Third cranial nerve (oculomotor nerve) palsy in children

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. Third nerve palsy may herald a life-threatening intracranial process (eg, tumor, aneurysm). 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 will be reviewed here. Palsies of the fourth and sixth cranial nerves are considered separately. (See "Fourth cranial nerve (trochlear nerve) palsy" and "Sixth cranial nerve (abducens nerve) palsy".)

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. The superior oblique muscle is innervated by cranial nerve IV and the lateral rectus muscle by cranial nerve VI (table 1). 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. It 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.

●The levator subnucleus is a single central caudate nucleus and innervates both 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). It 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 (figure 1).

CLINICAL MANIFESTATIONS

History — Patients with acquired third nerve palsies usually complain of the sudden onset of binocular horizontal, vertical, or oblique diplopia and a droopy eyelid. Children with congenital third nerve palsies may not complain of diplopia because they ignore or suppress the second image or because they have superimposed amblyopia; often they are brought to medical attention by their parents or caregivers, who have noticed ptosis or strabismus. (See "Evaluation and management of strabismus in children", section on 'Evaluation'.)

Eye examination

General findings — On physical examination, they may have a partial or complete ptosis (picture 1). The pupil may be of normal size and normally reactive, dilated and poorly reactive, or dilated and nonreactive to light and near stimulus. Deficits in ipsilateral adduction (medial rectus), elevation (superior rectus, inferior oblique), and/or depression (inferior rectus) may be present.

We consider third nerve palsies to be complete if impairment of the majority of function of all the somatic branches of the oculomotor nerve is present and ptosis is complete or almost complete.

●If the deficit of adduction is significant, a primary position exotropia (eye is turned out) worse in gaze toward the paretic medial rectus muscle occurs (figure 2).

●If the elevator muscles (eg, superior rectus or inferior oblique muscles) are involved, an ipsilateral hypotropia (eye is turned down) occurs (picture 1).

●If the inferior rectus muscle is more involved, an ipsilateral hypertropia (eye is turned up) occurs.

●Complete third nerve palsies usually are associated with a large-angle exotropia and hypotropia (eye is down and out) [1-8].

The remainder of the clinical presentation varies depending upon the location and type of lesion.

Nuclear lesions — Lesions of the third nerve nucleus are rare and usually are associated with other signs of mesencephalic (midbrain) involvement as described below. The levator palpebrae superioris muscles (which control the eyelids) are controlled by a single central subnucleus. Thus, in patients with nuclear lesions, they are affected either bilaterally or not at all. Nuclear lesions also can cause isolated muscle involvement of the extraocular muscles that are innervated by the third nerve.

●The most characteristic finding of a nuclear lesion is unilateral third nerve palsy with weakness of the ipsilateral and contralateral superior rectus (the superior rectus subnucleus is crossed) and bilateral incomplete ptosis (single central caudate subnucleus).

●Bilateral third nerve palsies with sparing of the eyelids (single levator subnucleus) and isolated bilateral ptosis with sparing of the extraocular muscles and pupils also can occur in nuclear lesions.

●Nuclear third nerve palsies can be associated occasionally 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.

●Unilateral or bilateral isolated medial rectus paralysis is unlikely to be caused by a nuclear lesion; 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 (INO) caused by damage to the medial longitudinal fasciculus. (See "Internuclear ophthalmoparesis".)

Nuclear lesions that are caused by infarction often are accompanied by lesions of the third nerve fascicle because both these structures are supplied by the paramedian branches of the basilar artery. Rarely does a fascicular third nerve lesion occur in isolation without other neurologic signs or symptoms. Nuclear and fascicular lesions are "defined by the company they keep"; the involvement of other midbrain structures 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).

Extra-axial lesions — In adults, extra-axial third nerve palsies usually are caused by ischemia. By contrast, ischemia is a rare cause for third nerve palsy in children; trauma and congenital third nerve palsies are more common.

Other extra-axial causes include uncal herniation; aneurysms of the internal carotid-posterior communicating, superior cerebellar, basilar, or posterior cerebral arteries; infection, inflammation, and neoplastic invasion of the meninges; and trauma (including neurosurgical procedures).

Ischemic lesions typically present with intact pupillary function, 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) [1-8]. By contrast, aneurysmal compression of the superficial pupil fibers of the third nerve as it passes through the subarachnoid space usually results in a dilated and unresponsive pupil. This important differentiating feature affects the choice of imaging procedure as discussed below.

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

●Sixth cranial nerve – Horizontal diplopia; esotropia (inward deviation)

●First (ophthalmic) branch of the trigeminal nerve – Pain or numbness

●Oculosympathetic fibers – Horner syndrome (see "Horner syndrome")

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

ETIOLOGY — Third nerve palsy is uncommon in children. A population-based study in Minnesota identified 36 cases over a 15-year period; the age- and sex-adjusted annual incidence was 1.7 per 100,000 county residents under the age of 18 [9].

Third nerve palsy in children often is congenital (intrauterine or birth-related events) but may occur after postnatal trauma, infection, inflammation, tumor, or childhood migraine (table 2) [10-15]. Aneurysms are rare, but certain children are at increased risk (eg, those with polycystic kidney disease, coarctation of the aorta, or Ehlers-Danlos syndrome) [12]. Traumatic third nerve palsy usually arises only from severe blows to the head [12,16]. Thus, third nerve palsy associated with mild head trauma should prompt evaluation for associated pathology. (See 'Differential diagnosis' below.)

●One review at the Wilmer Eye Institute identified 41 children younger than eight years of age with third nerve palsy. The most frequent causes were congenital (39 percent), traumatic (37 percent), and neoplastic (17 percent) [15].

●In another study of 49 children with 53 affected eyes, the palsy was congenital in 20 eyes and caused by postnatal trauma in 17 eyes [10]. Tumor (6), vascular problems (6), and infection (3) were responsible for the remainder.

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

●Intracranial lesion (eg, compressive lesion, aneurysm).

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

●Congenital fibrosis of the extraocular muscles can mimic third nerve palsy. This condition is inherited in an autosomal-dominant pattern and may be associated with absence of the superior division of the third cranial nerve [17].

●Myasthenia gravis can mimic any painless, pupil-spared, nonproptotic ophthalmoplegia and should be considered in every patient with a pupil-spared complete or incomplete third nerve palsy [18]. 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 [19-22]. A positive test (≥2 mm improvement in ptosis) was 80 percent sensitive and 100 percent specific in one study [19], although some authors have questioned the pathophysiologic basis of the test as perhaps simply an augmented rest test. (See "Clinical manifestations of myasthenia gravis".)

●Skew deviation is a vertical misalignment caused by disruption of the vestibulo-ocular connections and can result in hypertropia. Usually, it is associated with other posterior fossa signs (eg, other cranial neuropathies, hemisensory loss, or hemiparesis). (See "Ocular gaze disorders", section on 'Skew deviation'.)

●Ophthalmoplegic migraine, a diagnosis of exclusion, can cause recurrent third nerve palsy in children. (See "Types of migraine and related syndromes in children", section on 'Associated nonmigrainous conditions'.)

EVALUATION — The evaluation of children with third nerve palsy is centered on determining the underlying etiology because the treatment varies depending upon the cause (table 2). Historical features may help to distinguish congenital, traumatic, or infectious conditions. Inflammatory, neoplastic, and vascular conditions may be more insidious. Although aneurysms are rare in children, certain clinical features should increase suspicion for aneurysm:

●Lack of vasculopathic risk factors or alternative etiology (eg, diabetes mellitus, hypertension, increased cholesterol).

●History of polycystic kidney disease, coarctation of the aorta, Ehlers-Danlos syndrome.

●Severe headache or other signs of subarachnoid hemorrhage (eg, loss of consciousness, seizure, nausea, vomiting, meningismus). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation'.)

Neuroimaging almost always is necessary. Lumbar puncture should be performed if signs or symptoms of meningeal inflammation or infection are present and in children who have pupillary involvement and negative radiologic evaluation. In addition, evaluation for myasthenia gravis and consultation with a neurologist, ophthalmologist, or neuro-ophthalmologist may be indicated. (See "Lumbar puncture in children".)

RADIOLOGIC EVALUATION — Computed tomographic (CT) scan, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and carotid angiography all can provide useful information in the evaluation of children with third nerve dysfunction.

●CT scanning is the least sensitive of the imaging modalities for detection of aneurysms [23], but it is better than MRI in detecting subarachnoid hemorrhage.

●At most centers, CT angiography (CTA) has emerged as the first-line noncatheter angiography study for the evaluation of possible aneurysm in third nerve palsy. In many institutions, CTA has surpassed MRA in sensitivity and specificity [24-27]. It is rapidly supplanting catheter angiography in aneurysm evaluation, particularly in children in whom the risk of aneurysm is presumably lower than in adult patients with pupil-involved third nerve palsy.

●MRA is noninvasive and more sensitive than MRI.

●CTA and MRA have been evolving each year. Each technique has advantages and disadvantages, and although catheter angiography arguably remains the reference standard for detection of aneurysms [23,28-30], it is associated with a 1 to 2 percent risk of neurologic (principally stroke) and systemic complications.

Many institutions consider CT-CTA to be the first-line imaging study for third nerve palsy in adults. There is insufficient literature on children with third nerve palsy to make a strong evidence-based recommendation for CTA over MRI and MRA as a first-line study.

Overview of imaging strategy — The choice of diagnostic imaging technique for a particular patient is dependent upon the age of the patient and the clinical circumstances. The optimal imaging strategy permits the detection of significant intracranial pathology (eg, tumor, aneurysm) and minimizes the potential hazards (eg, radiation, sedation, neurologic compromise).

Third nerve palsies can be divided into those that are isolated and those that are accompanied by other contributory neurologic findings ("nonisolated"), as well as by the degree of involvement of the extraocular muscles and pupil [31].

●Patients with a nonisolated third nerve palsy require imaging directed at the topographical localization.

●Patients with isolated pupil-involved third nerve palsies should undergo neuroimaging and some type of angiography study to exclude aneurysm, even though aneurysm is uncommon in children. CTA is typically the first-line study, but in some cases, catheter angiography may still be required.

•In patients with a moderate or uncertain risk of aneurysm, the combination of magnetic resonance and MRA (or CTA) may not be sufficient to exclude aneurysm. In these cases, catheter angiography should be considered, even in a child.

•If the risk of aneurysm is low, or the risk of angiography is high (eg, high risk of renal failure, anaphylactic reaction, risk of stroke), MRI and MRA (or CTA) alone may be reasonable, provided that the clinician is confident in the capability, availability, and reliability of the neuroradiologist and the imaging technology.

●In patients with a low risk of aneurysm (ie, isolated complete third nerve palsy with normal pupillary function) and a high risk of angiography, catheter angiogram may be deferred.

Isolated third nerve palsies

Congenital or long-standing third nerve palsy — Congenital or long-standing third nerve palsies may not require neuroimaging if they are static. Patients with progressive disease, new neurologic findings, or uncertain etiology may require neuroimaging (usually with magnetic resonance).

Complete third nerve palsy with pupillary sparing — Children and young adults who have isolated complete third nerve palsies and normal pupillary function, particularly those without vasculopathic risk factors (diabetes mellitus, hypertension, and increased cholesterol), should have neuroimaging (usually magnetic resonance scan of the brain and orbit) to rule out intracranial mass lesions or developmental brain anomaly [32]. These patients generally do not need angiography.

Neuroimaging may be deferred in adult patients who have ischemic third nerve palsies. In children, however, ischemia is an uncommon etiology for third nerve palsy, and neuroimaging is recommended. All patients should be examined at 24- to 48-hour intervals for one week, because some patients with aneurysms develop delayed pupil involvement.

Partial third nerve palsy and pupillary sparing — Patients with incomplete motor third nerve palsy with pupillary sparing require a magnetic resonance scan to rule out a mass lesion. Aneurysm is an extremely uncommon cause for a third nerve palsy in children. MRI and MRA or CTA probably are sufficient to exclude aneurysm in patients with low suspicion of intracranial aneurysm. As a general rule, these patients do not require catheter angiography unless they are at high risk for intracranial aneurysms (eg, polycystic kidney disease, coarctation of the aorta, or Ehlers-Danlos syndrome) [12].

Catheter angiography should be considered in all patients, including children, if the clinical findings are highly suggestive of aneurysm (eg, severe headache or other signs of subarachnoid hemorrhage) and the magnetic resonance scan is normal.

Third nerve palsy with impaired pupillary function — Third nerve palsies with complete pupilloparesis are often due to compressive lesions (eg, aneurysm) or meningeal inflammation. Aneurysm is an uncommon cause of third nerve palsy in children, but the diagnosis must be pursued in all children with otherwise unexplained pupillary involvement.

Some type of angiography (CTA versus catheter angiography) should still be considered in all patients with complete pupil involvement or other clinical evidence for aneurysm (eg, severe headache or other signs of subarachnoid hemorrhage). The risk of catheter angiography must be weighed against the risk of observation. At selected institutions, the use of CTA may be sufficient if the quality of the study and interpretation are adequate to exclude aneurysm and the clinical suspicion is low.

Children with these findings also should undergo neuroimaging, usually with magnetic resonance. CT imaging may be preferred if there are signs or symptoms of subarachnoid hemorrhage, because noncontrast CT scan is better able to detect hemorrhage. In addition, CT may be more readily available than MRI and can be combined with a CTA. MRI, however, is better for imaging the course of the third cranial nerve and for detecting nonaneurysmal etiologies for third nerve palsy. Consultation with a neuroradiologist may be helpful in determining the optimal imaging modalities and the order of imaging (CT/CTA first versus MRI/MRA first) in children with a third nerve palsy.

Nonisolated third nerve palsies — Children with nonisolated third nerve palsies should undergo neuroimaging (preferably MRI with contrast) with attention to the topographic areas suggested by the associated neurologic signs and symptoms.

TREATMENT — Therapy should be directed at the underlying etiology of the third nerve palsy. The goal is to maximize visual function, including alignment.

●Children with infectious, inflammatory, or neoplastic lesions should receive appropriate therapy.

●Patients with known vasculopathic risk factors and acute, isolated, pupil-spared nerve palsies may be observed for improvement; their vasculopathic risk factors should be controlled. The majority of ischemic third nerve palsies, including those related to migraine headaches, usually improve with time.

●Children who have traumatic third nerve palsies, particularly those who have partial palsies, may experience spontaneous resolution. Improvement usually occurs within the first several months after trauma.

●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. Permanent prisms can be ground into the spectacle lens if the patient is happy with the result and the deviation fails to improve spontaneously.

●Strabismus surgery may be helpful in patients who fail prism therapy. However, this surgery is difficult to perform, particularly in children who have complete third nerve palsies, because multiple muscles are involved; ocular alignment may occur at the expense of more severe ophthalmoplegia. Ocular alignment can ultimately be achieved, but multiple procedures may be necessary, and binocular function often remains impaired [10,33].

●Amblyopia therapy may be effective in maintaining visual function in children who have congenital disease. Improvement in visual acuity is difficult to achieve, and visual outcome usually is poor in children younger than eight years of age [15].

●Ptosis surgery may be necessary in some patients.

COMPLICATIONS — The development of amblyopia is the major complication of third nerve palsy in children. It occurs in as many as 50 to 75 percent [10] and is caused by ptosis (deprivation amblyopia), loss of accommodation, and strabismus (ocular misalignment).

Aberrant regeneration of the third nerve causes lid gaze or pupil gaze synkinesia and is another complication of third nerve palsy in children [12]. In one study, it was present in 9 of 20 patients (45 percent) [15].

SUMMARY AND RECOMMENDATIONS

●The third cranial nerve (oculomotor nerve) supplies the levator muscle of the eyelid and four extraocular muscles (table 1). It also constricts the pupil. (See 'Anatomy' above.)

●Patients with acquired third nerve palsies usually complain of the sudden onset of binocular horizontal, vertical, or oblique diplopia and a droopy eyelid. Children may present after parents or caregivers notice ptosis or strabismus. (See 'History' above.)

●Examination findings may include partial or complete ptosis (picture 1); deficits in ipsilateral adduction, elevation, and/or depression (figure 2); and pupillary abnormalities. Other findings vary depending upon the location of the lesions. (See 'Eye examination' above.)

●The differential diagnosis includes intracranial lesions (compressive lesions and, less likely, aneurysm), orbital disease (fracture, tumor, inflammation), congenital fibrosis of the extraocular muscles, myasthenia gravis, skew deviation, and ophthalmoplegic migraine. (See 'Differential diagnosis' above.)

●The evaluation of children with third nerve palsy is centered on determining the underlying etiology (table 2), which affects treatment. (See 'Evaluation' above and 'Treatment' above.)

●Neuroimaging is almost always necessary. The approach to neuroimaging varies depending upon the age of the child and the clinical circumstances (eg, whether the third nerve palsy is isolated or associated with other neurologic findings and the degree of involvement of the extraocular muscles and pupil). Consultation with a neuroradiologist may be helpful in determining the optimal imaging modalities and the order of imaging, particularly when aneurysm is a consideration. (See 'Radiologic evaluation' above.)

●Amblyopia is the major complication of third nerve palsy in children. (See 'Complications' above and "Amblyopia in children: Classification, screening, and evaluation".)