The third, fourth, and sixth cranial nerves innervate the extraocular muscles that position the globes in the orbits. Extraocular muscle paralysis resulting from lesions in one or all of these cranial nerves results in failure of one or both eyes to rotate in concert with the other eye.
The primary symptom is diplopia caused by misalignment of the visual axes, and the pattern of image separation is the key to diagnosing which particular ocular motor cranial nerve (and extraocular muscle) is involved. With unilateral third cranial nerve palsy (ie, oculomotor nerve palsy), the involved eye usually is deviated "down and out" (ie, infraducted and abducted), and there may be partial or complete ptosis. In addition, pupillary dilatation can cause anisocoria (greater in the light), symptomatic glare in bright light, and accommodation deficit that may cause blurred vision for near objects.
A painful pupil-involved oculomotor nerve palsy may result from a life-threatening intracranial aneurysm. Therefore, recognition of oculomotor nerve palsy is critical to ensure prompt and appropriate evaluation and treatment.
See the image below.
View Image
Patient with left posterior communicating artery aneurysm and third cranial nerve palsy. Courtesy of James Goodwin, MD.
The anatomical relationship of the various portions of the oculomotor (third) cranial nerve accounts for many of the clinical features of third cranial nerve palsy as outlined below.
Nuclear portion: The cell bodies for axons that travel in the oculomotor nerve reside in the column-shaped nuclear groups on either side of the midbrain tegmentum. The axons destined for each extraocular and intraocular muscle derive from a specific subnucleus.[1] Interestingly, the superior rectus muscle is innervated by the contralateral subnucleus. Nuclear third nerve lesions may be isolated or may be accompanied by other neurologic symptoms given the proximity of the nucleus to other important brainstem structures.
Fascicular intraparenchymal midbrain portion: The fascicular portion of the oculomotor nerve courses ventrally from the nucleus in the dorsal midbrain tegmentum, passes through the red nucleus near the corticospinal tract, and emerges from the medial aspect of the cerebral peduncle. Because of its proximity to other midbrain structures, lesions in the fascicular portion of the nerve typically produce associated neurological findings in addition to oculomotor palsy.[2]
Subarachnoid portion: The cisternal portion of the nerve courses in the subarachnoid space anterior to the midbrain after exiting between the superior cerebellar artery and posterior cerebral artery and running in close proximity to the posterior communicating artery. Berry aneurysm at the junction between the posterior communicating artery and the internal carotid artery is an important cause of an otherwise isolated oculomotor nerve palsy.
Cavernous sinus portion: The next segment of the oculomotor nerve runs through the lateral wall of the cavernous sinus superiorly. It enters the cavernous sinus just above the petroclinoid ligament and inferior to the interclinoid ligament. Although the sixth cranial nerve is the most affected by intrinsic lesions of the cavernous sinus, masses invading the cavernous sinus from within the sella often cause third cranial nerve dysfunction prior to involvement of the other cranial nerves. This is probably because of the oculomotor nerve's close proximity to the unyielding interclinoid ligament above and the petroclinoid ligament below. Cavernous sinus lesions that produce a third nerve palsy are typically accompanied by one or more other neurologic findings (eg, IV, V, VI, or Horner syndrome).
Orbital portion: The oculomotor nerve enters the orbit through the superior orbital fissure adjacent to the fourth cranial nerve. The nerve branches into superior and inferior divisions, usually within the posterior orbit, but, occasionally, the branching occurs as far back as the cavernous sinus segment. The superior division innervates the levator palpebrae and the superior rectus muscles; the inferior division innervates all the other muscles innervated by the third nerve and supplies the preganglionic parasympathetic fibers to the ciliary ganglion, which innervates the iris sphincter to constrict the pupil. Orbital lesions may show proptosis if large enough.
The axons for most of the muscles are uncrossed from the nucleus to the eye, but there are 2 exceptions: (1) Axons for the levator palpebrae come from both sides of the central caudal subnucleus via bilateral, crossed, and uncrossed pathways. (2) Those for the superior rectus muscle come from the superior rectus subnucleus on the contralateral side.
The pupillomotor and ciliary muscle neurons derive from the Edinger-Westphal subnucleus, which is in the midline in the most rostral and anterior part of the oculomotor nerve nucleus. These autonomic pathways are all ipsilateral or uncrossed.
The oculomotor nerve innervates the following extraocular muscles of each eye: superior rectus, inferior rectus, medial rectus, inferior oblique, levator palpebrae superioris, ciliary muscle, and iris sphincter.
Oculomotor nerve palsy is uncommon, and its frequency varies depending on the etiology.
Mortality/Morbidity
Morbidity and mortality are essentially those of the diseases that cause oculomotor nerve palsy and are beyond the scope of this article.
The most significant causes of mortality and morbidity along with oculomotor nerve palsy are subarachnoid hemorrhage from ruptured berry aneurysm of the posterior communicating artery, and meningitis or meningeal infiltrative disorders, both infectious and neoplastic.
The prognosis of an oculomotor palsy depends on the etiology. Posttraumatic, postinfectious, postinflammatory, and ischemic oculomotor palsies may partially or completely recover spontaneously. Compressive lesions (eg, aneurysm or tumor) that are treated endovascularly or surgically may also improve or resolve following treatment. Patients with chronic and stable ptosis or ophthalmoplegia due to oculomotor nerve palsy may benefit from reconstructive lid or strabismus surgery.
Patients should be informed of the potentially life-threatening etiologies of unexplained oculomotor nerve palsy. They should undergo appropriate evaluation and treatment of underlying etiologies and understand the prognosis for recovery.
The following symptoms are encountered with lesions producing third cranial nerve dysfunction:
The most common lesions to affect the third cranial nerve involve the peripheral nerve or fascicular portion of the nerve at some level. The symptoms reflect reduced function in the muscles innervated by the nerve, usually in combination; isolated involvement of one or another muscle from nuclear or fascicular third cranial nerve lesions is very rare. The prime symptom is mixed horizontal and vertical binocular diplopia.
Ptosis may be partial or complete. Nuclear lesions that spare the central caudate subnucleus to the levator palpebrae superioris may produce third nerve palsies without ptosis. If the ptosis is sufficient to cover the pupil, the patient may complain that he or she cannot see from the eye on the involved side or may not have diplopia because the ptosis is acting as an “occluder.”
Ipsilateral pupil mydriasis, anisocoria, and lack of light/near reaction produces little in the way of symptoms, although there may be some glare sensation and photo aversion in bright light.
Neurologic symptoms
Neurologic symptoms associated with lesions involving various portions of the third cranial nerve include those discussed below.
Nuclear portion
Most of the lesions causing nuclear third cranial nerve palsy are due to dorsal midbrain infarction and commonly result in bilateral ocular symptoms. These tend to be small lesions with few associated neurologic symptoms or signs.
Fascicular midbrain portion
Lesions in the fascicular midbrain portion can lead to complete or incomplete palsies that may be indistinguishable from lesions outside the midbrain. Because of the proximity of the fascicular portion of the nerve to other structures in the midbrain, lesions typically produce neurologic symptoms associated with the damaged structures. Several syndromes have been recognized and are described below.
Nothnagel syndrome, which results from a lesion involving the fascicles and the superior cerebellar peduncle, includes third cranial nerve palsy and ipsilateral cerebellar ataxia.
Claude syndrome, although caused by involvement of the same structures as Nothnagel syndrome, includes third cranial nerve palsy and contralateral cerebellar ataxia.[2]
Benedikt syndrome results from involvement of the fascicles and the red nucleus and includes third cranial nerve palsy, contralateral flapping hand tremor (rubral tremor), and ataxia.
Weber syndrome results from a slightly more ventral lesion at the level of the fascicles in the midbrain with involvement of the cerebral peduncle, giving rise to third cranial nerve palsy along with contralateral hemiplegia or hemiparesis.
Subarachnoid portion
The fascicles of the third cranial nerve exit the mid brain through the medial aspect of the cerebral peduncles and are not near any of the other cranial nerves at this point.
The findings of third cranial nerve palsy tend to occur in isolation from lesions in this location. The pupil fibers are superficially located within the third cranial nerve in this location; therefore, pupil involvement is a common presentation of subarachnoid space compression of the nerve (eg, aneurysm).
Since the most common lesion to affect the third cranial nerve in the subarachnoid space is aneurysm, the signs and symptoms of subarachnoid hemorrhage, including sudden severe headache, stiff neck, and loss of consciousness, may be present.
Infundibulum refers to widening of the proximal segment of the posterior communicating and other arteries, and, unlike aneurysm in this location, it is usually asymptomatic. A case of posterior communicating artery infundibulum has been reported to cause recurrent ipsilateral third cranial nerve palsy and headache that masqueraded as ophthalmoplegic migraine.[3]
Ophthalmoplegic migraine presents in childhood with recurring bouts of unilateral headache and ipsilateral third cranial nerve palsy that can last several weeks at a time. The link to migraine in general has come under question because many or most of these patients demonstrate thickening and enhancement of the cisternal portion of the third cranial nerve on MRI with gadolinium.[4]
Basal meningeal infection, neoplastic infiltration, and miscellaneous inflammatory lesions may involve the third and all the other cranial nerves. The primary symptoms of meningitis are often present, including headache, stiff neck, fever, and alteration of consciousness. Eventually, these diseases tend to involve other cranial nerves, which is not the case with a very localized lesion, such as berry aneurysm.
Cavernous sinus portion
The third cranial nerve is more susceptible to compression against the interclinoid ligaments above and the petroclinoid ligament below than are the other cranial nerves in the cavernous sinus. For this reason, isolated third cranial nerve palsy may result from lateral extension of pituitary adenoma or other primary intrasellar mass.
More diffuse lesions within the cavernous sinus, often inflammatory in nature, typically give rise to simultaneous involvement of the third, fourth, sixth, and first 2 divisions of the fifth cranial nerves in various combinations, which serve to define a cavernous sinus syndrome. The sixth cranial nerve is the most commonly affected in these cases, as it resides within, and not around, the cavernous sinus. Nonspecific, idiopathic, and presumed granulomatous inflammation within the cavernous sinus is referred to as Tolosa-Hunt syndrome, which produces an acute, steroid-responsive, painful ophthalmoplegia.
Involvement of the fourth cranial nerve in the setting of a third cranial nerve palsy should be assessed by evaluating for intorsion in downgaze. The absence of intorsion suggests concomitant fourth (on top of third) cranial nerve palsy and may localize to the ipsilateral cavernous sinus.
Often, the involvement of the first 2 divisions of the fifth cranial nerve (trigeminal) presents with severe pain and numbness in the face, including the forehead back to the interaural line and the cheek down to the angle of the mouth. The pain may be constant and burning with unpleasant paresthesia, or it may include a lancinating component that can be confused with trigeminal neuralgia.
Carotid artery dural branch to cavernous sinus fistulas typically present with third cranial nerve palsy plus other cranial nerve involvement in the cavernous sinus and proptosis with arterialized episcleral/conjunctival veins due to a large volume shunt of arterial blood into the anterior draining veins of the cavernous sinus. Isolated third cranial nerve involvement without the orbital congestion can occur when the primary drainage is posterior from the cavernous sinus, the so-called white eye fistulas.[5]
Orbital portion
Lesions (eg, inflammatory, infectious, infiltrative, neoplastic, vascular, among others) in the orbit tend to produce associated proptosis, lid swelling, conjunctival injection, and chemosis.
There also may be involvement of the other cranial nerves that innervate extraocular muscles (fourth and sixth) or involvement of the muscles themselves.
Nonspecific idiopathic inflammation in the orbit is referred to as idiopathic orbital inflammatory syndrome (ie, orbital pseudotumor). Granulomatous and nongranulomatous lesions may also produce orbital involvement of the third cranial nerve.
Initially, physical findings attributable to involvement of the third cranial nerve are described (eg, ptosis, mydriasis, ophthalmoplegia). Subsequently, additional physical findings that are associated with lesions of particular portions or segments of the third cranial nerve are described.
Unilateral third cranial nerve palsy
Horizontal deviation is divergent or temporal (exotropia) because of weakness of the medial rectus muscle of the involved side. Vertical deviation results from weakness of the superior rectus, inferior oblique (both elevators), and inferior rectus (depressor) muscles.
Residual function of both the superior oblique muscle (depressor, intact fourth cranial nerve function) and the lateral rectus muscle (abductor, intact sixth cranial nerve function) tends to produce downward and outward deviation of the involved eye. A way to remember this combination is to think of a losing boxer, "down and out."
In very mild cases, one might have to resort to eliciting latent deviation or phoria with Maddox rod or alternate cover testing (to dissociate the 2 eyes and interrupt fusion).
Ptosis results from weakness of the levator palpebrae, and this often is complete or nearly so, in which case the pupil is covered and the patient cannot see from the involved eye.
Milder degrees of ptosis are examined best using measurements of the palpebral fissure width; more information can be gained from measuring the levator function and margin reflex distances (MRD), as follows:
The examiner sits in front of the patient and directs a point source of light (eg, handlight, Finnoff head, penlight) into both the eyes of the patient.
The examiner can observe the pinpoint light reflex in the center of the cornea. The position of this reflex is not affected by deviation of the eye, which makes it a useful reference point for measuring the distance to the upper and lower lids, respectively.
The MRD1 usually refers to the distance from the light reflex to the upper lid margin, and the MRD2 is the distance to the lower lid margin.
Levator palpebrae weakness reduces the MRD1 but will not affect the MRD2. On the other hand, ptosis from ocular sympathetic palsy (Horner or Claude Bernard syndrome) causes weakness of Mueller muscle in both the upper and lower lids, with consequent reduction of both the MRD1 and the MRD2.
Pseudoptosis from widening of the contralateral palpebral fissure may result from mild or old contralateral seventh cranial nerve lesion and orbicularis oculi weakness. In both these cases, MRD1 and MRD2 are increased on the side opposite to the apparent ptosis.
Careful examination of facial muscle strength and symmetry usually confirms the cause of the apparent ptosis in these cases.
Pupillary dilatation and sluggish or absent reaction to light results from involvement of parasympathetic fibers that originate in the Edinger-Westphal subnucleus of the third cranial nerve complex, as follows:
Fascicular or peripheral nerve involvement caused by compressive lesions often affects these autonomic fibers because they are situated very superficially within the nerve trunk.
This contingent of fibers are medially placed as the nerve exits the brainstem and gradually migrate to a more inferior and lateral position as they proceed anteriorly along the nerve.
If there is partial preservation of parasympathetic pupillary innervation with third cranial nerve disorders, the pupil on the involved side may react to light nearly as briskly as the pupil of the other eye, as follows:
Distinguishing pupillary involvement caused by third cranial nerve lesions from ocular sympathetic palsy (Horner or Claude Bernard syndrome) or physiological anisocoria requires detailed examination of pupil size in dim and in bright, ambient light. Third nerve palsy mydriasis can coexist with Horner syndrome–related miosis (eg, cavernous sinus lesion), and the two pupillary effects may obscure the diagnosis or cancel out the anisocoria in ambient lighting.
With sphincter weakness due to parasympathetic involvement in third cranial nerve lesions, the involved pupil is larger than the fellow pupil. However, with concomitant Horner syndrome or aberrant regeneration of the pupil, the pupil may be smaller rather than larger in a third nerve palsy.
The size difference between the 2 pupils (anisocoria) is greater in bright light (when the sphincter is called upon to act most strongly) and lesser in dim light (when the sympathetically innervated dilator fibers are the dominant contributors to pupil size). The reverse is true for ocular sympathetic lesions, in which the pathological pupil is the smaller one and the difference (anisocoria) is greater in dim light than in bright light. The anisocoria remains the same in dim and bright light in simple central anisocoria, also called physiological anisocoria.
Nuclear portion
Nuclear third cranial nerve palsy demonstrates, in addition to the ipsilateral findings, contralateral ptosis or no ptosis (single central caudate subnucleus innervates both lids) and elevation palsy (superior rectus subnucleus is crossed).
The contralateral ptosis stems from the bilateral distribution of innervation to the levator from the caudal central subnucleus.
Ptosis is typically more complete ipsilateral to the lesion because function is lost in both the ipsilateral neural cell bodies and their fibers on the lesioned side, plus the crossed fibers coursing through the lesion from the other side.
There is partial ptosis contralateral to the lesion because of the residual integrity of the uncrossed neural cell bodies and fibers from the caudal central subnucleus contralateral to the lesion.
Superior rectus nucleus output is totally contralateral with fascicles from the nucleus on one side coursing through the opposite superior rectus subnucleus. A lesion of the superior rectus subnucleus on one side causes bilateral elevation palsy. The deficit ipsilateral to the lesioned nucleus reflects involvement of fascicles coming from cell bodies on the opposite side, and the deficit contralateral to the lesion reflects loss of the cell bodies in the lesioned nucleus.
Fascicular midbrain portion
Ask the patient to hold both arms outstretched in front of them.
Patients with Benedikt syndrome have a gross "flapping" tremor that has been attributed to red nucleus involvement, usually from midbrain infarction. The tremor and ataxia are contralateral to the lesion and to the third cranial nerve palsy.
In Weber syndrome, the patient usually has a dense hemiplegia contralateral to the third cranial nerve palsy resulting from a lesion that also involves the pyramidal tract motor pathways in the cerebral peduncle. This should be obvious on simple inspection of the patient, since it is usually a fairly prominent hemiplegia.
Subtle hemiparesis may be observed by asking the patient to hold both arms outstretched forward with palms rotated upward. Slight pronation of the turned-up hand and downward drift of the outstretched arm are sensitive indicators of even very mild hemiparesis.
The hemiparetic gait is also characteristic with foot drop causing circumduction as the involved leg is swung out and forward before the next step. The arm on the involved side typically is held semiflexed at the elbow and wrist as the patient walks.
Another subtle sign in very mild hemiparesis is loss of the associated arm swing on the involved side as the patient walks.
Fascicular subarachnoid portion
Many patients who have had subarachnoid hemorrhage from rupture of a berry aneurysm have alteration of consciousness and may be difficult to examine. Even if they cannot co-operate with ocular motility assessment, the findings of a dense third cranial nerve palsy should be obvious. The eye on the involved side is deviated "down and out" from residual tone in the fourth cranial nerve (superior oblique muscle) and the sixth cranial nerve (lateral rectus muscle).[6, 7]
Usually, there is prominent ptosis also, but this may be difficult to observe if the patient is unconscious with eyes closed. Efforts should be made to arouse the patient at least to the point that there is some effort at eye opening, when the ptosis should be apparent.
The dilated, light-fixed pupil should be apparent on inspection without requiring any co-operation from the patient.
Pupillary involvement is the rule in third cranial nerve palsy resulting from posterior communicating artery aneurysm, with or without overt subarachnoid hemorrhage. In more than 95% of aneurysmal palsies, the pupil reacts sluggishly to light or is fixed and dilated, but, in 73%, of ischemic palsies, the pupil is spared. These observations have led to the pupil-sparing rule, which states that patients with third nerve palsies that spare the pupil do not have aneurysms and can be safely managed expectantly. Three important caveats are as follows:[8, 9, 10, 11, 12, 13, 14, 15]
Patients must have complete paralysis of the ocular muscles of the cranial nerve III and complete sparing of the pupil.
This rule should be applied sparingly to patients aged 20-50 years, an age group in whom ischemic infarcts are uncommon.
Patients should have isolated third nerve palsies.
This is probably because the pathophysiology of the third cranial nerve lesion involves leakage of blood from the aneurysm dome into the nerve across its outer margin. The pupil fibers are located very superficially and are nearly always involved in this process. On the other hand, pupil-sparing third cranial nerve palsy is a hallmark of ischemic lesions that tend to involve the central core of the nerve. This is the type of nonsurgical or medical third cranial nerve palsy that often results from microvascular disease and tends to resolve uneventfully within a few weeks.
Fascicular cavernous sinus portion
Fourth cranial nerve palsy
Fourth cranial nerve palsy is difficult to diagnose in the presence of third cranial nerve palsy because the small increment of depressor deficit (superior oblique muscle) cannot be discerned readily from the depressor palsy that results from weakness of the third nerve innervated depressor (inferior rectus muscle).
The superior oblique muscle depresses the globe most efficiently with the eye in adduction, a position that may not be achievable with medial rectus palsy from third cranial nerve involvement.
The best marker for fourth cranial nerve function in the presence of dense third cranial nerve palsy is intorsion of the globe on attempted down gaze. If no intorsion is present, one should suspect concomitant fourth cranial nerve palsy as part of a cavernous sinus syndrome. Torsion of the globe can be discerned by simultaneously watching landmarks, such as conjunctival vessels lateral and medial to the iris. With intorsion, the lateral vessels rise and the nasal vessels drop.
Trigeminal nerve sensory function
Trigeminal nerve sensory function can be tested with the aid of a cotton-tipped applicator. Tease a few fibers of the cotton into a pointed bundle by twirling it between the thumb and the forefinger after a small tuft of cotton is pulled free of the tip.
This wisp of cotton can be touched to the cornea near the limbus to test the corneal reflex. It should elicit a blink response that is symmetric between the sides.
Failure to blink may indicate reduced sensory function in the first division of the trigeminal nerve on the side of decreased response. The cotton wisp can be dragged lightly across the skin in various locations. With the eyes closed, the patient is asked to indicate when it is felt.
Asymmetry of light touch between sides should be sought. The wooden stick, when broken, can serve as a "pinprick" tester. Usually, the break is jagged and there is a pointed end that can be used like a pin to test for pain sensation. Lightly tap the point on the skin at various points. The patient should compare the "sharpness" of the feeling at homologous points on the right and left sides of the face.
Orbital portion
Orbital signs are usually matters for direct inspection, including conjunctival injection and chemosis, proptosis, and lid swelling.
Obtain exophthalmometry measurements with a Hertel instrument or similar equipment since it provides a more sensitive measure of relative proptosis.
Any focally destructive lesion along the course of the third cranial nerve can cause oculomotor nerve palsy or dysfunction. A painful pupil-involved oculomotor nerve palsy may result from a life-threatening intracranial aneurysm. See the table below.
Table 1. Etiology of Isolated Third Nerve Palsy[16, 17, 18, 19, 20, 21]
View Table
See Table
Some of the most frequent causes include the following:
Angiographic imaging studies (eg, computed tomographic angiography [CTA], magnetic resonance angiography [MRA], digital subtraction angiography [DSA]) are often necessary in the evaluation of acute oculomotor nerve palsy.
The combination of CT scanning/CTA followed by MRI/MRA is often necessary in the evaluation of unexplained oculomotor nerve palsy. Standard catheter angiography may be required upon high clinical suspicion for aneurysm.
In the acute setting, CTA is more sensitive than MRA in detecting aneurysms that cause oculomotor palsy. Both modalities can be used to detect aneurysms that are 4 mm in diameter or larger. DSA is the criterion standard and can reveal aneurysms smaller than 3 mm. If aneurysm is not the only pathology in the differential diagnoses, MRI and CTA combined is the most powerful imaging option.[24] Noncontrast CT scan of the head can cause subarachnoid hemorrhage in patients with third nerve palsy due to an underlying ruptured aneurysm.
MRI/MRA
MRI is a more sensitive imaging technique than CT scan for the evaluation of a nonaneurysmal cause of third nerve palsy (inflammation, demyelination, ischemic infarction, abscess, or tumor).
MRI is also the procedure of choice for demonstrating meningeal and dural inflammation and infiltration.
Abnormal signal intensity and enhancement in the intracavernous portion of the third cranial nerve has been demonstrated in a case of herpes zoster with third cranial nerve palsy.[25]
Special MR sequences such as diffusion-weighted imaging (DWI) can demonstrate a small and acute infarct in the midbrain involving the intraparenchymal segment of the third cranial nerve in a patient with acute onset third cranial nerve palsy.[26]
MRI/MRA also gives more specific information than CT scan on vascular flow patterns and is better for picking up lesions in the cavernous sinus, including aneurysm.
MRA using 1.5-Tesla or lower strength magnet is probably not adequate to rule out berry aneurysm causing third cranial nerve palsy, although 3-Tesla MRA with special attention to the circle of Willis can be definitive in this regard because of enhanced resolution.
CT scanning
CT scan is more sensitive than MRI to demonstrate subarachnoid hemorrhage.
CT scan is also better than MRI for demonstrating calcification within lesions, as may be found in certain tumors and in large aneurysms.
Sixteen-row multislice CT angiography rivals digital subtraction catheter angiography in sensitivity and specificity for detecting intracranial aneurysms.[27, 28]
CTA is faster than MRI/MRA and, in many centers, is superior to MRI/MRA for aneurysm.
The main purpose of lumbar puncture is to demonstrate the presence of blood in cerebrospinal fluid, an inflammatory reaction, neoplastic infiltration, or infection.
Bloody spinal fluid with oculomotor nerve palsy usually results from rupture of a posterior communicating artery berry aneurysm.
Meningeal inflammatory reaction may be idiopathic or may result from a specific infection that should be diagnosed by bacterial and fungal cultures and by fungus, protozoan, or virus-specific serology or specific antigen (polymerase chain reaction).
Cerebral angiography
Conventional angiography is the definitive test for berry aneurysm in all intracranial locations.
A small but definite risk of angiography causing serious complication, such as embolic stroke, exists. This risk varies with each institution and individual who does the procedure.
Angiography is indicated in a patient with third cranial nerve palsy and dilated, light-fixed pupil. It may be indicated in a patient younger than 55-60 years, especially without a history of long-standing diabetes, hypertension, or both.
When external ophthalmoplegia is partial, pupil sparing is not a reliable indicator of ischemia as opposed to aneurysm as the etiology, so angiography may be warranted in this setting, especially if the patient is young or lacks ischemic risk factors. See the image below.
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Angiography anteroposterior and lateral views, left posterior communicating artery aneurysm, indicated by red arrow. Courtesy of James Goodwin, MD.
Blood glucose and hemoglobin A1c measurements can help determine if the patient is diabetic and, if so, how well-controlled the diabetes is. The presence of vasculopathic risk factors supports, but does not confirm, microvascular ischemia as a cause of oculomotor palsy. Although microvascular ischemia is the most common cause of isolated cranial nerve palsy in patients with vasculopathic risk factors (eg, diabetes, hypertension, hypercholesterolemia, smoking), a considerable number of patients have other causes. In addition, many patients with other causes of oculomotor palsy have vasculopathic risk factors.[29] Evaluation for giant cell arteritis (eg, erythrocyte sedimentation rate, C-reactive protein, temporal artery biopsy) may be helpful in elderly patients.
Third cranial nerve palsy from ischemia in the nerve trunk is believed to result from insufficiency of the vasa nervosa or small vessels that supply the nerve.[30]
Third cranial nerve palsy is most frequent in persons older than 60 years and in those with prominent or long-standing atherosclerotic risk factors, such as diabetes or hypertension.[31, 32] The key finding in these patients is relative sparing of the pupillary sphincter with complete or near-complete palsy of the extraocular muscles innervated by the third cranial nerve, including levator palpebrae.[33, 31, 34] Ironically, these patients may have very severe pain in the eye or orbit ipsilateral to the involved nerve. The pathogenesis of this pain is not understood, but it is common in patients with medical palsy and does not in itself suggest aneurysm as the cause.
Medical management is actually watchful waiting, since there is no direct medical treatment that alters the course of the disease. Fortunately, nearly all patients undergo spontaneous remission of the palsy, usually within 6-8 weeks. Treatment during the symptomatic interval is directed at alleviating symptoms, mainly pain and diplopia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment of choice for the pain. Diplopia is not a problem when ptosis occludes the involved eye. When diplopia is from large-angle divergence of the visual axis, patching one eye is the only practical short-term solution. When the angle of deviation is smaller, fusion in primary position often can be achieved using horizontal or vertical prism or both.
Since the condition is expected to resolve spontaneously within a few weeks, most physicians would prescribe a Fresnel paste on prism.
For practical purposes, surgical care of third cranial nerve palsy includes clipping, gluing, coiling, or wrapping of the berry aneurysm by a neurosurgeon in the acute stage.[35]
Patients who do not recover from third cranial nerve palsy after 6-12 months may become candidates for strabismus surgery (eye muscle resection or recession) to treat persistent and stable-angle deviation.[36] Some of these patients also may require some form of lid-lift surgery for persistent ptosis that restricts vision or is cosmetically unacceptable to the patient.
Comparison of third cranial nerve palsy recovery following surgical intervention shows that aneurysm clipping is more likely to result in resolution than coiling since the latter does not reliably remove the mass effect of the aneurysm on the nerve.[37] Also, total third cranial nerve palsy has less recovery potential than partial palsy.[38, 39]
Initial workup of pupil-sparing, third cranial nerve palsy without any other evidence of aneurysm involves medical evaluation for arteriosclerotic risk factors, including diabetes and hypertension.
Certain patients may require screening for collagen vascular disease, systemic vasculitis, sarcoidosis, or other granulomatous systemic diseases.
If carcinomatous meningitis is diagnosed on cerebrospinal fluid workup, then a search for systemic metastatic disease, an occult primary carcinoma, lymphoma, or leukemia is warranted.
Neurosurgery
Third cranial nerve palsy due to berry aneurysm, with or without concomitant subarachnoid hemorrhage, requires neurosurgical management in most cases.
Ophthalmology
The ophthalmologist provides symptomatic treatment for diplopia using occlusion, prism, or eye muscle surgery, and various lid-lift procedures for ptosis.
Patients who are monocular from either ptosis or ocular patching and patients with diplopia should not climb on high places, drive a vehicle, or operate heavy machinery.
Patients should avoid any other activity where limitation of peripheral vision poses danger.
The monocular nasal crescent is lost when one eye is occluded, which effectively shrinks the field by some 20-30° on the side of the closed eye. Loss of depth perception with one eye poses another set of potential risks for activities that depend on accurate assessment of depth.
Have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.
Ophthalmologic outpatient follow-up care is the routine for patients with ischemic (pupil-sparing) third cranial nerve palsy.
These patients should have routine visits every month or so until the palsy remits. This is mainly to provide symptomatic intervention as is warranted at different stages and to document eventual recovery.
Patients who do not recover function after 12-16 weeks may need further diagnostic workup to look for alternative diagnoses.
Long-term follow-up care is mainly for those patients who do not recover and for those patients who may require eye muscle surgery for residual, stable diplopia or ptosis.
Inpatient management of berry aneurysm is up to the discretion of the neurosurgeon.
There are no ophthalmological indications for inpatient care.
Management of meningitis or systemic cancer may require inpatient care at the discretion of the internist, neurologist, or oncologist treating the case.
Sudden full rupture of berry aneurysm with massive subarachnoid hemorrhage may lead to devastating neurologic deficit and death.
This rupture is one of the most serious emergencies that patients presenting with isolated third cranial nerve palsy may develop, and it constitutes the compelling reason for careful differential diagnosis.
In much the same way, the natural history of all the diseases mentioned in this article might be listed as complications of third cranial nerve palsy but will not be further elaborated here.
The prognosis depends upon the etiological diagnosis in the individual case. Medical third cranial nerve palsy from presumed ischemia carries the best prognosis for recovery of nerve function, as almost all of these patients recover spontaneously within a few weeks.
Patients with third cranial nerve palsy from identifiable diseases, such as infectious or neoplastic meningeal infiltration and berry aneurysm, have varying prognosis depending on a myriad of factors that are beyond the scope of this article.
What is third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the pathophysiology of third cranial nerve palsy (oculomotor cranial nerve palsy)?How common is third cranial nerve palsy (oculomotor cranial nerve palsy) in the US?What is the mortality/morbidity of third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the prognosis of third cranial nerve palsy (oculomotor cranial nerve palsy)?What should patients with third cranial nerve palsy (oculomotor cranial nerve palsy) be educated about?What are the symptoms of third cranial nerve palsy (oculomotor cranial nerve palsy) associated with lesions?What neurologic symptoms of third cranial nerve palsy (oculomotor cranial nerve palsy) are associated with lesions?What are the symptoms of oculomotor nerve palsy due to lesions in the nuclear portion of the third cranial nerve?What are the symptoms of oculomotor nerve palsy due to lesions in the fascicular midbrain portion of the third cranial nerve?What are the symptoms of oculomotor nerve palsy due to lesions in the fascicular subarachnoid portion of the third cranial nerve?What are the symptoms of oculomotor nerve palsy due to lesions in the fascicular cavernous sinus portion of the third cranial nerve?What are the symptoms of third cranial nerve palsy (oculomotor cranial nerve palsy) due to lesions in the orbit?What are the physical findings in third cranial nerve palsy (oculomotor cranial nerve palsy)?What are physical exam findings in unilateral third cranial nerve palsy (oculomotor cranial nerve palsy)?How are the margin reflex distances (MRD) measured in unilateral third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the pupillary findings in unilateral third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the physical findings in nuclear third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the physical findings in fascicular midbrain third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the physical findings in fascicular subarachnoid third cranial nerve palsy (oculomotor cranial nerve palsy)?How is fourth cranial nerve palsy diagnosed in the setting of third cranial nerve palsy (oculomotor cranial nerve palsy)?How is trigeminal nerve sensory function tested in third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the physical findings in orbital third cranial nerve palsy (oculomotor cranial nerve palsy)?What causes third cranial nerve palsy (oculomotor cranial nerve palsy)?What causes nuclear third cranial nerve palsy (oculomotor cranial nerve palsy)?What causes fascicular third cranial nerve palsy (oculomotor cranial nerve palsy)?Which condition is associated with pupil-sparing third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the differential diagnoses for Third Nerve Palsy (Oculomotor Nerve Palsy)?What are the approach considerations in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?Which imaging studies are indicated in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the role of MRI/MRA in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the role of CT scanning in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the role of lumbar puncture in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the role of cerebral angiography in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?What histologic findings are associated with third cranial nerve palsy (oculomotor cranial nerve palsy)?Which lab studies are indicated in the workup of third cranial nerve palsy (oculomotor cranial nerve palsy)?What medical care is indicated in the treatment of third cranial nerve palsy (oculomotor cranial nerve palsy)?What surgical care is indicated in the treatment of third cranial nerve palsy (oculomotor cranial nerve palsy)?Which specialist consultations are indicated in the treatment of third cranial nerve palsy (oculomotor cranial nerve palsy)?What activity restrictions are indicated in patients with third cranial nerve palsy (oculomotor cranial nerve palsy)?Which medications are indicated in the treatment of third cranial nerve palsy (oculomotor cranial nerve palsy)?Which medications in the drug class Nonsteroidal anti-inflammatory agents are used in the treatment of Third Nerve Palsy (Oculomotor Nerve Palsy)?What follow-up care is indicated for patients with third cranial nerve palsy (oculomotor cranial nerve palsy)?When is inpatient care indicated in the treatment of third cranial nerve palsy (oculomotor cranial nerve palsy)?What are the complications of third cranial nerve palsy (oculomotor cranial nerve palsy)?What is the prognosis of third cranial nerve palsy (oculomotor cranial nerve palsy)?
James Goodwin, MD, Associate Professor, Departments of Neurology and Ophthalmology, University of Illinois College of Medicine; Director, Neuro-Ophthalmology Service, University of Illinois Eye and Ear Infirmary
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Andrew G Lee, MD, Chair, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital; Clinical Professor, Associate Program Director, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch School of Medicine; Clinical Professor, Department of Surgery, Division of Head and Neck Surgery, University of Texas MD Anderson Cancer Center; Professor of Ophthalmology, Neurology, and Neurological Surgery, Weill Medical College of Cornell University; Clinical Associate Professor, University of Buffalo, State University of New York School of Medicine
Disclosure: Received ownership interest from Credential Protection for other.
Additional Contributors
Bayan Ali Mahmoud Al Othman, MD, Fellow in Neuro-Ophthalmology, Houston Methodist Hospital
Disclosure: Nothing to disclose.
Edsel Ing, MD, MPH, FRCSC, Associate Professor, Department of Ophthalmology and Vision Sciences, University of Toronto Faculty of Medicine; Active Staff, Michael Garron Hospital (Toronto East Health Network); Consulting Staff, Hospital for Sick Children and Sunnybrook Hospital, Canada
Disclosure: Nothing to disclose.
Acknowledgements
Brian R Younge, MD Professor of Ophthalmology, Mayo Clinic School of Medicine
Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society
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