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).
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).
Schematic of optokinetic nystagmus induced by OKN drum. A: OKN drum rotated toward patient’s right leads to right-ward smooth pursuits and left-ward saccades (B). Reproduced with permission from Martin T, Corbett J: Practical Neuroophthalmology. New York: McGraw-Hill Education; 2013.
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.
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.
Schematic of the pathway for conjugate horizontal gaze to the left. See text for explanation. PPRF: paramedian pontine reticular formation. VN: vestibular nucleus. MLF: medial longitudinal fasciculus. Reproduced with permission from Ropper A, Samuels M, Klein J: Adams and Victor’s Principles of Neurology, 10th ed. New York: McGraw-Hill Education; 2014.
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.”
Gaze deviation in stroke and seizure. A: Gaze deviation in right MCA stroke. The patient has right gaze deviation and a left hemiparesis. B: Gaze deviation in right pontine stroke: the patient has left gaze deviation and a left hemiparesis. C: Gaze deviation in focal seizure originating in the right hemisphere: the patient has left gaze deviation and left-sided tonic-clonic movements. Reproduced with permission from Aminoff M, Greenberg D, Simon R: Clinical Neurology, 9th ed. New York: McGraw-Hill Education; 2015.
TABLE 11–2Gaze Deviation in Stroke And Seizure. ||Download (.pdf) TABLE 11–2 Gaze Deviation in Stroke And Seizure.
| || |
(Frontal Eye Field Affected)
(Lateral Gaze Center Affected)
(Frontal Eye Field Affected)
|Direction of gaze deviation ||Toward lesion ||Away from lesion || |
Away from lesion
(May be toward lesion in postictal state)
|Away from hemiparesis ||Toward hemiparesis || |
Toward shaking limb(s)
(May be away from Todd’s paralysis in postictal state, mimicking stroke)
TABLE 11–3Summary of findings in conjugate and dysconjugate gaze abnormalities. ||Download (.pdf) TABLE 11–3 Summary of findings in conjugate and dysconjugate gaze abnormalities.
| ||Effects of lesion ||Left-sided lesion ||Right-sided lesion |
|Frontal eye field ||Conjugate movements away from lesion impaired; deviation toward lesion ||Left gaze deviation ||Right gaze deviation |
|PPRF ||Conjugate movements impaired toward side of lesion; deviation away from lesion ||No left gaze; right gaze deviation ||No right gaze; left gaze deviation |
|Abducens Nucleus ||Conjugate movements impaired toward side of lesion; deviation away from lesion ||No left gaze; right gaze deviation ||No right gaze; left gaze deviation |
|Abducens Nerve ||Dysconjugate with failure to abduct affected eye ||On left gaze, right eye adducts, left eye does not abduct ||On right gaze, left eye adducts, right eye does not abduct |
|MLF || |
• Dysconjugate with failure to adduct one of the eyes on contralateral gaze; all other horizontal movements preserved
• Convergence may be spared
|On right gaze, right eye abducts, left eye does not adduct; right (abducting) eye often has right-beating nystagmus ||On left gaze, left eye abducts, right eye does not adduct; left (abducting) eye often has right-beating nystagmus |
|PPRF or CN 6 nucleus and MLF ||One-and-a-half syndrome: Contralateral abduction is the only functioning horizontal movement ||No movement of either eye on attempted left gaze; on right gaze, right eye abducts, but left eye does not adduct ||No movement of either eye on attempted right gaze; on left gaze, left eye abducts, but right eye does not adduct |
|Bilateral MLF ||Bilateral INO: No adduction in contralateral gaze in either eye ||On attempted gaze in either direction, abducting eye abducts, but contralateral eye does not adduct. In some cases eyes may appear abducted bilaterally at baseline (WEBINO). |
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.”
Left internuclear ophthalmoplegia in a patient with multiple sclerosis. A: Left gaze is normal. B: On attempted rightward gaze, the left eye does not adduct. Reproduced with permission from Hauser A, Josephson S: Harrison’s Neurology in Clinical Medicine, 3rd ed. New York: McGraw-Hill Education; 2013.
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:
Ipsilateral conjugate gaze is impaired due to the lesion of the PPRF and/or CN 6 nucleus.
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.
One-and-a-half syndrome in a patient with multiple sclerosis. A: On attempted right gaze, neither eye moves. B. On attempted left gaze, the left eye abducts, but the right eye does not adduct. This is consistent with a lesion in the right PPRF and/or CN 6 nucleus as well as the right MLF. Reproduced with permission from Martin T, Corbett J: Practical Neuroophthalmology. New York: McGraw-Hill Education; 2013.
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.
Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a patient with pontine stroke. At baseline (B), the patient’s eyes appear bilaterally abducted (“wall-eyed”). On attempted right gaze (A), the right eye abducts, but the left eye does not adduct, consistent with left INO due to involvement of the left MLF. On attempted left gaze (C), the left eye abducts, but the right eye does not adduct, consistent with right INO due to involvement of the right MLF. Reproduced with permission from Martin T, Corbett J: Practical Neuroophthalmology. New York: McGraw-Hill Education; 2013.
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
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).