Ocular Misalignment and Other Ocular Motor Disorders
CRANIAL NERVE III PALSY (OCULOMOTOR NERVE)
Cranial nerve III (CN III) innervates the superior, inferior, medial recti, and the inferior oblique muscles. It also innervates the levator palpebrae superioris and carries with it the parasympathetic innervation to the pupil. Involvement of CN III will produce a symptom complex that involves one or several of these muscles and usually results in double vision.
ANATOMY
The subnuclei that give rise to CN III reside in the midbrain. These subnuclei give rise to the fascicles of each of the extraocular muscles. The superior rectus subnuclei are crossed so that the fibers from the left superior rectus subnucleus eventually innervate the right superior rectus muscle. Another peculiarity of the nuclear structure of CN III is that the nucleus for the upper lids is a single midline structure innervating the levator muscles of both lids. The pupillary constrictor and accommodation muscles are under the control of an ipsilateral subnucleus.
As CN III leaves the brainstem near the medial aspect of the cerebral peduncle and enters the subarachnoid space, it travels between the superior cerebellar artery and the posterior cerebral artery next to the tip of the basilar artery. It then travels medially along the posterior communicating (PCOM) artery and lateral along the internal carotid artery. When the nerve enters the cavernous sinus, it lies in the lateral wall superior to CN IV and then goes through the superior orbital fissure dividing into a superior and an inferior division. The superior division contains the superior rectus and levator innervation, while the inferior division contains the rest of the innervation for CN III including the parasympathetic fibers from the ciliary ganglion. There is convincing evidence that the functional organization into a superior and an inferior division occurs before anatomic division occurs in the cavernous sinus.
ETIOLOGY AND PATHOPHYSIOLOGY
Cranial III neuropathy may be caused by a variety of processes, but the most frequent causes are either microvascular infarction of the nerve itself or compression. Microvascular
infarction occurs in older patients (over 50 years of age) and is due to occlusion of the vasa nervorum. This infarction involves the axial portion of CN III. Since the pupillary fibers are on the periphery of the nerve, the pupil is not usually involved by the axial infarction in microvascular disease. These patients often have identifiable risk factors such as diabetes mellitus, hypertension, atherosclerosis, and hyperlipidemia.
infarction occurs in older patients (over 50 years of age) and is due to occlusion of the vasa nervorum. This infarction involves the axial portion of CN III. Since the pupillary fibers are on the periphery of the nerve, the pupil is not usually involved by the axial infarction in microvascular disease. These patients often have identifiable risk factors such as diabetes mellitus, hypertension, atherosclerosis, and hyperlipidemia.
Compressive CN III palsies may be produced by tumors or aneurysms. The clinical syndrome of aneurysmal CN III palsy is an important one because it is a medical emergency. The patient will usually present with a painful (usually, but not always present) isolated CN III palsy. This is usually due to a PCOM artery aneurysm. The aneurysm exerts pressure from the outside; thus the pupillary fibers are often involved early and the CN III palsy is characterized by ptosis, ocular misalignment, and usually, a dilated pupil.
CLINICAL CHARACTERISTICS
• See Figure 10-1.
Symptoms
• Pain may be present with CN III palsies due to microvascular infarction or compression. It does not distinguish between the two causes.
• Ptosis may be complete or incomplete.
• Diplopia is usually oblique in nature.
Signs
• Ptosis may be complete or incomplete.
• Ophthalmoplegia: There is usually an exotropia in primary position with defective adduction, elevation, and depression of the eye.
• Anisocoria (Fig. 10-2) occurs with compression; otherwise the pupils are normal.
• The presence of anisocoria with a dilated pupil is critical to the diagnosis of aneurysmal CN III palsy. Thus, any patient diagnosed with a lesion of CN III must have the pupil evaluated. The rule of the pupil states that in a complete CN III palsy, the pupil will be normal if the cause is microvascular infarction but will be dilated and less reactive to light if the lesion is compressive, especially by a PCOM aneurysm. There are certain caveats to invoking the rule of the pupil.
It may be invoked only in the presence of a complete CN III palsy. It would be unwise to invoke this rule in incomplete or partial palsies (Fig. 10-3).
It has been reported that the pupil may initially be uninvolved with PCOM aneurysms, with anisocoria developing at any time within 5 days of the start of diplopia.
SYNDROMES ASSOCIATED WITH CN III PALSY
Nuclear III Nerve Lesions
• Nuclear CN III palsies are extraordinarily infrequent (Fig. 10-4 and Table 10-1).
• Ipsilateral CN III palsy, contralateral superior rectus paresis (because the superior rectus (SR) muscle is innervated by contralateral subnuclei), and bilateral ptosis (levators innervated by central midline nuclei)
• Bilateral CN III palsies without ptosis
• Bilateral ptosis alone
• Any isolated palsy of a muscle innervated by CN III
CN III Fascicle Syndromes
• Weber syndrome: Ipsilateral CN III paresis with contralateral hemiparesis (involvement of cerebral peduncle)
• Nothnagel syndrome: Ipsilateral CN III paresis and cerebellar ataxia (involvement of superior cerebellar peduncle)
TABLE 10-1. Midbrain Fascicular Third Cranial Nerve Palsies | |||||||||||||||||||||
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• Benedikt syndrome: Ipsilateral CN III paresis with contralateral hemitremor (involvement of red nucleus)
Lesions in the Subarachnoid Space
• PCOM artery aneurysm: This is the most common cause of an isolated pupil involving CN III palsy with the aneurysm occurring at the junction of the PCOM artery and internal carotid artery.
• Uncal herniation: As CN III travels through the subarachnoid space, it rests on the edge of the tentorium cerebelli with the uncal portion of the temporal lobe above it. A supratentorial mass may cause a downward displacement and herniation of the uncus across the tentorial edge, compressing the nerve. The patient usually has an altered mental status.
Cavernous Sinus Syndrome
• CN III paresis inside the cavernous sinus usually occurs in association with paresis of other CNs (IV, V, or VI).
Orbital Syndromes
• Since CN III divides into a superior and an inferior division as it enters the orbit, involvement in the orbit may result in paresis of structures innervated by either of these divisions.
DIAGNOSTIC EVALUATION
Once CN III palsy has been diagnosed, the next step is to determine whether the palsy is isolated. An associated CN VI deficit is usually easily seen, but an accompanying CN IV palsy may be less obvious. The primary action of CN IV is depression in adduction; however, in the presence of a complete CN III palsy, the eye cannot be adducted to test for CN IV integrity. The determination is made by looking for the secondary action of CN IV, intorsion of the globe. The patient is instructed to look down while the examiner looks for intorsion. Its absence indicates CN IV paresis (Fig. 10-5).
The investigation of an isolated CN III palsy will depend on the age of the patient, the completeness of the palsy, and the state of the pupil. Guidelines for investigations using these factors are in Table 10-2.
• Aneurysms are extraordinarily rare in children under 10 years of age, but ophthalmoplegic migraine is a frequent cause of CN III palsies with pupillary involvement; thus, the rationale for subjecting children with CN III palsies to MRI and MRA, but not catheter angiography.
• Patients in the vasculopathic age range with risk factors and no pupillary involvement require investigation to identify those risk factors if none are known to be present, for example, determination of glucose status and blood pressure. In addition, giant cell arteritis may present with any isolated CN palsy; so the patient should specifically be questioned regarding the signs and symptoms associated with giant cell arteritis. ESR/CRP may be helpful if this diagnosis is considered.
TABLE 10-2. Investigation of Third Cranial Nerve Palsies | ||||||||||||||||||||||||
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• However, if the pupil is involved, the patient should have an urgent MRI/MRA or CT/CTA, and if negative, because the chances of a PCOM aneurysm are still high, we still recommend catheter angiography.
• Patients younger than the vasculopathic age range but older than 10 years require MRI and MRA to rule out tumors or aneurysms even if the pupil is normal. If the pupil is abnormal, however, catheter angiography should be performed even if the neuroimaging is negative. If all imaging tests are unrevealing, then further hematologic and spinal fluid investigations are recommended.
DIFFERENTIAL DIAGNOSIS
• A variety of entities produce ocular motor syndromes that can be confused with complete or partial CN III palsies.
Thyroid eye disease often produces restriction of the inferior rectus muscles. However, typically, medial rectus restriction is also present producing esotropia and not the exotropia of CN III. Lid retraction, if present, and a positive forced duction test help to establish the correct diagnosis (see Fig. 9-7).
Myasthenia gravis (MG) also may simulate any pattern of CN III palsy. The pupil is never involved in MG, and the ptosis and ocular motility disturbances are variable.
Orbital trauma can produce an upgaze defect as the result of entrapment of the inferior rectus muscle or as part of a traumatic orbital apex/superior orbital fissure syndrome (see p. 241). Vertical diplopia can also occur following cataract surgery utilizing retrobulbar anesthesia (Fig. 10-6). The cause of the superior rectus “weakness” is actually trauma to the inferior rectus muscle and/or its nerve by the retrobulbar injection. These misalignments may resolve over several months but at times require corrective surgery.
Orbital inflammation involving the extraocular muscles may resemble partial CN III palsy. Orbital imaging will reveal the true cause of the ocular misalignment (Fig. 10-7).
NATURAL HISTORY
• Vasculopathic CN III palsies will resolve spontaneously over a period of 6 to 12 weeks. It is very uncommon for there to be residual diplopia.
• CN palsies due to compression will resolve if the compression is removed or will resolve in a pattern called aberrant regeneration.
• The conditions that should prompt investigation of a CN III palsy under observation are listed in Table 10-3.
ABERRANT REGENERATION OF CN III
Aberrant regeneration of CN III (Fig. 10-8), a stereotypic pattern, most often follows an acute CN III palsy due to a PCOM aneurysm or pituitary apoplexy. The ptosis resolves completely or is minimally evident. The eye usually will not elevate or depress well, but adduction usually is restored. Aberrant regeneration can be either lid-gaze dyskinesis or pupil-gaze dyskinesis. In pupil-gaze dyskinesis, some of the medial rectus fibers innervate the pupillary sphincter so that there is more pupil constriction on adduction than to light stimulation (a pseudo-Argyll Robertson pupil). With lid-gaze dyskinesis some of the inferior rectus or medial rectus fibers innervate the levator so that the upper lid elevates on adduction and downgaze fissure. This widening of the interpalpebral fissure on downgaze is known as the pseudo-Graefe sign.
TABLE 10-3. When to Investigate a Cranial Nerve III Palsy Under Observation | |||||
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Aberrant regeneration is a pattern of resolution in compressive or traumatic CN III palsies. It should never be attributed to vasculopathic CN III palsy.
Primary Aberrant Regeneration
Some patients never experience acute CN III palsy but develop a slowly progressive form of CN III aberrant regeneration. Slow growing compressive lesions, usually within the cavernous sinus, produce this syndrome. These lesions are usually meningiomas or cavernous sinus aneurysms, although other causes have been reported.
 FIGURE 10-1. Left upper lid ptosis is almost complete (A) and there is exotropia when the left lid is elevated (B) (top row). There is exotropia of the left eye in primary position. (C) The left eye cannot be elevated (D), adducted (E), or depressed (F). The pupils are equal in size. |
 FIGURE 10-2. Patient has right CN III palsy with a dilated pupil. |
 FIGURE 10-3. A. There is small left exotropia and hypertropia in primary gaze with the right eye fixing and slight ptosis of the right upper lid (middle photograph). Upgaze is minimally less OD. The pupils are equal (upper photograph). MRI, MRA, and lumbar puncture were normal, but because of the patient’s young age and the presence of headaches, catheter arteriography was done and revealed a right PCOM aneurysm (B, arrow). |
 FIGURE 10-4. A. Nuclear III palsy with bilateral ptosis, B. exotropia in primary position, and C, D. inability of any eye movement except abduction OU. |
 FIGURE 10-4. (Continued) E. There is no vertical movement. F. Both pupils are dilated and nonreactive to light. |
 FIGURE 10-5. Patient has a right pupil involving CN III following trauma. Note that the conjunctival blood vessel below the right upper lid is in the same position on both up- and downgaze. This lack of intorsion on attempted downgaze indicates a paresis of CN IV. |
 FIGURE 10-6. Vertical diplopia appeared after cataract surgery OD with retrobulbar anesthesia. Right upper lid ptosis and poor upgaze (A) improved over several months (B). |
 FIGURE 10-7. A. Diplopia present on downgaze due to the inability to depress the left eye. B. Coronal MRI scan reveals enlargement and increased enhancement of the left superior rectus, levator complex (arrow). The forced duction test was positive. |
 FIGURE 10-8. There is no ptosis (A), and normal abduction of OS (B). There is mild limitation in adduction of OS (C). There is some limitation of elevation of OS (D). The left upper lid elevates on downgaze (E) and OS shows some limitation of downgaze. (F). The left pupil is larger and does not constrict to light (G) but does so on adduction and depression of OS. (H) The patient had pituitary apoplexy 6 months before with a complete CN III palsy OS. |
CRANIAL NERVE IV PALSY
Cranial nerve IV (CN IV) innervates only the superior oblique muscle, which depresses the eye in adduction and intorts the eye. CN IV is the only CN that exits the brainstem dorsally, and it has the longest intracranial course. It also decussates so that the right nucleus of CN IV will eventually innervate the left superior oblique muscle. CN IV is enveloped in the anterior medullary velum where it is vulnerable to head trauma.
ETIOLOGY
• Head trauma
• Microvascular infarction
• Congenital
• Other causes such as tumors, multiple sclerosis, and inflammation are less frequent
CLINICAL CHARACTERISTICS
Symptoms
• Diplopia is oblique in nature
• Difficulty in reading or walking down stairs
Signs
• Vertical misalignment: The ocular misalignment is usually a hypertropia ipsilateral to the side of the CN involvement. It is worse on gaze to the contralateral side and on ipsilateral head tilt. (For example, a right CN IV palsy produces a right hypertropia worse in left gaze and right head tilt.) The method to most easily detect this misalignment is the Parks Three-Step Test, which determines by using coveruncover test whether (Fig. 10-9)
there is a hypertropia in primary position
the hypertropia increases in left or right gaze
the hypertropia increases on head tilt (Bielschowsky head-tilt test)
• The head is tilted away from the side of the CN palsy. The chin may be depressed (Fig. 10-10A).
• Elevation in adduction of the ipsilateral inferior oblique muscle, the antagonist of the paretic superior oblique muscle, is demonstrable (Fig. 10-10B).
• Excyclotorsion may be documented using the following:
The double Maddox rod or Lancaster red-green glasses (Fig. 10-10C)
Ophthalmoscopy: Normally, the fovea is 0.3 mm below imaginary line drawn through the geometric center of the optic disc. With direct ophthalmoscopy, the fovea will appear lower if excyclotorsion is present (Fig. 10-11). However, with indirect ophthalmoscopy the fovea appears higher than the optic nerve.
• Vertical fusional amplitude: The normal vertical fusional range is 1 to 3 prism diopters. Patients with a congenital CN IV palsy have an increased range of fusional amplitudes.
SYNDROMES ASSOCIATED WITH CN IV PALSY
• Nuclear-fascicular lesions: CN IV palsy with a contralateral Horner syndrome since the sympathetic pathways descend through the midbrain adjacent to the trochlear fascicles.
• Subarachnoid space lesions: Usually produces an isolated CN IV palsy; bilateral CN IV palsies may occur when the site of injury is at the anterior medullary velum.
• Cavernous sinus lesions: CN IV palsy is seen in combination with CN III palsy. To diagnose CN IV paresis, the patient should be
instructed to abduct the eye and then asked to look down. The ability of the eye to intort in this position is an indication of intact CN IV function.
instructed to abduct the eye and then asked to look down. The ability of the eye to intort in this position is an indication of intact CN IV function.
• Orbital lesions: In the orbit, CN IV palsy occurs in conjunction with other CN palsies as well as other features of orbital disease such as proptosis, chemosis, or conjunctival injection.
DIAGNOSTIC EVALUATION
In the presence of isolated CN IV palsy, a history of head trauma should be sought. In the absence of history of head trauma, isolated CN IV palsy in a patient over 50 years of age is assumed to be vasculopathic in nature. Patients younger than the vasculopathic age group should undergo neuroimaging. Patients over the age of 55 years should be investigated for giant cell arteritis. Congenital CN IV palsies may become manifest later in life. These patients complain of intermittent diplopia that becomes more frequent and more prolonged. Examination reveals increased vertical fusional amplitudes, which establishes the diagnosis of a congenital process. Examining old family photographs likewise may reveal a long-standing head tilt, another clue to the congenital nature of the strabismus. In patients with increased vertical fusional amplitudes, no further investigations are required. Vertical fusional amplitudes should be measured in all patients with CN IV palsy.
NATURAL HISTORY
• Patients in the vasculopathic age group with an isolated CN IV palsy and normal vertical fusional amplitudes require investigation for risk factors (e.g., diabetes mellitus and hypertension). These patients may then be observed since most of these palsies will resolve spontaneously within 6 to 12 weeks.
• Patients with traumatic CN IV palsies may also be observed. The misalignment, however, may take longer to resolve.
TREATMENT
• Prisms may be tried, but because of the incomitant and at times the torsional nature of this ocular misalignment, they are often not successful. Surgical realignment of the eyes is often the final solution for these patients.
BILATERAL CN IV PALSIES
Trauma often produces bilateral CN IV palsies. The bilaterality of the process may be masked and patients will sometimes appear to have a unilateral palsy. Clues to bilateral involvement include the following:
• Large cyclorotational misalignment: Patients with an apparent “unilateral” CN IV palsy but with excyclotorsion greater than 10 degrees should be suspected of having bilateral CN IV palsies.
• V-pattern esotropia
• Alternating hypertropia (right hypertropia on left gaze and left hypertropia on right gaze)
SKEW DEVIATION
Askew deviation is a vertical/torsional strabismus caused by a supranuclear lesion which must be differentiated from CN IV palsy. It is usually caused by a lesion in the prenuclear vestibular inputs to the oculomotor nuclei. It may be part of a full ocular tilt reaction (see below). Characteristics of a skew deviation include the following:
• Comitant or incomitant vertical misalignment
• With lower brainstem lesions the ipsilateral eye is usually hypotropic while with pons or
midbrain lesions the ipsilateral eye is hypertropic. An alternating skew is characteristic of cerebellar degeneration with the abducting eye being hypertropic.
midbrain lesions the ipsilateral eye is hypertropic. An alternating skew is characteristic of cerebellar degeneration with the abducting eye being hypertropic.
• The upright-supine test: A vertical deviation that decreases by 50% from the upright to supine position suggests skew deviation.
• Rarely, it may alternate with eye position so that there is right hypertropia in right gaze and left hypertropia in left gaze.
• Skew deviation may be associated with the ocular tilt reaction which is the triad of the following:
 FIGURE 10-9. A. There is an intermittent left hypertropia of 10 PD in primary gaze. B. It increases dramatically in right gaze due to elevation in adduction of the left inferior oblique muscle, left gaze is normal. It is larger on left (D) than on right head tilt (E). |
Skew deviation
Ocular torsion—such that the upper poles of both eyes rotate in the same direction as that of the head tilt (i.e., the hypotropic eye is excyclotorted and the hypertropic eye incyclotorted). This is the opposite of the physiologic counterroll during which the upper poles of both eyes rotate in the opposite direction to that of the head tilt.
Head tilt—the pathologic head tilt is ipsilateral to the hypotropic eye.
 FIGURE 10-10. A. Patient with right CN IV palsy with a left head tilt and a chin down position. B. Right gaze is normal but there is marked elevation in adduction of the right inferior oblique muscle in left gaze. C. Excyclotorsion is measured with the double Maddox rod. |
 FIGURE 10-11. Fundus photograph shows the normal position of the macula in relation to the optic disc in the right eye (left) and the lower position of the macula in the extorted left eye (right) of a patient with a left CN IV palsy.
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