Clinical manifestations

Presentation and course

The third nerve supplies the muscles of the iris sphincter and ciliary body, 4 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 (14).

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 (07; 12; 39; 59).

In “isolated” third nerve palsy, these ophthalmic abnormalities are unaccompanied by other neurologic deficits. Such 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 cases are caused by reversible ischemic lesions in patients with conventional arteriosclerotic risk factors.

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 (31). 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 (58), 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 (42). 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 (40). Very rarely, aneurysms of the anterior communicating artery will produce a third nerve palsy (54; 68).

An expanding lesion of the sella turcica, particularly hemorrhage into a pituitary adenoma (“pituitary apoplexy”), can cause an isolated third nerve palsy (70).

Lesions of the midbrain fascicles cause third nerve palsies with accompanying neurologic deficits (38). 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 (06).

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 (64).

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. Amblyopia may develop in children with strabismus or ptosis due to third nerve palsy.

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 6 months.

Biological basis

Etiology and pathogenesis

The cause of third nerve palsy depends chiefly on whether the palsy is accompanied by other pertinent findings, including other ocular motor neuropathies, other neurologic deficits, or a history of cancer (61; 12; 39; 43). If the palsy is isolated, differential diagnostic indicators are patient age, the status of the pupil, arteriosclerotic risk factors, and aberrant regeneration. Periocular pain is not a valuable differentiating feature.

In adults, most isolated third nerve palsies are caused by microvascular ischemia to the extra-axial portion of the nerve. In children, ischemic lesions are not a factor.

Ischemic lesions of the third nerve typically spare the pupil completely; anisocoria rarely exceeds 2 mm (28). Aneurysms, inflammations, and cancer variably affect the pupil, often sparing it. Thus, prompt brain imaging—including vascular imaging—is mandatory in all acute isolated third nerve palsies regardless of patient age or the status of the pupil. Aneurysms that cause third nerve palsy typically have a minimal cross-sectional diameter of at least 7 mm and are found at the junction of the carotid and posterior communicating arteries (63; 56). In 1 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 (02). 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 (53; 34).

Although arteriosclerotic risk factors favor a diagnosis of microvascular ischemia, they also predispose to aneurysm; therefore, their presence should not deter imaging.

Aberrant regeneration of the third nerve signifies a chronic disruptive lesion, including aneurysm, trauma, or severe inflammation. 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 (09; 67; 23). Aberrant regeneration has also been reported after Guillain-Barré syndrome (19).

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) (28). Another case-control study demonstrated a relatively high prevalence of diabetes, hypertension, and hyperlipidemia rather than coronary artery disease, left ventricular hypertrophy, or smoking (32).

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; 30; 15). 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 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 (13; 08; 41; 64). 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 (Walter and Trobe 2020).

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”) (43).

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 (51; Rucker 1966; 52; 50; 05). 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 (04; 18). Therefore, all patients must undergo imaging (47). CTA or MRA are 96% sensitive to cerebral aneurysms of at least 7 mm diameter, the size needed to cause third nerve palsy (66; 65; 45; 49; 29; 69; 35; 44). CT/CTA is preferred in adults because of accessibility (Vaphiades et al 2008). Time-of-flight (noncontrast) MRA is preferred in pregnancy. 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 of the study. Inexperienced radiologists may overlook aneurysms (16).

In adults, if the imaging is negative and there are arteriosclerotic risk factors, the presumptive diagnosis should be microvascular ischemia. 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 can be considered, but digital angiography is rarely necessary (37; 11; 60). 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 3 months of onset. If not, the cause may be a brainstem infarction or a nonischemic condition. Repeat brain imaging should occur. If contributory signs have appeared, body imaging and lumbar puncture must be considered. If all studies are negative and ocular misalignment is stable, eye muscle surgery can be undertaken.

In children, a negative imaging study allows the presumption of a viral or postviral cause and deferral of further investigations. If the palsy worsens or does not resolve, or if contributory manifestations appear, reimaging is indicated. Eye muscle surgery could be undertaken if the palsy has been stable for at least 9 months.

In a series of patients with aneurysms treated with endovascular coiling or neurosurgical clipping, older age, diabetes, delayed interventions, and complete third nerve palsy at presentation were associated with a worse prognosis for recovery of the palsy (01).

Management

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.

Bothersome diplopia can be averted by blocking the image from being seen by 1 eye. Occlusion can 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; 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 (36; 03; 37; 17). Occlusion of the fixating eye may be necessary in children under age 5 to prevent amblyopia (55; 46).

Outcomes

Among patients with vasculopathic third nerve palsies affecting the extra-axial course of the nerve, full recovery should occur spontaneously within 3 months in all patients. Recovery is variable for those with traumatic, inflammatory, and compressive palsies.

Aneurysmal procedures are associated with variable recovery rates of the palsy (20; 27; 21). In several small series, clipped patients recovered more often than coiled patients, although 1 series reported no difference in outcome (10; 33; 48; 62). 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 1 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 (57).

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.