Third cranial nerve (oculomotor nerve) palsy in adults

INTRODUCTION — Dysfunction of the third cranial nerve (oculomotor nerve) can result from lesions anywhere along its path between the oculomotor nucleus in the midbrain and the extraocular muscles within the orbit. The diagnosis and management of third nerve palsy varies according to the age of the patient, characteristics of the third nerve palsy, and the presence of associated signs and symptoms.

The manifestations and diagnosis of third nerve palsy in adults will be reviewed here. Third nerve palsy in children and other causes of diplopia, ptosis, and anisocoria are discussed separately. (See "Third cranial nerve (oculomotor nerve) palsy in children" and "Overview of diplopia" and "Overview of ptosis" and "Approach to the patient with anisocoria".)

ANATOMY — 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. The superior oblique muscle is innervated by cranial nerve IV and the lateral rectus muscle by cranial nerve VI. 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].

CLINICAL MANIFESTATIONS

General features — 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. Infrequently, the patient is aware of an enlarged pupil. Patients with chronic third nerve palsies (especially with primary aberrant regeneration) may be asymptomatic. Pain accompanying the onset of third nerve palsy is common, except in midbrain lesions, and is not useful to distinguish among etiologies [2]. Sudden, severe pain ("the worst headache of my life") might suggest subarachnoid hemorrhage due to a ruptured aneurysm as the cause of the third nerve palsy. 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. There may be complete or incomplete involvement of the extraocular muscles (external dysfunction) innervated by the third nerve, producing varying degrees of ptosis as well as weakness of ipsilateral adduction (medial rectus), elevation (superior rectus, inferior oblique), and/or depression (inferior rectus). 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).

Midbrain lesions — 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. (See "Internuclear ophthalmoparesis".)

Nuclear lesions that are caused by infarction are often accompanied by lesions of the third nerve fascicle because both structures are supplied by the paramedian branches of the basilar artery.

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)

Subarachnoid space — 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 contrast, ischemia is a rare cause for third nerve palsy in children. (See "Third cranial nerve (oculomotor nerve) palsy in children".) In addition to ischemia, other causes include aneurysmal compression, infection, inflammation, neoplasia, uncal herniation, and trauma (including neurosurgical procedures) (table 1).

The clinical features of lesions in this area are to some extent specific to etiology:

●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].

●Spontaneous improvement of symptoms should not be reassuring in regards to diagnosis; this has been described with aneurysmal lesions [15,16].

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.

ETIOLOGY — Etiologies of third nerve palsies are specific to the location (table 1). These include a wide variety of pathologies, including structural lesions, cerebrovascular disease, inflammatory or infectious conditions, and trauma. In this regard, a few deserve specific comment.

●Intracranial aneurysm — 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.

●Ischemia — 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].

●Trauma — 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.

●Migraine — Ophthalmoplegic 'migraine,' a condition affecting children and young adults, was reclassified as a cranial neuralgia in the revised International Headache Society (IHS) headache classification system published in 2004 [24]. This most commonly affects the third cranial nerve, sometimes with permanent deficits [25]. 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].

DIFFERENTIAL DIAGNOSIS — Several conditions can mimic the extraocular dysfunction of third nerve palsy.

●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. (See "Approach to the patient with anisocoria".)

●Orbital disease, eg, orbital fracture, tumor, and inflammation, can affect the extraocular muscles directly. Forced ductions, passive rotation of the eyes with ophthalmic forceps, might confirm the restrictive nature of the ophthalmoplegia caused by these problems.

●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). (See "Overview of diplopia".)

EVALUATION — The evaluation of the patient with a third nerve palsy depends on associated symptoms and signs and the pattern of oculomotor nerve involvement, both of which help to localize the lesion anatomically (table 1). The age of the patient and other historical features also help to distinguish congenital, traumatic, or infectious conditions. Inflammatory and neoplastic conditions have a more insidious onset compared with cerebral infarction.

Nonisolated third nerve palsy — Third nerve palsies that are accompanied by other neurologic deficits, orbital signs, or meningismus require an evaluation that usually includes neuroimaging. A lumbar puncture (LP) may also be required to evaluate for possible infectious, inflammatory, or carcinomatous meningitis.

●A brain magnetic resonance imaging study (MRI) is indicated for patients with findings suggesting a lesion of the nerve's nuclear or fascicular course within the brainstem. These findings include bilateral ptosis, contralateral superior rectus palsy, hemiparesis, ataxia, and tremor. (See 'Midbrain lesions' above.)

●Accompanying meningeal signs (eg, headache, stiff neck, and depressed level of consciousness) or other cranial nerve involvement, especially if bilateral, should prompt evaluation of the cerebrospinal fluid by LP for possible meningitis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

●The sudden onset of painful third nerve palsy with associated meningeal signs demands an emergent evaluation, regardless of the patient's age or the extent of third nerve involvement, including those that spare pupillary function. The emergent work-up should include head computed tomography (CT) without contrast looking for blood in the subarachnoid space. If the head CT is unrevealing, LP should be performed to exclude subarachnoid hemorrhage. In the absence of subarachnoid hemorrhage, testing should be performed to exclude an unruptured intracranial aneurysm. (See 'Isolated third nerve palsy' below.)

●Signs that localize to the cavernous sinus or orbital apex indicate a brain MRI with gadolinium [14]. (See 'Cavernous sinus lesions' above and 'Superior orbital fissure/Orbital lesions' above.)

Isolated third nerve palsy — The diagnostic approach to the patient with an isolated third nerve palsy differs among clinicians, and some issues remain controversial. Considerations include the extent of internal and external third nerve dysfunction, the age of the patient, and medical comorbidity [12,14]. While a selective approach to imaging is presented here, some clinicians recommend neuroimaging for all third nerve palsies regardless of pupil involvement, pain, age, or presence/absence of vasculopathic risk factors.

Evaluation for intracranial aneurysm — On presentation, the first consideration is to assess the risk of an underlying intracranial aneurysm because of the potential risk of imminent subarachnoid hemorrhage. Imaging studies used to diagnose or exclude an intracranial aneurysm include contrast-enhanced MRI with MR angiography (MRA), computed tomographic angiography (CTA), and cerebral angiography. Cerebral angiography remains the gold standard test but is invasive and associated with infrequent but significant risk [34-37]. The risk of the catheter angiography must therefore be weighed against the risk of missing an aneurysm in the individual patient. Factors to consider include:

●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]. The quality and reliability of each of these studies and their interpretation are to some extent institution-specific and should be ordered in consultation with the interpreting neuroradiologist [38]. 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. (See "Unruptured intracranial aneurysms", section on 'Diagnosis'.)

●The risk of standard catheter angiography also depends on institution-specific factors as well as on patient age and medical comorbidity.

●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].

When indicated, testing to exclude intracranial aneurysm should proceed emergently, as the risk of aneurysm rupture may be imminent.

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. A single case has been reported due to a basilar artery aneurysm, but this is exceptional [17].

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]. In some hospitals, combined examination with CT and CTA may be superior to MRA for aneurysm evaluation. However, MRI is superior to CT for imaging the cavernous sinus, posterior fossa, and meninges and is the preferred imaging study for third nerve palsy.

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. (See "Clinical manifestations of giant cell arteritis".)

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.

Third nerve palsy with complete internal dysfunction (pupil-involved) and complete or incomplete external dysfunction — 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.

Other patterns of isolated third nerve deficits — Other patterns of isolated third nerve deficits include incomplete external dysfunction with no pupil involvement (eg, divisional palsy) and incomplete or complete external dysfunction with partial internal dysfunction (relative pupil-sparing). These patients should undergo a contrast-enhanced brain MRI to exclude a mass lesion, with an MRA or CTA to look for an aneurysm or other mass lesion. If negative, catheter angiography should be considered to further investigate the presence of an aneurysm or the less likely possibility of a posterior draining carotid-cavernous sinus fistula [2]. In this intermediate risk category, individual and institution-specific assessments of risks and benefits determine the choice of testing.

As discussed above, 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 after neuroimaging.

Isolated third nerve palsy with signs of aberrant regeneration — 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.

TREATMENT AND PROGNOSIS — Therapy is directed at the underlying etiology of the third nerve palsy.

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].

Intervention for an aneurysmal third nerve palsy is primarily directed at preventing subarachnoid hemorrhage. Recovery of third nerve function occurs in most who undergo either neurosurgical clipping or endovascular embolization, but may be incomplete [3,14,37,42-53]. The time course of recovery varies from a few weeks to several months, and may be influenced by the degree and/or duration of deficit preoperatively [42,54]. (See "Unruptured intracranial aneurysms", section on 'Management'.)

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. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Overview of secondary prevention of ischemic stroke".)

Patients who have traumatic third nerve palsies, particularly those who have partial palsies, may experience spontaneous resolution, but the prognosis is not as favorable as with ischemic lesions [14].

Persistent deficits — Patching one eye is useful in alleviating diplopia, particularly in the short term.

Prism therapy may be employed for small, comitant, long-standing deviations. "Comitant" deviations are those in which the distance between the double images is little affected by the direction of gaze. A temporary press-on (Fresnel) prism of sufficient power to align the eyes is placed on the spectacle lens of the affected child. Prisms can be ground into the spectacle lens if the patient has a stable but symptomatic deviation alleviated with prism.

Strabismus surgery may be helpful in patients who fail prism therapy. However, this surgery is difficult to perform, particularly in those with complete third nerve palsies, because multiple muscles are involved; ocular alignment in primary position might be achievable but might require multiple procedures [49,55].

Ptosis surgery may be necessary in some patients. (See "Overview of ptosis", section on 'Management'.)

SUMMARY AND RECOMMENDATIONS

●A third cranial nerve palsy can result from lesions anywhere along its path between the oculomotor nucleus in the midbrain and the extraocular muscles within the orbit. (See 'Anatomy' above.)

●Deficits resulting from a third nerve palsy with complete external dysfunction include ptosis and paralysis of adduction, elevation, and depression. Complete internal (pupil sphincter) dysfunction is manifested by a large, unreactive pupil. Partial internal dysfunction can produce anisocoria with a sluggish but reactive pupil. Third nerve palsies are classified as being neurologically isolated or neurologically nonisolated. (See 'Clinical manifestations' above.)

●Associated clinical features, particularly other neurologic deficits, can help localize the site of injury and identify possible etiologies (table 1). (See 'Clinical manifestations' above.)

●The most feared cause of an isolated acute third nerve palsy is an intracranial aneurysm because of its attendant risk of potentially fatal subarachnoid hemorrhage. (See 'Etiology' above.)

●A patient with acute third nerve palsy and sudden headache and/or meningeal signs should have an emergent noncontrast head computed tomography (CT) to look for subarachnoid hemorrhage. Other testing should follow if suspicion for aneurysmal subarachnoid hemorrhage remains. (See 'Nonisolated third nerve palsy' above and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

●Other patients with nonneurologically isolated third nerve palsy should undergo neuroimaging (contrast-enhanced magnetic resonance imaging (MRI) with MR angiography or CT angiography) and if that is negative, lumbar puncture or other laboratory testing. (See 'Nonisolated third nerve palsy' above.)

●For isolated third nerve palsies, the degree of external and internal dysfunction can be used to determine the type and urgency of imaging, including the risk to benefit analysis for proceeding to catheter angiography (table 2). (See 'Isolated third nerve palsy' above.)

●Observation alone is appropriate only for isolated third nerve palsies with complete external dysfunction and normal internal function (pupil-sparing) in an older patient with vascular risk factors who improves and does not develop aberrant regeneration. However, some clinicians recommend neuroimaging for all third nerve palsies regardless of pupil involvement, pain, age, or presence/absence of vasculopathic risk factors. (See 'Isolated third nerve palsy' above.)

●Cranial contrast enhanced MRI with MR angiography, or cranial contrast enhanced CT angiography followed by MRI/MRA are appropriate initial imaging strategies for other presentations of third nerve palsy. (See 'Isolated third nerve palsy' above.)

●Catheter angiography might still be necessary in patients with a high pretest likelihood of aneurysm (eg, pupil-involved third nerve palsy) even in the setting of a negative MRI with MRA or CTA, depending on institution and patient-specific factors. (See 'Isolated third nerve palsy' above.)

●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).