Clinical manifestations

Presentation and course

The third nerve supplies the muscles of the iris sphincter and ciliary body, four extraocular muscles (medial, superior, and inferior recti, and inferior oblique), and the levator palpebrae superioris, which maintains upper lid elevation.

The parasympathetic fibers, which travel in the medial peripheral portion of the extra-axial portion of the third nerve, supply the muscles of the iris sphincter and ciliary body. A complete third nerve palsy causes ptosis, a fixed and dilated pupil, paralysis of accommodation, and an abducted eye that has no supraduction, infraduction, or adduction. A partial third nerve palsy may cause any combination of partial ptosis, pupillary abnormalities, accommodative paralysis, and ductional abnormalities.

The third nerve’s axons originate in the third nerve nucleus, which lies ventral to the Sylvian aqueduct in the midline of the rostral midbrain at the level of the superior colliculus. One set of paired subnuclei sends fibers to the medial rectus muscles that mediate adduction. Another set of subnuclei sends axons to the inferior rectus muscles that mediate infraduction. The inferior oblique subnuclei mediate supraduction-in-adduction. The paired superior rectus subnuclei are unique in that their axons decussate within the nucleus and pass through the contralateral superior rectus nucleus before joining the third nerve midbrain fascicles that eventually innervate the contralateral superior rectus. The superior rectus muscle mediates supraduction-in-abduction.

The central caudal nucleus is a midline subnucleus whose neurons send axons to the levator palpebrae muscles and are responsible for lid elevation. The neurons in this subnucleus are present on both sides of the midline, so that a caudal central nuclear lesion will cause bilateral ptosis.

The Edinger-Westphal subnucleus, lying at the rostral end of the third nerve nuclear complex, subserves parasympathetic innervation, including pupillary constriction elicited by light shined on the eye or by any stimulus viewed within reading distance. Pupil constriction to light is governed in part by photoreceptors within the ganglion cell layer of the retina, which contain melanopsin. The signal from photoreceptors and melanopsin-containing retinal ganglion cells is carried by retinal ganglion cell axons into the optic nerves, optic chiasm, and optic tracts, where axons peel off to enter the brachium of the superior colliculus, to synapse on the pretectal nuclei. The pretectal nuclei innervate the Edinger-Westphal nuclei, whose fibers synapse in the ciliary ganglion, which lies in the mid portion of the orbit and contains the neurons whose axons synapse on the iris sphincter and ciliary muscles. Activation of the iris sphincter induces pupillary constriction in response to light; activation of the ciliary muscles causes relaxation of the lens zonules and an increase in lens curvature, allowing for increased refractive power, and the accommodation necessary to focus targets viewed at reading distance (13).

Patients with third nerve palsies complain of binocular diplopia. The images may be displaced in horizontal or vertical planes, or both. There may be partial or complete ipsilateral ptosis. The pupils may be equal in size and constrict equally to direct light, or the ipsilateral pupil may be relatively dilated and poorly constrictive to light. Examination will reveal deficits in adduction, supraduction, and/or infraduction. Misalignment of the eyes will usually be present with an orientation that depends on the degree of impairment of the various extraocular muscles (06; 11; 40; 60).

In “isolated” third nerve palsy, these ophthalmic abnormalities are unaccompanied by other neurologic deficits, and there is no history of cancer or a systemic inflammatory process that would predispose to a nonischemic cause. Such isolated palsies almost always derive from lesions of the extra-axial, precavernous portion of the nerve, where it is away from neurologic traffic. In adults, most isolated third nerve palsies in patients with conventional arteriosclerotic risk factors are caused by reversible extra-axial ischemic lesions.

Other causes of isolated third nerve palsy are severe head trauma, infection, inflammation, neoplastic invasion of the meninges, and most urgently, aneurysms located at the junction of the internal carotid and posterior communicating arteries internal and basilar artery apex. Third nerve palsies may also rarely result from direct compression by a dolichoectatic basilar artery (32). Compression of the third nerve by an aneurysm usually results in a dilated and unresponsive pupil caused by the superficial location of the pupil fibers of the third nerve within the subarachnoid space.

The third nerve runs in close proximity to the posterior communicating artery in this location (59), and until proven otherwise, an isolated pupil-involving third nerve palsy should be presumed to be due to aneurysm. Although the posterior communicating artery-internal carotid artery junction is the most common site of aneurysmal compression of the third nerve, alternative sites include the basilar artery apex and the junction of the basilar and superior cerebellar arteries (43). The cavernous sinus portion of the internal carotid artery is another potential site, but such aneurysms often also compress the sixth nerve and the oculosympathetic fibers to cause a Horner syndrome (41). Very rarely, aneurysms of the anterior communicating artery will produce a third nerve palsy (55; 70).

An expanding lesion of the sella turcica, particularly hemorrhage into a pituitary adenoma (“pituitary apoplexy”), is an important cause isolated third nerve palsy (72); new headache is common, but there may be no other clinical deficits.

Lesions of the midbrain fascicles cause third nerve palsies with accompanying neurologic deficits (39). Lesions of the red nucleus lead to contralateral tremor (Claude syndrome); lesions of the superior cerebellar peduncle lead to contralateral ataxia (Benedikt syndrome); lesions of the cerebral peduncle lead to contralateral hemiparesis (Weber syndrome).

Because the fascicles of the third nerve in the midbrain have a wide rostrocaudal distribution, lesions here often cause partial palsies. For example, the parasympathetic fibers destined for the ciliary muscle and iris sphincter are located at the extreme rostral end, and the fibers destined for the levator muscle are located at the extreme caudal end, therefore sparing of pupils and lids by fascicular lesions is common. Selective involvement of the lids by brainstem lesions may also rarely occur, but selective involvement of the pupil does not occur. Lesions limited to the third nerve nucleus are extraordinarily rare (05).

Temporal arteritis is an uncommon but important cause of a third nerve palsy and should be suspected in patients 55 or older who present with diplopia accompanied by headache, jaw claudication, scalp tenderness, or elevated serum markers (65).

Orbital lesions can give rise to ocular ductional deficits that resemble a third nerve palsy, but the damage is to the extraocular muscles and levator, not to the third nerve. Signs of orbital congestion, including proptosis, lid swelling, increased resistance to globe retropulsion, and conjunctival hyperemia, are usually present.

Prognosis and complications

The prognosis for recovery depends on the cause of the palsy (see Outcomes).

Amblyopia is a concern in young children who have congenital or traumatic third nerve palsy that interferes with binocularity; hence, the need for prompt care by an ophthalmologist.

Clinical vignette

A 60-year-old man with hypertension and diabetes presented with acute, binocular oblique diplopia and severe headache. There was a partial ptosis of the right upper eyelid and a dilated and sluggishly constricting right pupil. Ocular ductional testing revealed moderately reduced adduction, supraduction, and infraduction of the right eye. The left eye had full ductions. On ocular alignment examination, there was an exotropia of 40 prism diopters and a left hypertropia of 20 prism diopters in primary gaze position. The right eye intorted on infraduction, suggesting an intact right fourth nerve. All other aspects of the ophthalmic and neurologic examination were normal. A diagnosis of isolated right third nerve palsy was made. The patient underwent a noncontrast head CT scan, which showed no subarachnoid hemorrhage, but a CT angiogram (CTA) showed an aneurysm of the right posterior communicating artery that was subsequently confirmed on catheter angiography and later successfully clipped. Third nerve function recovered fully within six months.

Biological basis

Etiology and pathogenesis

The cause of third nerve palsy depends chiefly on whether the palsy is “isolated” or “non-isolated,” that is, accompanied by other pertinent findings such as other neuro-ophthalmic or neurologic abnormalities, a history of cancer, or evidence of a systemic inflammatory process (62; 11; 40; 44). If the palsy is nonisolated, microvascular ischemia cannot be the cause, and a full evaluation of nonischemic causes is warranted. If the palsy is isolated, the likely cause in adults is microvascular ischemia; the differential diagnosis is based on patient age, arteriosclerotic risk factors, the degree of mydriasis, and the presence of aberrant regeneration. Periocular pain is not a valuable differentiating feature.

In children, third nerve palsy is uncommon. When it is isolated, the cause is often congenital. Inflammation, compression by tumor, and head trauma are less common causes, and typically also produce other abnormalities. Aneurysm is an extraordinarily rare cause and microvascular ischemia is never a cause (27; 16).

In adults, isolated third nerve palsies are overwhelmingly caused by reversible microvascular ischemia to the extra-axial portion of the nerve. In a population-based study in Olmsted Country, Minnesota, microvascular ischemia accounted for 72% of 81 isolated third nerve palsies. That diagnosis was made in patients from age 45 to 96, clustering in the sixth to eighth decades of life. Ipsilateral periocular pain, often severe, accompanied 61% of cases. Anisocoria was present in 16%, but never greater than 2 mm (16). Other reports have confirmed that microvascular ischemic lesions rarely cause anisocoria greater than 2 mm (29). Aneurysms, inflammations, and cancer may spare the pupil or cause a broad range of anisocoria.

Aneurysms are an uncommon but important cause of third nerve palsy in adults. The aneurysms may be intradural, (supraclinoid carotid artery, junction of carotid and post-communicating arteries, junction of basilar and posterior cerebral or superior cerebellar arteries) or extradural (cavernous sinus). In the Olmsted County study, aneurysms accounted for 6% of isolated cases, 3% of which were intradural and 3% were extradural. The aneurysms occurred in the 7th to 9th decade. Periocular pain was present in 78% and anisocoria (often > 2 mm) in 33%. Among patients with posterior communicating artery aneurysms who do not have a third nerve palsy before aneurysm repair, the procedure itself may cause a palsy (54; 35).

Head trauma explained only 5% of isolated palsies in the Olmsted study. There were single cases of isolated third nerve palsy caused by pituitary apoplexy, brain metastasis, herpes zoster, teratoma, and giant cell arteritis.

Aberrant regeneration of the third nerve signifies a chronic disruptive lesion following aneurysm, trauma, and rarely inflammation (19). In the Olmsted County series, aberrant regeneration was present in 8% of cases, limited to compressive causes and concussive or neurosurgical trauma. (16). It represents mischanneling of axons, leading to innervation of the levator palpebrae by axons originally destined for the inferior rectus, so that attempted infraduction leads to upward movement of the upper lid. Similarly, but less commonly, adduction may cause constriction of the pupil. The finding of aberrant regeneration mandates brain imaging oriented toward mass lesions, particularly aneurysm (08; 69; 23).

Although arteriosclerotic risk factors favor a diagnosis of microvascular ischemia, they also predispose to aneurysm. Their presence, therefore, does not allow exclusion of aneurysm as a cause of third nerve palsy.

Epidemiology

In one study, the most important independent risk factors for ischemic third nerve palsies were previously diagnosed diabetes, left ventricular hypertropia (indicating end organ damage by hypertension), and elevated hematocrit (indicative of high blood viscosity) (29). Another case-control study demonstrated a relatively high prevalence of diabetes, hypertension, and hyperlipidemia rather than coronary artery disease, left ventricular hypertrophy, or smoking (33).

Prevention

Given that reduced perfusion of the extra-axial third nerve is responsible for the preponderance of third nerve palsies in adults, control of conventional arteriosclerotic risk factors ought to be preventive.

Differential diagnosis

Orbital disorders can cause ocular ductional deficits that mimic a third nerve palsy (22; 31; 14). Clinical clues to an orbital process are proptosis, lid swelling, resistance to retropulsion, and conjunctival hyperemia. Myasthenia gravis may simulate a third nerve palsy but always with sparing of the iris sphincter. Giant cell arteritis may rarely cause a third nerve palsy, but it more commonly causes ischemia to the extraocular muscles that mimics a palsy. Elderly patients with diplopia, new headache, or scalp tenderness should be promptly evaluated for that condition (12; 07; 42; 65). Skew deviation, a vertical misalignment owing to disruption of vestibulo-ocular connections, produces a hypertropia that may mimic third nerve palsy, but ocular ductions are expected to be normal, and there should be no ptosis or pupillary abnormality. Moreover, skew deviation is usually associated with ataxia or other brainstem dysfunction.

Diagnostic workup

Classification of isolated third nerve palsy. For purposes of evaluation, third nerve palsies should be divided into those in which there are other pertinent manifestations (“nonisolated palsies”) and those in which the palsy is the only manifestation (“isolated palsies”) (44).

Nonisolated third nerve palsies. Nonisolated third nerve palsies are never caused by microvascular ischemia. Neoplasm, inflammation, and intracavernous (extradural) aneurysm are reasonable considerations. Therefore, appropriate imaging should be undertaken with attention to areas suggested topographically by the associated neurologic signs and symptoms. If clinical signs of a meningeal process are present and the neuroimaging is negative, a lumbar puncture should be considered (52; 53; 51; 04). An evaluation for myasthenia gravis is indicated for pupil-sparing third nerve palsies, especially if there are other signs of myasthenia.

Isolated third nerve palsies. Although most isolated third nerve palsies in adults can be attributed to microvascular ischemia, clinical features do not permit exclusion of aneurysm (03; 18). Therefore, all patients must undergo imaging (48). CTA and MRA are 96% sensitive to cerebral aneurysms of at least 7 mm diameter, the size needed to cause third nerve palsy (67; 66; 46; 50; 30; 71; 36; 45). Aneurysms that cause third nerve palsy typically have a minimal cross-sectional diameter of at least 7 mm and are most commonly found at the junction of the carotid and posterior communicating arteries (64; 57). In one study, the distance between the internal carotid artery and the anterior-posterior clinoid process, rather than the size of the aneurysm, was a predictor of a third nerve palsy (01).

CT/CTA is preferred over MRI/MRA in adults because of greater accessibility and superior vascular delineation (68). Time-of-flight (noncontrast) MRA is preferred in pregnancy to avoid contrast dye exposure. MRI/MRA is preferred in children to avoid radiation exposure. A negative study ought to exclude aneurysm, but that depends on the expertise of the interpreter; inexperienced radiologists may overlook aneurysms (15).

In adults with an arteriosclerotic profile, a negative vascular imaging study justifies the presumption of microvascular ischemia as the cause. No further studies are necessary. Risk factor abatement is indicated, and the palsy should be allowed to resolve spontaneously. If the imaging is equivocal and there are no arteriosclerotic risk factors, a complementary noninvasive vascular imaging study should be considered, but digital angiography is rarely necessary (38; 10; 61). Patients older than 55 years of age, especially those with new headache, jaw or tongue claudication, or polymyalgia rheumatica, should have an evaluation for giant cell arteritis. If there are clinical suggestions of a meningeal process, lumbar puncture should be performed.

Microvascular extra-axial third nerve palsies should resolve completely within three months of onset (16). If they have not fully resolved by that time, if they have worsened after being stable for 21 days, or if contributory abnormalities have appeared in that interval, the cause may be a brainstem infarct or a nonischemic condition, prompting the need for reevaluation, including imaging.

In children with an isolated palsy, a negative MRI and MRA study allows the presumption of a viral or postviral cause. Lumbar puncture and other studies are not indicated. If the palsy worsens or does not resolve, or if contributory manifestations appear, reevaluation is indicated.

In children and adults, eye muscle surgery to alleviate diplopia and realign the eyes—a challenging task—can be undertaken if the palsy has been stable for at least nine months.

Management

After a diagnosis has been established, further management depends on the cause of the diplopia. Treatment of aneurysm is aimed at isolating the pouch from the circulation, typically achieved by clipping or coiling with or without stenting. Most current approaches to unruptured aneurysms that cause third nerve palsies are able to isolate the aneurysm with low recurrence rates. However, successful aneurysm surgery may not lead to resolution of the third nerve palsy (see Outcomes).

Bothersome diplopia can be averted by blurring or blocking the image from being seen by one eye. Blurring may be accomplished with a semi-opaque foil. Occlusion may be accomplished with a “pirate” patch, an occluder placed on the spectacle, or by an opaque contact lens. For small misalignments, press-on or ground-in prism on the spectacles is often successful in alleviating diplopia. In large misalignments, occlusion with a patch or contact lens is often necessary. For profound palsies, eye muscle surgery is rarely effective in relieving diplopia. However, the combination of eye muscle and lid lifting surgery may restore a more cosmetic appearance and pave the way for the use of an opaque contact lens (37; 02; 38; 17). Occlusion of the fixating eye may be necessary in children under age 5 to prevent amblyopia (56; 47).

Outcomes

Among patients with vasculopathic third nerve palsies affecting the extra-axial course of the nerve, full recovery should occur spontaneously within three months in all patients (16). Recovery is variable for those with traumatic, inflammatory, and compressive palsies.

Aneurysmal procedures are associated with variable recovery rates of the palsy (20; 28; 21). In several small series, clipped patients recovered more often than coiled patients, although one series reported no difference in outcome (09; 34; 49; 63). In a comprehensive review of 26 studies of treatment of unruptured posterior communicating artery aneurysms, 55% of clipped patients and 32% of coiled patients recovered completely (26). In that review, decompression of the aneurysmal sac after clipping did not add any benefit in palsy recovery over clipping alone (25).

In one study of 20 patients who underwent endovascular coiling of posterior communicating artery aneurysms, complete recovery occurred in 50% of those who presented with a complete palsy and in 33% of those who presented with an incomplete palsy (24). In another study of patients whose aneurysms had already ruptured, nearly one half sustained complete recovery of the palsy (58).

Special considerations

Pregnancy

There are no special issues for third nerve palsy in pregnancy except that imaging should avoid the use of contrast dyes.

Anesthesia

There are no special issues for anesthesia in third nerve palsy.