on 31-Jul-2021 (Sat)

The third cranial nerve supplies the levator muscle of the eyelid and four extraocular muscles: the medial rectus, superior rectus, inferior rectus, and inferior oblique. These muscles adduct, depress, and elevate the eye

In addition, the third cranial nerve constricts the pupil through its parasympathetic fibers that supply the smooth muscle of the ciliary body and the sphincter of the iris.

The third nerve begins as a nucleus in the midbrain that consists of several subnuclei that innervate the individual extraocular muscles, the eyelids, and the pupils. Each subnucleus, except the superior rectus subnucleus, supplies the ipsilateral muscle.

● The superior rectus subnucleus innervates the contralateral superior rectus muscle

● The levator subnucleus is a single central caudate nucleus and innervates both levator palpebrae superioris muscles (which control the eyelids)

● The parasympathetic pupil nucleus (Edinger-Westphal nuclei) controls pupil constriction

The third nerve fascicle leaves the nucleus and passes ventrally near important structures in the midbrain (eg, red nucleus, corticospinal tract). The third nerve then enters the subarachnoid space, passes into the lateral wall of the cavernous sinus, and finally divides into superior and inferior branches as it enters the superior orbital fissure in the orbit to innervate the extraocular muscles (figure 1).

The superior division of the third nerve supplies the levator palpebrae and the superior rectus, while the inferior division supplies the medial and inferior rectus muscles, the inferior oblique, and the pupillary sphincter. Because the fibers are topographically organized within the third nerve fascicle and nerve, a pattern of deficits that represents a divisional palsy is not helpful in anatomic localization [1].

Patients with an acute acquired third nerve palsy usually complain of the sudden onset of binocular horizontal, vertical, or oblique diplopia and a droopy eyelid.

Pain accompanying the onset of third nerve palsy is common, except in midbrain lesions, and is not useful to distinguish among etiologies [ 2]

Severe pain may also be present in inflammatory lesions or pituitary apoplexy, but mild or moderate pain is also common in ischemic lesions.

On examination, patients with a complete nonpupil-sparing third nerve palsy have ptosis, a large unreactive pupil, and paralysis of adduction, elevation, and depression. The eye rests in a position of abduction, slight depression, and intorsion "down and out" (picture 1) [3].

In partial lesions, the pupil may be of normal size and normally reactive (no internal dysfunction), dilated and poorly reactive (partial internal dysfunction), or dilated and non-reactive to light and near stimulus (complete internal dysfunction). The asymmetry of pupil size is greater in the light than in the dark.

A partial third nerve palsy with a normal pupil, ptosis, and restricted upgaze is shown ( picture 2).

The remainder of the clinical presentation varies depending upon the location and type of lesion (table 1).

Classification — For the purposes of clinical evaluation, we classify third nerve palsies as neurologically isolated or neurologically non-isolated according to the presence of other neurologic deficits or systemic symptoms. We further characterize neurologically isolated lesions as having normal internal function (pupil-sparing) or abnormal internal function (nonpupil-sparing). Complete external dysfunction is identified when there is impairment of the majority of function of all the somatic branches of the oculomotor nerve and ptosis is complete or almost complete; otherwise the external dysfunction is incomplete (eg, divisional palsy).

Lesions of the third nerve nucleus are rare and are usually associated with other neurologic deficits localized to the midbrain. The most characteristic finding of a nuclear lesion is a complete unilateral third nerve palsy with weakness of both the ipsilateral and contralateral superior rectus (because the superior rectus subnucleus is crossed) and bilateral, incomplete ptosis. The levator palpebrae superioris muscles are controlled by a single central subnucleus. Thus, in patients with nuclear lesions, if ptosis is present, it is bilateral.

Other patterns of third nerve deficits can be seen occur in nuclear lesions, including bilateral third nerve palsies with sparing of the eyelids and isolated bilateral ptosis with sparing of the extraocular muscles and pupils. Nuclear third nerve palsies can occasionally be associated with ipsilateral ptosis and contralateral eyelid retraction (plus-minus lid syndrome) if supranuclear inhibitory input to the third nerve is disrupted and ptosis from a fascicular lesion on the contralateral side occurs.

Nuclear lesions can also cause isolated extraocular muscle involvement. However, unilateral or bilateral isolated medial rectus paralysis is unlikely to be caused by a nuclear lesion because medial rectus neurons probably lie at three different locations within the oculomotor nucleus. For this reason, patients with presumed isolated medial rectus paresis should be evaluated for internuclear ophthalmoplegia.

A nuclear or fascicular third nerve lesion almost always occurs with other neurologic signs or symptoms, which identifies the midbrain location of the lesion:

● Contralateral ataxia will be present if the red nucleus/superior cerebellar peduncle is involved

● Cerebellar tremor may be present in Claude syndrome (ipsilateral third nerve palsy and contralateral cerebellar signs)

● Contralateral hemiparesis may be present in a cerebral peduncle lesion (Weber syndrome)

● Contralateral choreiform movements or tremor are present when red nucleus/substantia nigra involvement occurs (Benedikt syndrome)

Isolated third nerve palsies often localize to a lesion within the subarachnoid space. In adults, extra-axial third nerve palsies usually are caused by ischemia.

In addition to ischemia, other causes include aneurysmal compression, infection, inflammation, neoplasia, uncal herniation, and trauma (including neurosurgical procedures) (table 1).

Inflammatory, infectious, and neoplastic disorders affecting the meninges will often produce other cranial nerve deficits along with a third nerve palsy; otherwise these lesions are typically neurologically isolated.

Ischemic third nerve lesions typically present with intact pupillary function (80 to 90 percent of cases), probably because of the lack of damage to the superficial periphery of the third nerve where the majority of pupillomotor fibers are thought to pass [4-11]. When the pupil is involved, impairment is usually incomplete [5,12]. In one series of 26 patients with ischemic third nerve palsy, most patients with impaired pupillary function had only mild anisocoria (<1 mm) and none had a fully dilated pupil [5].

In contrast, aneurysmal compression of the superficial pupil fibers of the third nerve in the subarachnoid space usually results in a dilated and unresponsive pupil. However, aneurysms can rarely present without pupil involvement, especially if there is incomplete external dysfunction (eg, divisional palsy). When there is incomplete external dysfunction, the lack of pupil involvement does not have the same diagnostic significance as true pupil-sparing in the setting of a third nerve palsy with complete external dysfunction.

Signs of aberrant regeneration or oculomotor synkinesis are common with lesions caused by nerve compression or after trauma and are rare with ischemic lesions [13]. These signs include lid retraction with adduction or down-gaze, globe retraction and/or adduction with attempted vertical gaze, and pupil constriction with eye movement using third nerve-innervated muscles [14].

Cavernous sinus lesions — Lesions of the third nerve in the cavernous sinus and superior orbital fissure often involve other cranial nerves and have the following clinical manifestations:

● Fourth cranial nerve - vertical diplopia (look for lack of intorsion in downgaze in a patient with complete third nerve palsy and possible fourth nerve deficit)

● Sixth cranial nerve - horizontal diplopia; esotropia (inward deviation)

● First (ophthalmic) branch of the trigeminal nerve - pain or numbness

● Oculosympathetic fibers - Horner syndrome (look for a smaller pupil on the side of the third nerve palsy)

Superior orbital fissure/Orbital lesions — Lesions within the orbit that produce third-nerve dysfunction usually produce other orbital signs, including optic neuropathy, chemosis, conjunctival injection or chemosis, and proptosis.

The most dreaded cause of a third nerve palsy is compression by an enlarging intracranial aneurysm. The most common site of an aneurysm causing a third nerve palsy is the posterior communicating artery; however, aneurysms involving the internal carotid artery and basilar artery are reported to produce third nerve palsies as well [17-20]

In the setting of an acute third nerve palsy, the aneurysm is believed to be acutely enlarging and therefore at risk of imminent rupture. In this setting, subarachnoid hemorrhage can occur within hours or days of initial presentation of the third nerve palsy. The mean age of presentation of aneurysmal subarachnoid hemorrhage is 55 years; however, aneurysms have been reported in young children and in the elderly.

Ischemic third nerve palsies, also called diabetic third nerve palsies, are the most common etiologic subset of third nerve palsy in adults. The pathogenesis is felt to be microvascular; hypertension and advanced age are also risk factors. While some isolated ischemic third nerve palsies are due to midbrain infarction, most are peripheral [21].

Traumatic third nerve palsy usually arises only from severe blows to the head, with skull fracture and/or loss of consciousness [14,22,23]. Thus, a third nerve palsy associated with mild head trauma should prompt evaluation for associated pathology.

Several cases have been reported in which ophthalmoplegic 'migraine' is associated with MRI (magnetic resonance imaging) gadolinium enhancement of the cisternal segment of the affected cranial nerve in patients with a typical clinical presentation, suggesting that the condition may be a recurrent demyelinating neuropathy [26-29].

While often considered, third nerve palsy is extremely unlikely to be the cause of isolated mydriasis. Tonic pupil, iris sphincter damage, and pharmacologic mydriasis should be specifically excluded by careful neuroophthalmologic evaluation and pharmacologic testing in this setting. A complete evaluation of the lid and the ocular motility should also be performed to insure that the anisocoria is an isolated finding.

Myasthenia gravis can mimic any painless, pupil-sparing ophthalmoplegia and should be considered in every patient with a pupil-sparing third nerve palsy [30]. Other signs of myasthenia gravis, such as ptosis, variability, and fatigue, usually are present. The "ice test" (a two-minute application of ice to the eyelid with ptosis) may help to differentiate myasthenia from other causes of ptosis [31-33]. A positive test (≥2 mm improvement in ptosis) was 80 percent sensitive and 100 percent specific in one study [31]. (See "Ocular myasthenia gravis".)

Skew deviation is a vertical misalignment caused by disruption of the vestibuloocular connections and can result in hypertropia. Usually it is associated with other posterior fossa signs (eg, other cranial neuropathies, hemisensory loss, or hemiparesis).

Contrast-enhanced MRI with MRA or CTA have a sensitivity as high as 95 to 98 percent for the detection of aneurysm in the setting of a third nerve palsy [34-37].

While some centers prefer CTA as a first study to exclude aneurysm, MRI is superior for nonaneurysmal etiologies of a third nerve palsy. A combination of CTA and MRI (with or without MRA) might be necessary in this regard

The relative risk of an underlying aneurysm is assessed based in large part on the degree of external and internal third nerve dysfunction as discussed in the following sections, (table 2) [39].

Complete external dysfunction with normal internal function (pupil-sparing complete third nerve palsy) — A neurologically isolated third nerve palsy with a normal pupillary sphincter and completely palsied extraocular muscles (complete external dysfunction) is almost never caused by an aneurysm.

In older adults, this presentation is most commonly caused by ischemic injury [12,39]. Observation alone is an appropriate diagnostic option for older patients with vascular risk factors (hypertension, diabetes) [39]. However, contrast-enhanced brain MRI and MRA should be strongly considered in patients without vascular risk factors whose deficits progress or do not improve by 6 to 12 weeks of follow-up or in those with signs of aberrant regeneration [13].

Older patients (>55 years) should be evaluated for signs or symptoms of giant cell arteritis (headache, jaw or tongue claudication, polymyalgia rheumatica, visual loss) [40,41]. These patients may require serum erythrocyte sedimentation rate and C reactive protein, steroid treatment, and temporal artery biopsy.

If a third nerve palsy persists in a patient with normal imaging studies, a lumbar puncture (LP) should be considered, especially if historical or examination features suggest an infectious, inflammatory, or neoplastic process affecting the meninges.

Complete internal dysfunction (pupil-involved) third nerve palsy should be assumed to be due to aneurysmal compression until proven otherwise. Patients should undergo MRI and MRA (or CTA); however, even if the noninvasive study is negative, a catheter angiogram should be strongly considered to exclude aneurysm.

Once aneurysm and other mass lesions have been excluded, an evaluation for giant cell arteritis should be undertaken in older patients; and an LP should be considered for persistent or progressing deficits when the cause remains unclear.

Signs of aberrant regeneration are unlikely in ischemic lesions and suggest the presence of a compressive lesion, including aneurysm (see 'Subarachnoid space' above). Contrast-enhanced brain MRI with MRA (or CTA) is the procedure of choice for these patients.

In most cases, third nerve deficits, diplopia, and ptosis recover over weeks to months. Deficits that are present at six months are usually persistent over time [14].

The majority of ischemic third nerve palsies, including those related to migraine headaches, usually improve over three to six months [14]. Vascular risk factors should be treated; antiplatelet therapy is usually provided.

In most cases, diplopia and ptosis recover over several weeks to months. Deficits present at six months are generally persistent. Such patients may benefit from surgical interventions to alleviate disabling diplopia and/or ptosis (see 'Treatment and Prognosis' above).