontal Gaze

Internuclear ophthalmoplegia (Fig. 11–10)—A lesion of the MLF impairs the coordination of CN 6 and contralateral CN 3. This leads to inability to adduct the eye on the side of the MLF lesion with gaze in the opposite direction. For example, a lesion of the left MLF causes impaired left eye adduction on rightward gaze. The phenomenon of impaired adduction on horizontal gaze due to an MLF lesion is called internuclear ophthalmoplegia (INO)—internuclear because the lesion of the MLF is between the nuclei of CN 6 and CN 3. In INO, there is often nystagmus in the abducting eye, appearing as though it is “trying to tell the other (non-adducting) eye to come along.”

Consider the example of a lesion of the left MLF. Recall that the MLF is named for the side of the CN 3 nucleus with which it communicates (i.e., not the contralateral CN 6 nucleus where the signal to the CN 3 nucleus originates for conjugate horizontal gaze). Therefore, a lesion of the left MLF is a lesion of the MLF that connects the right CN 6 nucleus with the left CN 3 nucleus. Leftward gaze will be normal since the left CN 6 nucleus, right MLF, and right CN 3 nucleus are not affected (Fig. 11–10A). On rightward gaze, the right eye can abduct, but the right CN 6 nucleus is unable to tell the left CN 3 nucleus to adduct the left eye (Fig. 11–10B). Therefore, the right eye abducts, but the left eye does not adduct. The patient will have double vision worst on right gaze since the eyes become dysconjugate with gaze in that direction when the left eye cannot adduct, and there will be right-beating nystagmus in the right eye on rightward gaze.

INO is seen commonly in multiple sclerosis (since the MLF is a highly myelinated tract and thus prone to the effects of demyelination), but can also be caused by pontine stroke or tumor. INO can also occur bilaterally (most commonly seen in multiple sclerosis). With bilateral INO, patients have no adduction on horizontal gaze to either side, but preserved abduction to both sides.

How can INO be distinguished from simply failure of adduction due to a partial CN 3 palsy or medial rectus problem? In INO, the CN 3 nucleus and nerve are functioning, but they are cut off from their communication with the contralateral CN 6 nucleus. Therefore, if the medial rectus is activated via a different pathway, it will function. This can be demonstrated if convergence (bilateral adduction) is found to be preserved since this activates the third nerve (and nucleus) through an alternative pathway. (Note that skew deviation [see below] can accompany INO, causing vertical dysconjugate gaze in addition to INO. Skew deviation may make it difficult for the patient to converge.)

One-and-a-half-syndrome (Fig. 11–11)—The PPRF, CN 6 nucleus, and MLF are all very close to each other. If the PPRF and/or CN 6 nucleus and the already-crossed MLF are affected together on one side, this has two consequences:

1. Ipsilateral conjugate gaze is impaired due to the lesion of the PPRF and/or CN 6 nucleus.

2. Adduction of the ipsilateral eye on contralateral gaze is impaired since the MLF that has crossed over from the contralateral CN 6 nucleus en route to the CN 3 nucleus on the side of the lesion is unable to signal CN 3 to adduct.

For example, a lesion of the right PPRF and/or CN 6 nucleus and the right MLF (i.e., the MLF that crossed over from the left CN 6 nucleus en route to the right CN 3 nucleus) will cause:

• Loss of conjugate horizontal gaze to the right (due to the lesion of the right PPRF and/or right CN 6 nucleus)

• Loss of right eye adduction on left gaze (due to the lesion of the right MLF, which connects the left CN 6 nucleus to the right CN 3 nucleus)

This leaves only one horizontal movement: abduction of the eye contralateral to the lesion on contralateral gaze (because the contralateral PPRF and CN 6 nucleus are spared). In the above example, out of all of the horizontal eye movements, only left eye abduction is preserved. This syndrome is called one-and-a-half syndrome since three “half-movements” are impaired, where each “half” is one direction of horizontal gaze (left eye abduction + left eye adduction + right eye abduction + right eye adduction).

WEBINO (Fig. 11–12)—If a lesion affects both MLFs, there will be no adduction of either eye on horizontal gaze in either direction (bilateral INO). In some such cases, the eyes are abducted in primary gaze (exotropic), causing a “wall-eyed” appearance. This constellation of findings is called wall-eyed bilateral INO, or WEBINO. As with INO, multiple sclerosis and stroke are the most common causes.

Vertical Gaze

Vertical eye movements are controlled by two brainstem nuclei, the rostral interstitial nucleus of the MLF and the interstitial nucleus of Cajal, both located in the dorsal midbrain close to the CN 3 and CN 4 nuclei, as would be expected (CN 6 does not participate in vertical gaze). Like the brainstem horizontal gaze centers, these nuclei are under the control of the cortical eye fields.

Impaired conjugate vertical gaze can be caused by lesions of the dorsal midbrain or in the region of the fourth ventricle (e.g., pineal pathology, tectal glioma, hydrocephalus with expansion of the fourth ventricle) and neurodegenerative diseases (e.g., progressive supranuclear palsy; see Ch. 23). Upgaze limitations may be seen in otherwise normal in elderly patients. Pathology that compresses the dorsal midbrain can cause a constellation of ocular motor findings known as Parinaud’s syndrome:

• Impaired upgaze with downgaze preference

• Light-near dissociation of pupillary reactions (constriction on accommodation but not in response to light)

• Eyelid retraction (called Collier’s sign), causing a wide-eyed appearance to the eyes

• Convergence-retraction nystagmus, in which the eyes are pulled medially and retracted inward. This can be brought out in upward gaze

Skew deviation

A common dysconjugate vertical gaze palsy not caused by a CN 3 or CN 4 lesion is skew deviation. Skew deviation is caused by a unilateral lesion in the vestibular pathways (CN 8, brainstem, or cerebellum; see Ch. 12). Most commonly, skew deviation is caused by a central lesion (i.e., in the brainstem or cerebellum) rather than a peripheral lesion (i.e., in CN 8). In skew deviation, the eyes are misaligned vertically (one higher than the other), and which eye is higher may change in different positions of gaze. In some patients with skew deviation, an ocular tilt reaction is also present: The asymmetric disruption in vestibular function leads the brain to think that the head is tilted when it is not, so the eyes assume positions as if the head were tilted to the side of the lesion (i.e., eye on the side of the lesion higher and intorted).

There is no vertical gaze correlate to the INO, although a vertical-one-and-a-half syndrome has been rarely reported.

Supranuclear Versus Nuclear/Infranuclear Lesions Affecting Eye Movements

Lesions in the frontal eye fields and brainstem gaze centers that control the cranial nerve nuclei are referred to as supranuclear lesions. Supranuclear lesions lead to problems with gaze in both eyes rather than in just one eye because the gaze centers are responsible for bilateral conjugate gaze. Another system that interfaces with the brainstem horizontal and vertical gaze centers is the vestibular system. To maintain ocular fixation with head movement, the eyes have to move in the opposite direction of the head (the vestibulo-ocular reflex [VOR]). This is accomplished by transmitting information from the inner ear to the brainstem via CN 8, and then to the cranial nerve nuclei for CNs 3, 4, and 6 by way of the MLF. This pathway is discussed in Chapter 12. Here, the vestibulo-ocular reflex is introduced because of its utility in localizing a gaze palsy as supranuclear or nuclear/infranuclear.

If a gaze palsy is supranuclear, the gaze palsy can often be overcome by passive head movement because the VOR pathway goes straight from the vestibular nuclei to the CNs 3, 4, and 6 nuclei, bypassing the supranuclear control systems (i.e., bypassing PPRF, rostral interstitial nucleus of the MLF, interstitial nucleus of Cajal). If a gaze palsy is caused by a lesion in CNs 3, 4, and/or 6 (or one or more of their nuclei), it cannot be overcome by passive head movement because the nerves/nuclei are not able to respond to the vestibular signals. Vertical gaze abnormalities in neurodegenerative disease are supranuclear and, therefore, can be overcome by the VOR. Supranuclear vertical gaze palsies may also be overcome by lifting the patient’s eyelids while the patient attempts to close the eyes tightly: The upgaze palsy in supranuclear vertical gaze palsies will be overcome by Bell’s phenomenon (spontaneous conjugate elevation of the eyes upon eye closure).

Double vision (diplopia) is most commonly caused by misalignment of the two eyes (strabismus), leading to binocular double vision (i.e., double vision only with both eyes open). In binocular double vision, the double vision resolves if the patient covers either eye. If diplopia is monocular such that the patient sees double when looking out of just one eye, this suggests ocular pathology (usually pathology of the lens).

For diplopia due to ocular misalignment, the potential localization includes:

• The extraocular muscles (e.g., thyroid ophthalmopathy, intraorbital tumor or inflammation, myasthenia gravis)

• CNs 3, 4, and/or 6 (in the subarachnoid space, cavernous sinus, or orbit)

• Pathways for eye movement control in the brainstem and cerebellum

Supranuclear lesions (e.g., PPRF, frontal eye fields) generally do not lead to diplopia since gaze is affected in one particular direction in both eyes symmetrically (skew deviation is an exception in that it is a supranuclear lesion that leads to ocular misalignment).

If diplopia is intermittent rather than constant, this may indicate fatigability of the extraocular muscles, and myasthenia gravis should be considered (see Ch. 29).

In patients with constant binocular diplopia, the clinician must determine which particular muscle(s) is/are affected. Extraocular muscles may either be weak or restricted. For example, inability of one eye to look laterally could be due to weakness of the lateral rectus or restriction of the medial rectus preventing lateral movement. A common cause of restriction of eye movements is thyroid eye disease, in which extraocular muscle inflammation leads to restriction of eye movement. In thyroid eye disease, the rectus muscles are most commonly affected, and among those the inferior rectus is most commonly affected (impeding elevation of the eye). In thyroid eye disease, the examiner will note restriction when attempting to passively move the patient’s globe.

If weakness is the issue, once the weak muscle(s) is/are determined, the problem can be localized to one or more cranial nerves or their pathways in the brain stem. When there is only one muscle involved, diplopia will be worse when looking in the direction of the weak muscle. For example, if the left lateral rectus is weak and the patient attempts to look right, up, or down in midline gaze position, both eyes will move normally. However, when attempting to look left, the right eye will adduct but the left eye will not abduct, leading to increased misalignment of the eyes. Double vision will be worst when looking to the left in this example (i.e., in the direction of the weak muscle).

When the eyes are misaligned at rest or with testing of extraocular movements, the localization can generally be easily deduced by seeing which movements are impaired. This condition is called strabismus or tropia, and the type of tropia is named for the abnormal deviation (i.e., hypertropia for superior deviation, hypotropia for inferior deviation, esotropia for medial deviation, and exotropia for lateral deviation). However, some patients report diplopia but do not have clear misalignment on initial evaluation of the extraocular movements. In such cases, subtle misalignment may be elicited on examination by using the alternate cover test and the Maddox rod. Misalignment elicited with these tests is called phoria (i.e., hyperphoria for superior deviation, hypophoria for inferior deviation, esophoria for medial deviation, and exophoria for lateral deviation).

Alternate Cover Test in the Diagnosis of Diplopia

In the alternate cover test, the examiner moves from covering one of the patient’s eyes to covering the other, looking for subtle movements of each eye as it is uncovered (Fig. 11–13). When the eye is covered, it assumes its most natural position, so if a muscle is weak, that muscle “gives up” all of the extra work it was trying to do to try to overcome its weakness and fixate when the eye was not covered. When uncovered, it must resume its hard work, so it moves once again in the direction of the weakness.

For example, imagine that the right lateral rectus is slightly weak. To try to fixate, the right lateral rectus must work harder than normal because it is weaker. So when the right eye is covered and no longer fixating, the weak right lateral rectus can relax, and the eye moves inward. When uncovered, the weak right lateral rectus must get back to work, and so the eye moves outward. This is an esophoria—an inward deviation when covered (noted by seeing the eye move outward when uncovered). In this scenario, the left (normal) eye will also have an esophoria revealed when uncovered. This is because all of that neural “work” being used to try to maintain the right eye abducting in spite of its weak lateral rectus also gets applied to the left medial rectus for the left eye to look right (a phenomenon called Hering’s law). Therefore, the left eye “overworks” in adduction. So when the left (normal) eye is covered and the right lateral rectus has to work extra hard, the left eye is also working extra hard by overadducting. When the left eye is uncovered and the right eye is covered, the left eye relaxes outward since the extra force applied to the right lateral rectus (and “shared” with the left medial rectus) is relaxed while the right eye is covered. So lateral rectus weakness on either side will cause bilateral esophoria on alternate cover testing.

To determine which eye/muscle is the problem, the alternate cover test is repeated in all of the cardinal positions of gaze. If the degree of phoria(s) is the same in all positions of gaze, this is called a comitant phoria. This generally suggests a congenital misalignment (congenital strabismus). In some patients, a latent congenital phoria becomes symptomatic as patients age (decompensated phoria). In such cases, phorias should be comitant.

If the degree of phoria differs in different positions of gaze, this is called an incomitant phoria and suggests focal weakness of a particular extraocular muscle. In an incomitant phoria, the degree of movement of each eye when it is uncovered worsens when the patient looks in the direction of the weak muscle. Resuming the example above, if there is isolated right lateral rectus weakness, the alternate cover test should reveal the greatest degree of movement of each eye when uncovered when the patient is looking to the right, and there should be less (or no) phoria seen on left gaze (since that movement does not involve the weak muscle in any way).

The Maddox Rod in the Diagnosis of Diplopia

The Maddox rod is a red lens that is placed over the patient’s right eye (by convention) when used in assessing diplopia (Fig. 11–14). When the examiner shines a penlight in the patient’s eyes at a distance, the uncovered (left) eye will see the dot of light, and the Maddox rod converts the light into a red line in the covered (right) eye. The line may be oriented vertically or horizontally depending on how the Maddox rod is held. If the eyes are perfectly aligned, the white light and the red line should overlap perfectly. If there is misalignment, the patient will see the white light and the red line as being separate.

To interpret the pattern of separation of the white dot and red line in patients with ocular misalignment, recall that each part of the retina sees the opposite side of the world: The medial retina sees the lateral visual field, the lateral retina sees the medial visual field, the superior retina sees the inferior visual field, and the inferior retina sees the superior visual field (see Ch. 6). If an eye is deviated, light will hit a different part of the retina than it normally would have. For example, if the eye is medially deviated, light will end up hitting the retina more medially; if the eye is superiorly deviated, light will end up hitting the retina more superiorly. With light hitting the retina in the “wrong place” compared to where it should normally land, the image of the white light will be displaced from the red line. The deviation of the white light will be opposite the deviation of the eye, since each part of the retina sees the opposite part of the visual field. For example, if light hits the left eye more medially, the light will be seen as being more lateral; if light hits the left eye more superiorly, this light will be seen as being more inferior.

For horizontal diplopia, the Maddox rod is used to create a vertical red line so the degree of horizontal separation between the red line and white light can be determined. If there is left lateral rectus weakness, the left eye will be turned slightly medially. This will cause the white light to hit a more medial part of the retina than normally. Since the medial retina sees the lateral visual field, the white light will appear lateral to the red line. This degree of separation will worsen as the patient tries to look in the direction of the weak muscle (in this example, to the left).

For vertical diplopia, the Maddox rod is used to create a horizontal red line so that the degree of vertical separation between the red line and white light can be determined. If there is a left hypotropia (right hypertropia), the white light will hit a more inferior part of the left retina than normally. Since the inferior retina sees the superior visual field, the white light appears above the red line.

With vertical misalignment, it can be challenging to determine which eye is abnormal. For example, if the left eye appears higher, is there a problem with left eye depression (left superior oblique muscle or inferior rectus muscle weakness) or a problem with right eye elevation (right inferior oblique muscle or superior rectus muscle weakness)? The first step is to determine whether the superior oblique is involved. Since the main function of the superior oblique is to intort the eye, the patient may tilt the head away from the affected side, and may have worsening double vision when tilting the head toward the affected side (See “Cranial Nerve 4” above). Recall that the superior oblique muscle depresses the eye in the adducted position. So if this muscle is weak, vertical diplopia should be worse when the affected eye is in the adducted position.

If the left eye appears to be higher, and diplopia worsens on right gaze (or the distance between the red line and white dot increases on Maddox rod testing), this suggests a problem with the left superior oblique. This is because the superior oblique muscle is needed to depress the eye in the adducted position, and so a superior oblique palsy will cause the greatest deviation between the two eyes on attempted downgaze when the affected eye is adducted. Therefore, if there is a left hypertropia/phoria (= right hypotropia/phoria) in which double vision worsens in right gaze, the problem is with the left superior oblique (inability to depress the adducted left eye).

If either the superior rectus or the inferior rectus appears to be affected in isolation, double vision will worsen in the direction of the weak muscle. For example, if a left hypertropia/right hypotropia is due to left inferior rectus weakness, double vision would worsen in down gaze; if a left hypertropia/right hypotropia is due to right superior rectus weakness, double vision would worsen in upgaze.

The superior and inferior recti and the inferior oblique muscles are all controlled by CN 3, so if vertical diplopia is due to a third nerve palsy, it is common to see multiple eye movement abnormalities in the affected eye. If weakness can be isolated to the superior and/or inferior rectus in isolation, extraocular muscle pathology (e.g., thyroid eye disease) or myasthenia gravis should be considered.

A skew deviation can also cause vertical misalignment of the eyes (see “Skew Deviation” above). Unlike unilateral CN 4 palsy, skew deviation is usually comitant (although it can be incomitant), and when the ocular tilt reaction accompanies it, the more elevated eye is intorted. This is in contrast to a CN 4 palsy, in which intorsion is impaired in the hypertropic eye (because CN 4 palsy leads to impaired intorsion and impaired depression).