CN-III begins at its nucleus in the midline upper midbrain. The nucleus is a lepidopteroid collection of nine subnuclei located in the center of the rostral midbrain at the level of the superior colliculi (Fig. 5-1). The most ventral of these subnuclei is the central caudate nucleus, a midline structure that innervates both levator palpebrae muscles. Uniquely, axons from the medial subnuclei or columns decussate completely to innervate the contralateral superior rectus muscles. The other six subnuclei, three left-and-right pairs, innervate ipsilateral extraocular muscles. The ventral subnucleus, intermediate column, and dorsal subnucleus, respectively, control the medial rectus (eye adduction), inferior oblique (intorsion and some elevation), and inferior rectus (depression).

Figure 5-1 Oculomotor (III), Trochlear (IV), and Abducent (VI) Nerves: Schema.

Sometimes considered a subnucleus of CN-III, the Edinger–Westphal nucleus abuts the others rostrodorsally, residing at the ventral edge of periaqueductal gray matter. The Edinger–Westphal nucleus supplies the cholinergic efferents producing pupillary constriction and ciliary muscle contraction (lens accommodation). Afferents from the pretectal nuclei mediate the pupillary light reflex, whereas inputs influencing pupil constriction and lens accommodation in response to near visual stimulus originate from striate and prestriate cortex and the superior colliculus. When the pupillary fibers join the oculomotor nerve, they move exteriorly and dorsally within the nerve, a clinical continuation of the spatial relation of the Edinger–Westphal nucleus to CN-III.

The CN-III nucleus receives numerous afferents, including inputs from the paramedian pontine reticular formation for horizontal eye movement, the rostral interstitial nucleus of the medial longitudinal fasciculus for vertical and torsional movements, and the vestibular nuclei. Other afferents come from the superior colliculi, the occipital cortex, and the cerebellum.

Axons from the CN-III nucleus gather into a fascicle that sweeps ventrally in an arc curving toward the medial surface of the cerebral peduncle, then passes through the red nucleus.

The nascent oculomotor nerve emerges from the medial surface of the cerebral peduncle to enter the interpeduncular cistern. It crosses the cistern for approximately 5 mm, passing under the posterior cerebral artery. The fibers subserving pupillary constriction are located externally at the caudal aspect of the nerve and are less prone to microvascular changes as deeper fibers are. This arrangement is thought to explain the pupil’s resilience to ischemia affecting CN-III and to its susceptibility in compression. The nerve follows beneath the posterior communicating artery (p-com) for 10 mm and then pierces the dura underneath the p-com before it passes the internal carotid artery (ICA) en route to the cavernous sinus.

The cavernous sinus is part of the intracranial venous system. It receives blood from the ophthalmic vein and sphenoparietal sinus, transmitting this flow to the superior and inferior petrosal sinuses. The left and right cavernous sinuses are connected via the intracavernous plexus; they also communicate with the basilar sinus and the pterygoid and foramen ovale plexuses. The cavernous sinus resides lateral to the pituitary gland, resting atop the roof and lateral wall of the sphenoid sinus. Besides venous blood, the space contains the intracavernous portions of CN-III, -IV, and -VI; the ophthalmic branch of CN-V and its maxillary nerve posteriorly; the ICA; and the sympathetic nerve fibers investing the adventitia of the ICA. CN-III, -IV, and -VI and the ophthalmic nerve all leave the cavernous sinus to enter the orbit via the superior orbital fissure.

Given the confluence of multiple structures into this relatively small sinus, cavernous lesions are prone to produce multiple cranial nerve palsies often with pain or numbness in the ophthalmic distribution of CN-V. If the pathologic process is extensive, signs of venous obstruction in the orbit also develop (proptosis and chemosis).

CN-III typically divides into superior and inferior branches within the anterior cavernous sinus, thus entering the orbit as two distinct structures. The superior branch supplies the superior rectus and levator palpebrae muscles. The inferior branch provides somatic innervation to the medial and inferior recti and the inferior oblique, and it supplies the parasympathetic pupillary input to the ciliary ganglion, located superolaterally to the optic nerve. The parasympathetic axons from the Edinger–Westphal nucleus synapse here, with the postsynaptic neurons providing visceral motor control to the iris sphincter and the ciliary muscles via the short ciliary nerves.

Etiology and Pathogenesis

Etiologies for CN-III are broadly divided into two groups: those due to microvascular nerve infarction (e.g., diabetes mellitus) and those due to compression. There are also other, less frequent etiologies.

In the patient presenting with acute, severe headache and pupil-involved CN-III palsy, an expanding aneurysm, usually of the posterior communicating artery (p-com), is the most important cause (Fig. 5-2). The location of these aneurysms is the origin of p-com at the ICA (Fig. 5-3) and 90% of these aneurysms present with CN-III palsy. Aneurysm in other nearby arteries can likewise present as CN-III palsy, with up to 30% of acquired CN-III palsies being caused by aneurysms.

Figure 5-2 Ophthalmologic Manifestations of Cerebral Aneurysms.

Figure 5-3 Aneurysms Causing Oculomotor Nerve Palsy.

However, the majority of acquired CN-III palsies will be due to vascular compromise of some portion of CN-III, commonly affecting patients with known risk factors for vasculopathy or microvascular disease. In 60–80% of microvascular CN-III palsy cases the pupil is spared. Typically, these palsies have a favorable prognosis and uncomplicated recovery within 2–4 months. Although common vasculopathies secondary to diabetes and hypertension are seen most frequently, attention should be paid to the possibilities of other systemic vasculitides, temporal arteritis, clotting disorder, and infiltrative processes.

Third-nerve palsies due to lesions of the nucleus or fascicle within the midbrain are usually part of a larger midbrain syndrome (see below). The usual etiologies of such palsies are stroke for older patients and inflammatory or demyelinating disease (i.e., multiple sclerosis) in the young.

Open or closed head injuries may lead to traumatic oculomotor nerve palsy. The suspected mechanism is traction or shearing where the third-nerve root is relatively fixed at its origin and at its entrance into the dura.

Typically, traumatic CN-III palsy is associated with severe frontal deceleration impact with loss of consciousness and, usually, skull fracture (e.g., unrestrained occupant in a motor vehicle accident). In cases where pupil-involving CN-III palsy is discovered after seemingly trivial injury, neurovascular imaging to detect a possible underlying skull base tumor, often meningioma, or aneurysms should be performed.

Cavernous sinus thrombosis may produce a cranial polyneuropathy that features CN-III palsy. Often it is a septic complication of central facial cellulitis and a dreaded clinical entity typically producing proptosis, ophthalmoplegia, and optic neuropathy. Septic phlebitis of the facial vein or pterygoid plexus is the usual intermediary between cellulitis and infectious thrombosis.

Tolosa–Hunt syndrome is a painful ophthalmoplegia caused by idiopathic cavernous sinus inflammation, with most instances considered within the spectrum of inflammatory pseudotumor. It typically involves multiple cranial nerves and varies in degree over days. MRI of the cavernous sinus is needed to confirm the diagnosis, and treatment with high-dose corticosteroids is indicated once tumor and infection have been excluded.

Intrinsic, extrinsic, and metastatic tumors can cause third-nerve palsy. Carcinomatous or granulomatous meningitis can affect multiple cranial nerves in succession, often simulating Tolosa–Hunt syndrome.

Clinical Presentations

The classic presentation of a complete CN-III palsy is unmistakable: because of the unopposed actions of the superior oblique and lateral rectus muscles, the eye is turned outward and usually down. Upper-lid ptosis often requires that the lid be held up by the examiner to assess ocular motility.

The presence or absence of ipsilateral mydriasis (“pupil-involvement” or “pupil-sparing,” respectively) has traditionally been considered a major diagnostic consideration. CN-III palsies of compressive origin have pupillary involvement in the vast majority of cases and, if acute with severe headache, strongly suggest aneurysm as the etiology. Pupil-sparing usually implies temporary CN-III palsy due to microvascular ischemia. Patients with microvascular oculomotor palsy may report a mild ache in the ipsilateral brow, but occasionally the pain can be severe.

Motor involvement of CN-III palsies are generally characterized as complete, incomplete (where the innervated muscles show subtotal palsy), and, since the CN-III divides into superior and inferior rami just before its entrance into the orbit, divisional. “Superior division” CN-III palsy involves ipsilateral dysfunction of the superior rectus and levator palpebrae muscles, whereas an “inferior division” palsy has impaired downgaze, medial gaze, and on occasion, loss of pupillary constriction. Divisional palsies would seem to imply an orbital or anterior cavernous sinus pathologic site; however, more proximal intracranial disease is often responsible. Many cases will have negative imaging and recover well, and are then assumed microvascular in etiology.

Incomplete CN-III palsies show partial losses of up-, down-, and medial-gaze, along with partial ptosis with some CN-III-innervate muscles more affected than others. In such cases—as the clinical vignette illustrates—recognition that the patient’s ocular misalignment is a form of third-nerve palsy can be challenging. It is generally agreed that the presence of the pupil-sparing in such cases does not rule out compressive etiology.

A patient with an isolated medial rectus dysfunction (inability to adduct the eye) should not be considered to have an incomplete CN-III palsy. Most often, this condition is caused by internuclear ophthalmoplegia (see below). It may also be seen in cases of myasthenia gravis or from orbital disease involving the horizontal rectus muscles.

When the origin of third nerve palsy is at the nucleus, the presentation is one of ipsilateral medial rectus, inferior rectus, and inferior oblique dysfunction, with contralateral superior rectus weakness because of the decussation of axons from the medial column subnucleus. Because of bilateral lid innervation by the central caudate subnucleus, the eyelids exhibit either bilateral blepharoptosis or are normal, depending on the extent of the insult. In clinical practice, such cases are exceedingly rare.

With insult to the third-nerve fasciculus, clinical localization is often aided by the presence of other signs of midbrain dysfunction. CN-III fasciculus lesions at the red nucleus present as oculomotor palsy with crossed hemitremor, Benedikt syndrome. If the lesion extends to the medial lemniscus, there is also contralateral hypesthesia. Similar lesions with caudal extension into the brachium conjunctivum produce ipsilateral cerebellar ataxia or Claude syndrome. When damage extends ventrally into the basis pedunculi and the corticospinal tract, hemiplegia contralateral to the CN-III palsy occurs (Weber syndrome).

In comatose patients, unilateral mydriasis (“blown” or Hutchinson pupil) is indicative of supratentorial increased intracranial pressure (ICP), sufficient to force the uncus of the temporal lobe laterally and caudally to compress the third nerve against the anterior edge of the tentorial foramen (uncal herniation). In fact, using oculocephalic maneuvers, additional evidence of compressive CN-III palsy can be uncovered. Pupil checks and oculocephalic maneuvers need to be monitored frequently in any unresponsive patient, since uncal herniation can be rapidly fatal if not detected and addressed at its earliest sign. The laterality of the blown pupil does not always correlate with the side of the lesion.

Although a few cases exist of mydriasis as a possible sign of compressive third-nerve palsy in patients who are awake and alert, this remains exceedingly unlikely without evolving signs of altered consciousness and usually indicates another etiology, such as pharmacologic pupillary mydriasis or Adie tonic pupil (below).

Whereas microvascular CN-III palsy is generally followed by full recovery, the prognosis for traumatic or postoperative compressive CN-III palsy is guarded. If recovery occurs, it is usually marked by aberrant regeneration and synkinesis. The best-known example is the pseudo–von Graefe sign: the branch of CN-III that normally innervates the inferior rectus now synkinetically innervates the levator palpebrae, causing the upper lid to lift on downward gaze (clinically simulating the lid lag, or von Graefe sign, of Graves orbitopathy). Internal motor efferents can likewise be involved, resulting in a change of pupil size as gaze is shifted.

Occasionally, primary aberrant regeneration (aberrant regeneration without history of prior palsy) will be encountered. This finding is due to chronic compression of the third nerve, typically within or near the cavernous sinus usually due to meningioma and occasionally from an aneurysm of the intracavernous ICA. Adie tonic pupil is another example of aberrant regeneration affecting a facet of CN-III function with a probable intraorbital location within the ciliary ganglion and is discussed further in the section pertaining to pupils.

As opposed to the preceding discussion of isolated CN-III disease, the oculomotor nerve can be involved in cranial polyneuropathies, in which case the accompanying deficits typically help localize the etiology. Cavernous sinus syndrome typically affects CN-III, -IV, and -VI and the ophthalmic branch of CN-V. When the intracavernous carotid artery wall is also involved, sympathetic pupil dysfunction (Horner pupil) will result, producing miosis; the Horner pupil will be unnoticeable if CN-III-related mydriasis obscures it. The clinical history in the case of slowly expanding tumor in the cavernous sinus often includes chronically increasing diplopia, sometimes with pain or numbness in the CN-V ophthalmic distribution; in cases of inflammation or infection, the onset is usually dramatic and painful. Superior orbital fissure syndrome is often indistinguishable from cavernous sinus syndrome.

Lesions producing diminished vision, internal (i.e., pupillary involvement) or external ophthalmoplegia, orbital pain, and corneal hypesthesia characterize orbital apex syndrome. In simplified terms, this syndrome is clinically characterized by findings of superior orbital fissure syndrome with a concomitant compressive optic neuropathy. It must be distinguished from pituitary apoplexy where sudden, painful visual loss due to chiasmal compression by pituitary hemorrhage is often accompanied by unilateral or bilateral CN-III palsy as impingement upon the adjacent cavernous sinuses evolves.

Differential Diagnosis

Myasthenia gravis, a disorder of somatic neuromuscular junction failure that does not affect the pupil, will occasionally simulate pupil-sparing third-nerve palsy. A history of diurnal variability, findings of inducible fatigability, and resolution of the “palsy” during intravenous administration of edrophonium chloride is often sufficient to expose the diagnosis, which can then be confirmed by serum antibody testing and electromyography.

Chronic, progressive external ophthalmoplegia (CPEO) presents as slowly progressive bilateral ptosis and loss of extraocular movements, usually without diplopia. CPEO has been associated with specific mutations of mitochondrial and nuclear DNA and can be part of a larger syndrome, oculopharyngeal dystrophy. The Kearns–Sayre variant of CPEO includes pigmentary retinopathy with nyctalopia, and hormonal dysfunction.

The Miller Fisher variant of Guillain–Barré syndrome produces an external ophthalmoplegia that may be initially confused with CN-III palsy; the presence of viral prodrome, ataxia, areflexia, cerebrospinal fluid albuminocytologic dissociation, and positive serum anti-GQ1b IgM and IgG antibodies will confirm the diagnosis.

Patients with internuclear ophthalmoplegia have inability to move the ipsilateral eye into adduction when attempting horizontal gaze to the contralateral side. The responsible lesion is in the medial longitudinal fasciculus, interrupting the interneurons traveling from the CN-VI nucleus to the CN-III ventral subnucleus that innervates the medial rectus (see discussion of CN-VI anatomy, below). Such patients are often assumed to have a “medial rectus palsy”; however, such a variant of CN-III palsy is rarely if ever seen clinically, and the preservation of adduction during convergence to near stimulus (mediated by the mesencephalon) in internuclear ophthalmoplegia serves to confirm its central nervous system supranuclear origin.

Duane syndrome is an example of a congenital aberrant innervation. In affected individuals, prenatal abducens nerve dysgenesis or injury causes subsequent misdirected CN-III innervation of the lateral rectus. Therefore, attempted lateral eye movement results in simultaneous stimulation of the medial and lateral recti, causing variable eye movement, measurable globe retraction into the orbit, and consequent pseudoptosis. In type II Duane syndrome, the combination of poor adduction and pseudoptosis during globe retraction may simulate CN-III palsy. The congenital nature of this condition is most easily deduced by the absence of symptomatic diplopia in lateral gaze despite the presence of incomitant strabismus.

Patients with isolated ptosis are often screened for the presence of CN-III palsy. The most common cause of ptosis, typically encountered in patients older than age 50 years—but occasionally seen in younger patients with a history of frequent eye rubbing—is aponeurotic ptosis, a lengthening of the tendon (aponeurosis) connecting the levator palpebrae muscle to the upper lid. Aponeurotic ptosis is particularly common in patients who have undergone cataract surgery. In those patients who, in addition, experienced intraoperative iris injury with postoperative mydriasis, erroneous suspicion of a partial compressive CN-III palsy can be easily prompted.

Marcus Gunn jaw-winking is a syndrome of congenital aberrant innervation of the levator palpebrae muscle by the motor neurons of CN-V that innervate the pterygoid muscles of the mandible. The typical patient will have ptosis that partially resolves with lateral and forward jaw movements with costimulation of the levator.

In the traumatic setting, ophthalmoplegia due to CN-III palsy must be distinguished from that due to orbital disease (e.g., orbital floor fracture with entrapment of the inferior rectus muscle).

Diagnostic Approach

Whether a spared pupil in otherwise complete CN-III palsy reliably excludes an aneurysm deserves discussion. Certainly, with instances of an incomplete extraocular CN-III palsy, the absence of pupil involvement must not be considered evidence of a benign etiology; however, total pupil-sparing in otherwise complete CN-III palsy due to acute compression seems exceedingly rare.

In 1985, neurovascular imaging of patients with isolated, complete, pupil-sparing CN-III palsy was not recommended for patients older than age 50 years. This recommendation was based in part on the frequency of microvascular palsies in this age group, the relative danger of intracranial catheter angiography, and the lack of noninvasive neurovascular imaging modalities. With the emergence of detailed CTA and gadolinium-enhanced magnetic resonance angiography, the number of patients with acute CN-III palsy who should be excluded from imaging is vanishingly small.

Once aneurysm has been excluded in those patients without clear precipitants, testing for diabetes mellitus, hypertension, vasculitis and other inflammatory disease, clotting disorders, spirochetal disease (syphilis and Lyme disease) and myasthenia gravis is recommended. Even in patients with microvascular CN-III palsy without evidence of causative disease, consideration may be given to reevaluate already defined cerebrovascular risk factors.

Any patient presenting with diplopia, initially thought to be related to a cranial mononeuropathy, must have careful examination of the adjacent cranial nerve to exclude their involvement. Also, patients with apparently isolated CN-III palsy should be checked for signs of ataxia, areflexia, or contralateral rubral tremor, hemiparesis, or hypesthesia. Similarly, patients presenting with new upper facial pain or numbness must always be checked for impaired eye movements and corneal hypesthesia to exclude early cavernous sinus syndrome.

Management and Therapy

The management of symptomatic intracranial aneurysm is usually urgent, via endovascular or surgical intervention if the general state of the patient permits (see Chapter 57). Management of microvascular palsy usually centers on prevention of recurrent events via reduction of risk factors. Optimization of any causative disease, such as diabetes, is crucial, and daily aspirin is often recommended. Therapy for other underlying causes of CN-III palsy will vary, appropriate to etiology.

Visual management of nonhealing CN-III palsies is complicated by the number of paretic extraocular muscles involved, as ocular misalignment changes significantly depending on the direction of gaze. Prismatic spectacles are often unavailing, except in cases of minimal residual misalignment. Strabismus surgery, often involving two or three staged procedures, has the limited goal of stable relief of diplopia in primary gaze only. Often the simplest management tool, if acceptable to the patient, is a patch on the affected eye to eliminate diplopia, if the ptosis does not already accomplish that.