Chapter 199 – Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

Chapter 199 – Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia

 

MARK L. MOSTER

 

 

 

 

 

DEFINITION

• Dysfunction of one or more of the three cranial nerves that move the eyes.

 

KEY FEATURES

• Diplopia.

• Dysconjugate gaze.

 

ASSOCIATED FEATURES

• Ptosis.

• Pupillary abnormalities.

• Pain.

• Proptosis.

• Chemosis.

• Arterialization of conjunctival vessels.

 

 

 

INTRODUCTION

One of the common clinical presentations in neuro-ophthalmology involves dysfunction of the ocular motor nerves, cranial nerves III (oculomotor nerve), IV (trochlear nerve), and VI (abducens nerve). In this chapter the anatomy of the peripheral course of the ocular motor nerves is reviewed, and various clinical syndromes are discussed. The syndromes include isolated involvement of each nerve, involvement of multiple cranial nerves simultaneously, involvement of the third, fourth, and sixth cranial nerves with other neurological or orbital symptoms and signs, and involvement of these cranial nerves with severe pain. An approach to the differential diagnosis of patients who seek treatment for involvement of the ocular motor nerves and guidelines for evaluation and treatment are also given.

ANATOMY

The clinical localization and subsequent differential diagnosis of cranial neuropathies requires knowledge of the anatomy of the third, fourth, and sixth cranial nerves. The anatomy within the brainstem is covered in Chapter 198 ; here, the relevant anatomy of the motor nerves from the brainstem exit to the eye is given ( Fig. 199-1 ).

The third cranial nerve exits the midbrain anteriorly to enter the subarachnoid space. It moves forward and laterally, passes between the posterior cerebral artery and superior cerebellar artery, and then runs alongside the posterior communicating artery. The nerve pierces the dura to enter the cavernous sinus, where it runs along the lateral wall, superior to the fourth cranial nerve. It enters the orbit via the superior orbital fissure. In the anterior cavernous sinus, it divides into the superior and inferior divisions. The superior division ascends lateral to the optic nerve to supply the superior rectus and levator palpebrae superioris muscles. The inferior division divides into branches that supply the inferior rectus, inferior oblique, and medial rectus muscles and the pupillary sphincter. Parasympathetic preganglionic fibers travel along the branch to the inferior oblique and terminate in the ciliary ganglion near the apex of the extraocular muscle cone. The postganglionic fibers from the ciliary ganglion travel in the short ciliary nerves, along with the sympathetic fibers, to enter the globe at the posterior aspect near the optic nerve. They terminate in the ciliary body and iris, and control pupillary constriction and accommodation via the ciliary muscles.

The trochlear nucleus lies in the midbrain, at the level of the inferior colliculus, inferior to the third nerve complex, and anterior to the cerebral aqueduct. The fourth cranial nerve exits the midbrain dorsally and crosses to the opposite side, within the anterior medullary velum, just below the inferior colliculi. The nerve crosses forward within the subarachnoid space around the cerebral peduncle and runs between the posterior cerebral and superior cerebellar arteries, along with the third nerve. The fourth cranial nerve pierces the dura at the angle between the free and attached borders of the tentorium cerebelli to enter the cavernous sinus. It runs within the lateral wall of the cavernous sinus, just below the third cranial nerve and above the first division of the fifth cranial nerve (trigeminal nerve). It enters the orbit via the superior orbital fissure, but runs outside the annulus of Zinn and diagonally across the levator palpebrae superioris and superior rectus muscle to reach the superior oblique muscle. As a consequence of decussation, the fourth cranial nerve emanates from the brainstem and innervates the contralateral superior oblique muscle. The fourth cranial nerve is the thinnest cranial nerve; it is the only nerve to both exit from the dorsal brainstem and have all the fibers crossed, and it has the longest intracranial course of all the cranial nerves. It supplies the superior oblique muscle, the main action of which is to depress the eye in the adducted position. Secondary actions are incyclotorsion and abduction of the eye.

The abducens nerve exits the brainstem at the junction of the pons and pyramid of the medulla, and ascends through the subarachnoid space along the surface of the clivus. It runs forward over the petrous apex of the temporal bone and beneath the petroclinoid ligament to enter the cavernous sinus. In the cavernous sinus, it runs lateral to the internal carotid artery, but medial to the third and fourth cranial nerves and first and second divisions of the fifth cranial nerve, which run in the lateral wall. It enters the superior orbital fissure and passes through the annulus of Zinn to innervate the lateral rectus muscle.

 

1324

 

 

Figure 199-1 Lateral view of cranial nerves III, IV, and VI from the brainstem nuclei to the orbit. The third nerve exits the midbrain anteriorly, crosses near the junction of the internal carotid and posterior communicating artery in the subarachnoid space, and enters the cavernous sinus, where it runs in the lateral wall. The fourth nerve exits the midbrain posteriorly and crosses to the opposite side, to move forward in the subarachnoid space and into the cavernous sinus. The sixth nerve exits the pons anteriorly, ascends along the clivus bone, crosses the petrous apex, and descends below the petroclinoid ligament to enter the cavernous sinus, where it runs between the lateral wall and the carotid artery.

OCULAR MANIFESTATIONS

General Symptoms

The universal symptom associated with dysfunction of the ocular motor nerves is binocular diplopia. With third cranial nerve dysfunction, ptosis and mydriasis are also symptoms. Diplopia occurs when an object projects onto retinal points that do not correspond in both eyes. The diplopia is worst in the direction of action of the weak muscle(s). However, diplopia may not occur with poor visual acuity or in patients affected by a suppression scotoma from congenital strabismus.

On examination, a patient who has binocular diplopia demonstrates an ocular deviation. Numerous examination techniques are available to measure ocular deviations, which include the use of prism lenses with the cover–uncover or alternate cover technique, the red glass test, the Maddox rod, and the Hess or Lancaster screen. The examiner must become familiar and proficient with one or more of these techniques ( Chapter 70 ) to adequately assess patients who have diplopia.

A tendency toward ocular deviation that variably is present is termed a phoria, whereas a constantly manifest deviation is a tropia. When a measured deviation is similar in all gaze directions, it is a comitant deviation; when it varies by direction it is incomitant. Congenital strabismus appears with a comitant deviation.

Acquired cranial neuropathies appear with a ductional deficit on examination that corresponds to weakness in the appropriate muscle(s) innervated by the cranial nerve(s) involved. In a more subtle deficit, ductions may appear full, but an incomitant deviation greatest in the direction of action of the paretic muscle is seen. When a cranial neuropathy is chronic, spread of comitance may occur, and the deviation mimics that of congenital strabismus.

Isolated Cranial Neuropathies

In this section, the assessment of patients affected by isolated involvement of the third, fourth, or sixth cranial nerve, with no other neurological or ophthalmologic signs, is discussed.

ISOLATED SIXTH CRANIAL NERVE PALSY.

An isolated sixth nerve paresis appears with a unilateral abduction deficit of variable degree, from a complete inability to abduct past the midline to a mild incomitant esodeviation greatest on lateral gaze. Abduction saccades in the affected eye are slow. The history consists of binocular uncrossed diplopia, worse in the direction of the lesion and worse at distance than near. Figure 199-2 demonstrates the deviation seen using a Maddox rod in a patient who has a right sixth nerve paresis. Some children affected by isolated sixth nerve paresis appear to have a gaze paresis in both eyes, because they avoid looking to the side that has diplopia.[1]

A congenital sixth nerve palsy is rare and may be related to birth trauma. The deficit often is transient, and resolves in the first month of life. [1] [2] [3] Other congenital abnormalities of the sixth nerve, such as Möbius’ syndrome and Duane’s retraction syndrome, show other findings and are discussed in the section on differential diagnosis.

An isolated, acquired sixth nerve paresis may arise from a lesion anywhere in the course of the sixth nerve, from the fascicular portion in the brain to the orbit. Since other symptoms and signs are not present to help localization, the differential diagnosis is extensive. In children, isolated sixth nerve paresis may be a relatively benign occurrence after viral infection, but it is also a presenting sign of intracranial tumor.[2] [3] In old age, isolated sixth nerve paresis is quite common because of ischemic infarction. In young adults, postviral and ischemic lesions are less common, but trauma, neoplasm, and demyelinating disease are more common.[4]

Traumatic sixth nerve injury is often associated with fractures of the petrous bone or clivus. Other clinical findings include mastoid ecchymosis (Battle’s sign) and cerebrospinal fluid otorrhea. Chronic sixth nerve paresis results from many of the same causes as acute sixth nerve paresis but more often arises from a compressive lesion.[5] [6] [7] [8]

A syndrome of benign recurrent sixth nerve paresis may occur, [9] particularly in children. However, skull-base tumors also

 

1325

 

 

Figure 199-2 Right sixth cranial nerve paresis evaluated by the Maddox rod test. A Maddox rod is placed in front of the patient’s right eye. Subjective deviation between the light and the line is noted by the patient in different positions of gaze. An esodeviation greatest as the patient looks to the right is consistent with a right lateral rectus muscle weakness.

may present in this manner,[10] and remission of a sixth nerve paresis is not always a sign of a benign sixth nerve paresis.

Even though each series reviews patients differently, some generalizations are apparent from the numerous series of both isolated and nonisolated sixth nerve paresis.[2] [3] [4] [11] [12] [13] [14] [15] [16] [17] In adults affected by isolated sixth nerve paresis, the cause is more likely to be ischemia, in comparison with those who have nonisolated sixth nerve paresis. Tumor, trauma or aneurysm are more often present in nonisolated cases. Also, tumor is a more common cause of sixth nerve paresis in young adults and children than in older patients.

ISOLATED FOURTH CRANIAL NERVE PALSY.

A fourth nerve or trochlear palsy manifests with an isolated, vertical, diagonal, or incyclotorsional diplopia and is the most common cause of vertical diplopia. The diplopia is usually worse close up and down, as in reading, and is worse when looking to the side opposite the lesion.

On examination a spontaneous head tilt may occur to the side opposite the fourth nerve paresis, which helps compensate for some of the vertical deviation. In addition, the head may be turned down, with the chin depressed, the eyes up, and the face turned to the side opposite the paresis, to diminish the diplopia.

Ductions may be normal or show a mild decrease of depression of the adducted eye. Examination using the Parks–Bielschowsky three-step test ( Fig. 199-3 ) shows a hyperdeviation that is worse on contralateral gaze, downgaze, and ipsilateral head tilt. A fourth step that demonstrates the deviation is worse in downgaze than upgaze is confirmatory. With time, spread of comitance may develop. Double Maddox rod testing shows excyclotorsion ( Fig. 199-4 )—if the excyclotorsion is >10°, fourth nerve paresis is likely to be bilateral.

Congenital fourth nerve paresis is common. Patients affected by a congenital paresis may experience acute diplopia at any age, but often they are in the fifth to seventh decades of life. The diplopia may occur as a decompensation during periods of stress. Examination of photographs of the patient at a younger age is important, in that a persistent head tilt to one direction may be demonstrated. In addition, if a fourth nerve paresis is congenital, a large-amplitude vertical fusional capacity of >6D, often 10–15D, is present.

 

 

Figure 199-3 Parks–Bielschowsky three-step test. In a patient who has a vertical deviation because of a weakness in a single muscle, this three-step test determines which muscle is weak. Step four confirms that the correct muscle has been identified and helps to rule out other causes of vertical deviation.

The most common cause of acquired fourth nerve paresis is trauma that affects the nerve along the tentorial edge or the anterior medullary velum. In addition, the fourth nerve is the ocular motor nerve most commonly injured by trauma. In this situation, the fourth nerve paresis may be bilateral (discussed below in the section on bilateral ophthalmoplegia). Inflammatory and infectious lesions in the subarachnoid space may also affect the fourth nerve. Pinealoma or tentorial meningioma may compress the fourth nerve.

In children with fourth nerve paresis, congenital factors are likely the leading cause (which may appear later in childhood or in adulthood), followed by trauma.[2] Structural lesions account for a minority of cases.

In elderly patients, particularly those who have hypertension or diabetes, vasculopathic ischemic infarction is a likely cause of fourth nerve paresis. Less common causes include tumor that involves the midbrain or cerebellum, aneurysm, or herpes zoster ophthalmicus.[18] The fourth nerve may become involved with herpes zoster ophthalmicus because it shares the same connective tissue sheath as the ophthalmic division of the fifth cranial nerve.

The cause of fourth nerve paresis has been studied in numerous series.[2] [3] [12] [15] [16] [17] [19] [20] [21] [25] Causes include trauma, ischemia, tumor, aneurysm, and demyelination. Trauma is a more common cause of a fourth nerve paresis than of third and sixth nerve pareses.

 

1326

ISOLATED THIRD CRANIAL NERVE PALSY.

Patients who have third nerve palsy have a history of horizontal and/or vertical binocular diplopia, ptosis, or complaints of enlarged pupil or difficulty in focusing, with involvement of accommodation ( Fig. 199-5 ); various combinations of these may occur. Diplopia may

 

 

Figure 199-4 Double Maddox rod test for excyclotorsion. A red Maddox rod is placed in front of the right eye and a white Maddox rod in front of the left eye in a trial frame or phoropter. In a patient who has vertical diplopia, one line is above the other. With excyclotorsion, the two lines are not parallel, but cross each other. One of the Maddox rods is then rotated until the two lines appear parallel. The degree of rotation required (in this case about 12°) to make the lines parallel determines the degree of excyclotorsion.

 

 

 

 

 

 

 

 

 

 

Figure 199-5 Isolated third nerve palsy in the setting of herpes zoster ophthalmicus. At the time of acute illness. Note the presence of herpes zoster lesions in the distribution of the first division of the fifth nerve. Third nerve palsy consists of ptosis, adduction, elevation, and depression deficit with preserved abduction.

be absent because ptosis effectively occludes one eye. Isolated ptosis or mydriasis usually is not a sign of third nerve palsy. When complete, the eye may be deviated down and out. When the motility defect is more subtle, an exotropia on adduction, a hypotropia on elevation, and a hypertropia on depression occurs in the involved eye. The diagnostic considerations in an isolated third nerve palsy depend on the age of the patient, in a similar way to involvement of the fourth or sixth cranial nerves.

In a truly isolated third nerve palsy, the presumed location is the subarachnoid space. However, lucencies in the midbrain have been demonstrated by magnetic resonance imaging (MRI) in patients who have isolated third nerve palsies on a vasculopathic basis; these suggest the infarct is in the brainstem itself.

The major differential diagnoses in an adult who has isolated third nerve palsy are vasculopathic infarction, vasculitic infarction (as in giant cell arteritis), a compressive lesion (usually from aneurysm), trauma, meningeal inflammation (such as with infection or tumor), ophthalmoplegic migraine, or demyelination.

Several series have looked at the causes of isolated and nonisolated third nerve paresis with similar findings as in fourth and sixth nerve paresis.[2] [3] [12] [15] [16] [17] [22] [23] [24] [25] From these studies, third nerve paresis is associated more frequently with aneurysm than are fourth or sixth nerve pareses. Ophthalmoplegic migraine is only associated with a third nerve paresis. As with the sixth nerve paresis, isolated lesions more often are ischemic than nonisolated ones.

Patients who have a vasculopathic third nerve palsy often have pain that precedes the ptosis or diplopia. In a vasculopathic lesion, the pupillary reaction is usually spared, and the pupil does not become enlarged. However, in up to 20% of cases, the pupil may be involved. Clinical associations include diabetes, hypertension, or other risk factors for atherosclerosis. The natural course of a vasculopathic, isolated third nerve palsy is one of recovery over weeks to months, usually 3 months. The pupil is spared because the infarction occurs in the center of the nerve and good collateral supply exists in the nerve periphery, where the pupillary fibers are located.

 

1327

One of the true neuro-ophthalmologic emergencies occurs when compression of the third nerve results from an expanding aneurysm at the junction of the internal carotid and posterior communicating arteries. Such compressions most often, but not always, are painful, and in almost all instances involve the pupil. However, numerous case reports of isolated third nerve palsy caused by expanding aneurysms show that the pupil may be spared initially.[26] Often, these patients have only partial ptosis and extraocular muscle involvement, and, with very rare exceptions, the pupil becomes involved within 1 week of symptom onset. This situation is one of the few life-threatening emergencies in neuro-ophthalmology and one in which appropriate diagnosis and treatment is lifesaving.

In contrast to an acute third nerve palsy, a slowly progressive third nerve palsy that involves the pupil usually is a sign of an enlarging cavernous sinus lesion.[27] Ophthalmoplegic migraine is a syndrome that becomes apparent with a migraine-type headache and the development of a third nerve palsy; the pupil is usually involved. The pain precedes the oculomotor paresis and is intense, continuous, and located in the orbital region. As the paralysis reaches its maximum, the headache begins to recede. The initial presentation is usually in childhood, multiple attacks may occur, and a family history of migraine is often present. The third nerve palsy may last from hours to weeks, and permanent deficits occur after repeated attacks.[28]

A rare syndrome in children is a recurrent isolated third nerve palsy, which resolves without deficit. Some patients later develop migraine, and some investigators consider this a variant of ophthalmoplegic migraine.[1] Other causes of isolated third nerve palsy in the subarachnoid space include trauma and infectious or neoplastic meningitis.

Aberrant regeneration refers to an abnormality found on examination, after recovery of the third nerve from damage that caused disruption of the axons as a result of a structural lesion.[29] The abnormal activation of one part of the third nerve is found when another part should be in action. For instance, if fibers originally destined for the medial rectus now supply the levator palpebrae superioris, then on adduction of the eye the lid elevates (so-called lid–gaze dyskinesis). If the same fibers now innervate the pupil, on adduction of the eye the pupil constricts. This may give rise to pupillary light–near dissociation (pseudo-Argyll Robertson pupil). Another common pattern of aberrant regeneration is elevation of the eyelid on downgaze, the pseudo–Von Graefe’s phenomenon, because fibers destined for the inferior rectus now go to the levator palpebrae superioris. Cocontraction of vertically acting muscles may limit vertical excursion of the eye and be associated with retraction of the globe. When aberrant regeneration is found, the diagnosis is not an isolated ischemic lesion, but a structural lesion.

Primary aberrant regeneration refers to the findings above, but with no antecedent third nerve palsy. This suggests a compressive lesion of the third nerve that slowly evolves with ongoing recovery to produce the aberrant regeneration without clinical realization of a third nerve palsy. This has been described with lesions that slowly evolve, usually in the cavernous sinus. Most often these are internal carotid artery aneurysms, intracavernous meningiomas, or neurinomas.[30] [31]

A rare congenital condition, with unknown cause, is cyclic oculomotor paralysis with spasm. This encompasses a condition that cycles between an oculomotor paresis as described above and periods of oculomotor spasm that occur every 1.5–2 minutes and persists throughout life. During the periods of oculomotor spasm, the eye may be adducted, the lid elevated, the pupil miotic, and accommodation increased. After a 10–60–second interval, the eye becomes deviated outward with ptosis and mydriasis.[32]

DIVISIONAL THIRD CRANIAL NERVE PALSY.

The third nerve divides in the anterior cavernous sinus into a superior and inferior division—lesions may affect either division. A superior division third nerve palsy manifests with an isolated elevation deficit and ptosis of one eye. An inferior division third nerve palsy may cause mydriasis, and an adduction and depression deficit without ptosis or elevation deficit. Divisional palsies usually result from a structural lesion in the anterior cavernous sinus or orbit. A characteristic example is a superior division third nerve paresis from an ophthalmic artery aneurysm. However, divisional palsies have been described as far posteriorly as the anterior midbrain, likely because fibers have segregated into different portions of the nerve at this point. In addition, cases exist of benign, remitting pareses of either division of the third nerve.[33]

Nonisolated Cranial Neuropathies

When a patient affected by involvement of an ocular motor nerve has other findings, the approach to evaluation changes. The associated findings are clues to the localization and character of the lesion and may include brainstem neurological deficits, meningeal signs, involvement of other ocular motor or other cranial nerves, and orbital signs.

Nerve palsies that arise in the brainstem most often are associated with long-tract findings, alterations in consciousness, or other cranial neuropathies, and are covered in Chapter 198 . When accompanied by other cranial nerve involvement without brainstem findings, the likely localization includes the subarachnoid space, cavernous sinus, and orbit. Those nerve palsies associated with proptosis, chemosis, and visual loss often arise in the orbit, and are covered in Chapter 95 .

In this section nonisolated cranial neuropathies are reviewed. They are subdivided into categories of multiple cranial neuropathies, bilateral cranial neuropathies, and lesions in the subarachnoid space that may cause both multiple unilateral or bilateral cranial neuropathies.

MULTIPLE CRANIAL NEUROPATHIES.

In contrast with isolated mononeuropathies, which are often benign and vasculopathic in nature, involvement of more than one ocular motor nerve rarely results from vasculopathic lesions.[34] It is very important to ascertain that multiple nerves are involved, because establishment of this enables localization of the lesion responsible. For the most part, these patients have lesions of the cavernous sinus, superior orbital fissure, or orbital apex. Since the first division of the fifth cranial nerve is also involved in such lesions, pain may be a prominent feature.

Causes of multiple cranial nerve involvement have been reviewed in numerous series.[12] [15] [17] In contrast to isolated mononeuropathies, ischemia is an infrequent cause, and tumor, inflammation, trauma, and aneurysm are more common.

Typically, fourth nerve paresis is associated with hyperdeviation, most noticeable when the eye is adducted. In the presence of a third nerve paresis, the eye does not adduct, which makes it difficult to determine the presence of a coexisting fourth nerve paresis. In this situation, the eye is examined carefully for intorsion of the globe on attempted downgaze, from which secondary action of the fourth nerve is assessed. This is accomplished most easily by visualization of a conjunctival vessel for intorsion ( Fig. 199-6 ).

On occasion the third and fourth cranial nerves may be involved together in the brainstem. However, such patients have large lesions that cause other neurological deficits. These cranial nerves may be involved together in the subarachnoid space also, as discussed below.

Because the sixth nerve crosses along the petrous apex, a syndrome that includes sixth nerve palsy, facial pain, hearing loss, and (sometimes) facial paralysis may occur.[35] This is known as Gradenigo’s syndrome and may result from infectious mastoiditis, tumor, trauma, aneurysm of the petrosal segment of the internal carotid artery, or inferior petrosal sinus thrombosis. Petrous bone fractures involve combinations of the fifth, sixth, seventh, and/or eighth cranial nerves and other findings of hemotympanum, Battle’s sign (mastoid hematoma), and cerebrospinal fluid otorrhea.

 

1328

The cavernous sinus consists of a plexus of veins. Within the plexus lies the sixth nerve and within the lateral wall lies the third nerve, fourth nerve, first division of the fifth nerve, and, posteriorly, the second division of the fifth nerve. Within the cavernous sinus, the sympathetic fibers form a plexus along the carotid artery ( Fig. 199-7 ).

The superior orbital fissure contains the same nerves as the anterior cavernous sinus. Therefore, signs and symptoms of cavernous sinus and superior orbital fissure lesions may be identical. The findings include involvement of any of the above cranial nerves in isolation or in various combinations. Therefore, third nerve paresis, fourth nerve paresis, sixth nerve paresis, Horner’s

 

 

 

 

Figure 199-6 Demonstration of intact fourth cranial nerve in the presence of a third nerve paresis. A, The patient’s right eye is exotropic from a complete third nerve palsy. B, However, an intact fourth nerve is noted on attempted downgaze because of incyclotorsion of the eye. This is best seen by comparison of the conjunctival vessels in A with their position in B on attempted downgaze.

 

 

Figure 199-7 Anatomy of the cavernous sinus. Coronal and lateral views. (From Kline LB. The Tolosa–Hunt syndrome. Surv Ophthalmol. 1982;27:79–95.)

syndrome, and sensory loss of the first division of the fifth nerve all may be present, and, if a lesion is in the posterior cavernous sinus, there may be involvement of the second division of the fifth nerve. The pupil may be involved, spared, or appear spared with concomitant oculosympathetic and parasympathetic involvement. Various degrees of pain may be involved and, if pain is severe, “painful ophthalmoplegia syndrome” is diagnosed.[36]

Broad categories of diseases that involve the cavernous sinus include neoplasms, inflammation, infection, vascular lesions, and trauma. [37] [38] [39] [40] Neoplastic lesions include local metastatic disease from nasopharyngeal cancer, olfactory neuroblastoma, adenoid cystic carcinoma, cylindroma, ameloblastoma, and squamous cell carcinoma, or disease that spreads from distant lesions, which includes carcinoma, sarcoma, multiple myeloma, and lymphoma. Local spread of benign tumors includes pituitary adenoma, meningioma, craniopharyngioma, neurilemmoma, and epidermoid tumor. Chordomas, chondromas, and giant cell tumors may also spread in the cavernous sinus. Meningiomas may arise in the cavernous sinus itself. Neuromas or neurofibromas may occur on the gasserian ganglion or other cranial nerves.

Pituitary apoplexy is a clinical syndrome caused by sudden enlargement in a pituitary tumor as a result of acute hemorrhage or edema. The patient may have had previous symptoms or have a clinically silent lesion that appears acutely because of the sudden change. The presentation has variable features that include acute and severe headache, diplopia with ophthalmoplegia from cavernous sinus involvement, visual loss from optic nerve, chiasm, or tract involvement, meningismus from hemorrhage into the subarachnoid space, and endocrine insufficiency.

Inflammatory lesions may be both infectious and noninfectious. Bacterial infections may cause cavernous sinus thrombosis, which causes a unilateral or bilateral cavernous sinus syndrome, proptosis, and chemosis associated with signs of fever, depressed mental status, and signs of sepsis. Spread of infection from sinusitis or a mucocele from the paranasal sinuses may cause compression of the cavernous sinus.

Mucormycosis is a life-threatening infection that may affect the cavernous sinus, superior orbital fissure, or orbit. Multiple cranial neuropathies may occur relatively rapidly in a predisposed patient, such as a diabetic or an immunosuppressed patient. Often an indicative eschar is seen in the nose in such patients. An occlusive vasculitis may occur with stroke that affects the brain or eye. To make the diagnosis, a high index of suspicion is required in the appropriate patient.

 

1329

Aspergillosis also may involve the orbital apex or cavernous sinus. Rarely, other infections such as syphilis or tuberculosis may affect the cavernous sinus. Herpes zoster may be followed by abnormalities of the cavernous sinus. Most often this consists of involvement of one cranial nerve—an isolated third, fourth, or sixth dysfunction—after zoster in the first division of the fifth cranial nerve.[18] Occasionally, multiple cranial nerves may be involved.

Inflammatory, noninfectious lesions include sarcoidosis, Wegener’s granulomatosis, eosinophilic granuloma, and the idiopathic Tolosa–Hunt syndrome; the last causes painful ophthalmoplegia. The pain is described as gnawing or boring and may precede ophthalmoplegia. The ophthalmoplegia arises from combinations of third (most frequently), fourth, or sixth nerve involvement. Other findings include Horner’s syndrome, proptosis, optic nerve involvement, fifth nerve (divisions 1–3) involvement, or seventh nerve paresis.[36] [41] [42] The symptoms last for days to weeks and spontaneous remissions occur, with or without residual deficits. Recurrences may occur at intervals of months to years.

Vascular causes of a cavernous sinus syndrome include carotid artery aneurysm, cavernous sinus thrombosis (as noted above), direct carotid artery to cavernous sinus fistula, and dural arteriovenous fistula. Intracavernous carotid artery aneurysms are saccular aneurysms that develop most commonly from atherosclerosis. They cause slowly progressive ophthalmoplegia through enlargement, often with aberrant regeneration, and may cause an acute carotid–cavernous fistula if they bleed. The other cause of a direct carotid–cavernous fistula is a condition resulting from trauma that directly damages the internal carotid artery.

A direct carotid–cavernous fistula causes a cavernous sinus syndrome, as well as headache, facial pain, severe proptosis, chemosis, and injection of the eye, with arterialization of conjunctival and episcleral vessels. Often pulsatile tinnitus and an orbital bruit occur, and retinal venous engorgement and hemorrhage, central retinal vein occlusion, retinal ischemia, serous retinal or choroidal detachment, and anterior ischemic optic neuropathy may also be seen. Intraocular pressure may be elevated and angle-closure or neovascular glaucoma may develop.

A less serious fistula results from a dural arteriovenous connection in which multiple dural vessels that come off the arterial system connect directly with the cavernous sinus. This occurs most often in elderly women and has a subacute or chronic course. The findings include the above cranial neuropathies, as well as proptosis, orbital bruit, and conjunctival injection, none as severe as

 

 

 

 

Figure 199-8 Dural arteriovenous fistula. A, Patient had diplopia that resulted from a left sixth nerve paresis, Horner’s syndrome, proptosis, chemosis, and injection with arterialization of the conjunctival vessels. (Pupils are pharmacologically dilated.) B, Arteriogram demonstrates filling of the cavernous sinus and a huge dilated superior ophthalmic vein in the arterial phase of an external carotid artery injection in the same patient.

those associated with a direct internal carotid artery–cavernous sinus fistula. The more subtle clinical picture means that these patients are often misdiagnosed with chronic conjunctivitis, episcleritis, or thyroid ophthalmopathy ( Fig. 199-8 ).

Involvement of the sixth nerve with loss of tearing and sometimes sensory loss in the second division of the fifth nerve localizes a lesion to the sphenopalatine fossa; such lesions commonly result from metastatic tumor or nasopharyngeal carcinoma.[43] Poliomyelitis may involve one or more cranial nerves, most often the sixth cranial nerve.[43]

Bilateral Ophthalmoplegia.

Bilateral ophthalmoplegia, a unique variant of the syndrome of multiple cranial neuropathy, refers to involvement of more than one of the above cranial nerves that includes at least one on each side. This implies a lesion that is large enough to cause deficits bilaterally or is situated in a location such that bilateral cranial nerves are involved.

Möbius’ syndrome is a congenital syndrome associated with bilateral sixth nerve or horizontal-gaze paresis and seventh nerve (facial nerve) paresis and other deficits, which may include tongue atrophy, hand and face deformities, and other malformations. Bilateral sixth nerve paresis is seen in posterior fossa or clivus lesions. Clivus tumors, such as meningioma, chordoma, chondroma, or chondrosarcoma, or spread of nasopharyngeal carcinoma often cause bilateral sixth nerve palsies because the two sixth nerves run adjacent to each other along the clivus.

Increased intracranial pressure of any cause may produce unilateral or bilateral sixth nerve palsy by downward pressure and shift of the brainstem. This is because the sixth nerve is fixed as it exits the pons and as it pierces the dura to enter Dorello’s canal under the petroclinoid ligament. Papilledema inevitably is present.

After myelography, spinal anesthesia, or even lumbar puncture, a bilateral sixth nerve paresis may rarely develop in association with a severe, postlumbar puncture headache syndrome.[44] A similar mechanism of downward shift of the brainstem that arises from a pressure differential may be responsible. With this syndrome of intracranial hypotension, diffuse enhancement of the meninges also may be seen on MRI ( Fig. 199-9 ). Basilar artery aneurysm or dolichoectasia of the basilar artery also may cause unilateral or bilateral sixth nerve paresis. When the presentation of bilateral sixth nerve paresis is compared with that of unilateral cases, ischemic causes are less frequent and trauma is more common.[13] [14]

Bilateral fourth nerve paresis may be seen after head trauma. Trauma likely involves the nerves in the area of decussation in

 

 

Figure 199-9 Magnetic resonance image (with gadolinium) of a patient with bilateral sixth cranial nerve palsy. The palsy resulted from intracranial hypotension after lumbar spine surgery. Note the diffuse enhancement of the meninges.

 

1330

the anterior medullary velum. Bilateral fourth nerve paresis also may be seen with hydrocephalus, tumor, arteriovenous malformation, or demyelinating disease.[43]

With bilateral fourth nerve paresis, right hyperdeviation in left gaze or right head-tilt and left hyperdeviation in right gaze or left head-tilt occur. In primary position, depending on the relative symmetry of the bilateral fourth nerve paresis, orthophoria, or right or left hyperdeviation may occur. An additive effect of excyclodeviation occurs, with the result that greater than 10° of excyclotorsion is often seen. Because a tertiary action of the superior oblique muscle is abduction, loss of action of both superior obliques in downgaze causes a relative esodeviation in downgaze, which results in a characteristic V-pattern horizontal deviation.

Rarely, bilateral simultaneous ophthalmoplegia may have a vasculopathic cause.[34]

Subarachnoid Involvement.

With subarachnoid involvement, signs of multiple cranial nerve involvement may occur on one or both sides and produce the above syndromes, as well as headache, stiff neck, photophobia, and fever. With elevated intracranial pressure, papilledema occurs. In the subarachnoid space, causes of cranial neuropathies include subarachnoid hemorrhage, trauma, infectious or neoplastic meningitis, idiopathic intracranial hypertension (pseudotumor cerebri), tumors on the sixth nerve, or tumors in the clivus that compress the sixth nerve.

Infectious meningitis may arise from bacterial, fungal (mainly cryptococcal), tuberculous, or syphilitic causes, or from Lyme disease. Inflammatory meningitis occurs with sarcoidosis.

NONISOLATED THIRD CRANIAL NERVE PALSIES.

Nonisolated third nerve palsies occur in the subarachnoid space and are accompanied by meningeal signs. The processes are similar to those described above—mainly infectious, neoplastic, or traumatic. However, one additional nonisolated third nerve syndrome occurs with uncal herniation through the tentorium, with large hemispheric mass lesions (such as tumor, hemorrhage, or infarct with edema). The patient has a corresponding neurological deficit and is lethargic. The third nerve is compressed against the tentorial edge, petrous ridge, and clivus by the uncus of the temporal lobe. Usually, pupillomotor fibers are involved first. Rarely, upward herniation from a mass in the posterior fossa may cause a third nerve palsy.

Miscellaneous Disorders

SUPERIOR OBLIQUE MYOKYMIA.

Superior oblique myokymia, also known as superior oblique microtremor, is a rare condition that causes intermittent diplopia or the sense of oscillopsia in one eye. It consists of an intermittent torsional movement in the direction of the superior oblique muscle and is best seen under the slit lamp. The movements may be induced when the patient is asked first to look in the direction of action of the superior oblique muscle followed by a return to the primary position.

Most often, superior oblique myokymia is idiopathic, but it may be a sequela of superior oblique palsy, as well as multiple sclerosis or pontine tumor.[35] [45]

OCULAR NEUROMYOTONIA.

Ocular neuromyotonia is a paroxysmal monocular deviation that arises from spasm of the extraocular muscles. It is believed to result from episodic spontaneous discharges in the third (most commonly), fourth, and sixth cranial nerves. Neuromyotonia usually is seen after irradiation for sella turcica, cavernous sinus, or other skull-base tumors. It develops between 2 months and 7 years (mean 2.6 years) after surgery and radiation (mean dose 51?Gy). [46] [47] [48] [49] Rarely, it occurs without prior history of tumor or radiation.

Patients complain of intermittent diplopia, which is usually painless but sometimes is associated with a feeling of discomfort in the eye. Diplopia may occur several times per hour and last from only seconds to 3 minutes. It may be induced by movement into the field of action of the muscles, which then tonically

 

 

 

 

Figure 199-10 Ocular neuromyotonia. A 25-year-old woman, who had received irradiation 6 years previously after resection of a right lateral ventricular ependymoma, developed episodic diplopia that lasted from 30 seconds to 1 minute. A, Left gaze is initially normal. B, After gazing to the right for at least 30 seconds, an exotropia develops on attempted left gaze, with a right adduction deficit. Her symptoms responded to carbamazepine. (From Moster ML. Complications of cancer therapies. In: Miller N, Newman NJ, eds. Walsh & Hoyt’s neuro-ophthalmology, ed 5. Baltimore: Williams & Wilkins; 1997.)

contract and do not relax. Patients may have had motility deficits from the original tumor, but the neuromyotonia usually does not involve the previously affected cranial nerve.

On initial examination, ocular motility may appear normal. After a sustained gaze in the direction of action of the involved nerve followed by an attempt to look away, a motility deficit appears because the previously active muscle does not relax ( Fig. 199-10 ). With third nerve involvement the pupil may become fixed during episodes.[46]

DIAGNOSIS

The above histories and examination techniques should allow identification of the dysfunctional nerve(s). Although identification of the cranial nerve involved is important in the differential diagnosis, perhaps the most important feature is not the cranial nerve itself but the associated findings (“company it keeps”). The “company it keeps” may include involvement of other cranial nerves, other neurological deficits, or findings suggestive of an orbital process. These other findings help to localize the lesion and differentiate the likely causes.

In some instances, the cranial neuropathy is truly isolated and involves only the third, fourth, or sixth nerve. When this occurs, a unique approach to differential diagnosis is undertaken.

The evaluation of patients for ophthalmoplegia is dependent on the age of the patient. For infants, a congenital deficit or birth trauma is considered; for children a postviral syndrome, trauma or posterior fossa tumor; for young adults trauma, multiple sclerosis, aneurysm, or arteriovenous malformation; and for older adults diabetes, hypertension, atherosclerosis, or giant cell arteritis.

The character of the onset and progression also is important in differential diagnosis. Acute onset is consistent with a vascular, inflammatory, or traumatic cause. Progressive deficits are consistent with mass lesions such as tumor or aneurysm. Intermittent symptoms are suggestive of myasthenia gravis.

Although cranial neuropathy commonly results from trauma, such deficits are attributed to mild trauma with caution. In these

 

1331

instances, an underlying structural lesion, such as aneurysm or tumor, often is present. [50] [51]

Isolated Cranial Neuropathies

ISOLATED SIXTH CRANIAL NERVE PALSY.

In a child who has an acquired, isolated sixth nerve paresis, early investigation using MRI is reasonable because of the frequent presentation of tumor with sixth nerve paresis.

In an elderly person, with or without a history of diabetes or hypertension, an erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood pressure recording, measurement of levels of glucose, antinuclear antibodies (ANA), rapid plasma reagin (RPR), fluorescent treponemal antibodies (FTA), and a Lyme titer are indicated. The patient may be followed with expectant improvement over a few months. Should no improvement occur over a few months, then neuroimaging, preferably with MRI, is indicated. The imaging must focus on the course of the sixth nerve, which includes the pons, clivus, petrous apex, cavernous sinus, and orbit. Cerebrospinal fluid (CSF) and nasopharyngeal examination are considered if no cause is otherwise found.

In a young adult, particularly without evidence of hypertension or diabetes, the above serologic tests and neuroimaging are performed and, if negative, a CSF examination is reasonable. If no abnormality is found, the patient is followed at regular intervals and re-evaluated at 6 months if resolution does not occur.

ISOLATED FOURTH CRANIAL NERVE PALSY.

The evaluation of patients affected by isolated fourth nerve paresis depends on the age group and setting. A history of significant trauma or evidence of a congenital fourth nerve paresis with decompensation requires no further workup.

In older patients subject to vascular risk factors an ESR and CRP are obtained to rule out giant cell arteritis (see Chapter 206 ), and the patient may be followed clinically. For the patient who does not have this history, blood pressure is checked, as well as glucose level, Lyme titer, and ESR. If no resolution occurs within 6 months, neuroimaging, preferably MRI, is performed. Examination of CSF may be indicated although, without other neurological symptoms or signs, the diagnostic yield is low.

In children and young adults who have no history of trauma or evidence to suggest a congenital cause, neuroimaging and a search for vasculitis are indicated. A CSF examination is indicated if no clear cause can be established and if the deficit does not resolve.

ISOLATED THIRD CRANIAL NERVE PALSY.

In adults of vasculopathic age, the most important issue is whether the pupil is involved or not. If the pupil is spared with otherwise complete involvement of ocular motility and ptosis, and the patient is over 50 years of age, diabetic, or hypertensive, a diagnosis of vasculopathic third nerve paresis may be presumed. Since aneurysms that do not at first involve the pupil have been described, the patient is followed carefully for the first week, and if the pupil becomes involved, further evaluation is indicated.[26] [52] [53] If the pupil does not become involved, the patient is presumed to have a vasculopathic third nerve palsy and expected to recover over 3–6 months. At follow-up visits during this period, the patient is evaluated for aberrant regeneration; if present, further workup for a structural lesion is dictated.

If the pupil is involved, the appropriate evaluation must be pursued until aneurysm is excluded adequately. The initial study is an MRI scan or, if not available, a computed tomography (CT) scan, with and without contrast, is carried out for subarachnoid blood and evidence of aneurysm. If negative, a magnetic resonance angiogram (MRA) or CT angiography (CTA) may show an aneurysm.[54] However, in many centers the sensitivity of MRA and CTA is not considered sufficient to exclude an aneurysm. In this situation, urgent angiography must be carried out to exclude aneurysm. If an aneurysm is found, emergency neurosurgery must be performed to prevent subarachnoid hemorrhage.[55]

A presentation with complete ptosis and ophthalmoplegia and partial pupil involvement (mildly dilated and mildly less reactive) is known as relative pupillary sparing. Although controversial, most neuro-ophthalmologists consider this similar to pupillary sparing and monitor the patient carefully for the first week or perform MRA or CTA. Angiography is indicated if the pupil becomes more involved. [55]

Another controversial presentation is when partial ptosis and ophthalmoparesis occur, with complete sparing of the pupil. Many investigators consider this condition to be similar to that of a pupil affected by third nerve paresis and make evaluations to exclude an aneurysm, whereas other investigators monitor the patient carefully and evaluate if the pupil becomes involved. It is reasonable to at least evaluate as far as MRA and CTA in this situation.[55]

If a pupil-sparing third nerve paresis does not resolve within the expected 3–6 month period, further workup is indicated, which includes MRI scan, vasculitis workup, and, if no diagnosis can be made, a CSF examination.

For children, many cases are congenital and no further workup is indicated. In such patients, the third nerve palsy often is incomplete and associated with signs of aberrant regeneration. With a difficult delivery, trauma is the most likely cause.[1] In those conditions that are acquired, even those with pupillary involvement, angiography may not be indicated for patients less than 7 years of age, since the youngest reported age for a child to have an aneurysm is 7 years.[56] If no clear history of ophthalmoplegic migraine or known trauma is found, evaluation is carried out as above to establish the underlying causes. Numerous recent reports have documented enlargement and enhancement of the third nerve on MRI in patients with ophthalmoplegic migraine.[57]

In adults below the vasculopathic age, all third nerve palsies are worked up, which includes neuroimaging with MRI, blood tests (ESR, RPR, FTA, Lyme titer, glucose, ANA) to rule out vasculitis or infection, and CSF examination if no other cause is found.

For any patient who develops signs of aberrant regeneration, workup for a structural lesion is initiated, or repeated if previous workup has been carried out and no lesion found.

Nonisolated Cranial Neuropathies

MULTIPLE CRANIAL NEUROPATHIES.

The management of patients who have cavernous sinus and superior orbital fissure lesions depends on the age of the patient, acuteness of presentation, speed of progression, presence of pain, history of systemic diseases or tumors, and accompanying features. Patients who have fever, somnolence, or a toxic appearance must be evaluated rapidly for evidence of cavernous sinus thrombosis or mucormycosis. Those who seek treatment acutely with prominent vascular features, with arterialization of conjunctival vessels, proptosis, and bruits, must be evaluated for direct carotid cavernous fistula.

The workup includes neuroimaging with MRI, with and without gadolinium, as the procedure of choice. If MRI is contraindicated, CT scans, with and without contrast using very thin axial and coronal sections, is carried out. Most often the structural lesion is imaged by one of these techniques. For a dural arteriovenous fistula or direct fistula, MRA, as well as conventional angiography, may be performed. In rare instances, CSF examination is helpful. When appropriate, blood tests such as level of angiotensin-converting enzyme, Lyme titer, RPR, and FTA are considered.

When a mass lesion consistent with tumor is found, a primary tumor source that has metastasized is possible. The diagnosis may be made by biopsy elsewhere, if more accessible lesions are present. With primary tumors, biopsy of the cavernous sinus lesion is often necessary.

With the onset of painful ophthalmoplegia consistent with idiopathic inflammation, a course of corticosteroids may be initiated.

 

1332

A positive response to corticosteroids has been used as diagnostic support for Tolosa–Hunt syndrome. However, since similar responses may occur in association with tumors, such as chordoma, giant-cell tumor, lymphoma, and epidermoid, the diagnosis must be made with caution and must be considered a diagnosis of exclusion. Differential diagnostic considerations for the presentation of painful ophthalmoplegia are listed in Box 199-1 .[36] Evaluation to exclude the above causes of the cavernous sinus syndrome, as well as numerous other conditions, includes neuroimaging, complete blood count, ESR, FTA, ANA, serum protein electrophoresis, and, occasionally, nasopharyngeal and CSF examinations. Neuroimaging may be normal or may show a lesion consistent with inflammation. With recurrent episodes consistent with Tolosa–Hunt syndrome, biopsy of any lesion noted on neuroimaging is indicated to rule out these other entities. In the few cases reviewed pathologically, idiopathic chronic granulomatous inflammation is seen.

When a patient who has a known or an occult pituitary adenoma has an acute onset of painful ophthalmoparesis, often pituitary apoplexy is found by demonstration of acute hemorrhage or swelling of the pituitary adenoma on neuroimaging. These patients undergo surgery, using trans-sphenoidal hypophysectomy.

To diagnose direct or indirect carotid–cavernous fistula, arteriography is the definitive diagnostic procedure. However, MRI and MRA may demonstrate enlargement of the superior ophthalmic vein or the actual fistula. Other helpful procedures include CTA, Doppler ultrasound, color Doppler, and measurement of ocular pulse amplitude. Reversal of flow may be demonstrated in the superior ophthalmic vein.[58]

 

 

 

Differential Diagnosis of Painful Ophthalmoplegia Syndrome

TRAUMA

ANEURYSM

Intracavernous carotid artery

 

Posterior cerebral artery

 

Basilar artery

 

CAROTID CAVERNOUS FISTULA

CAVERNOUS SINUS THROMBOSIS

TUMORS

Primary intracranial

 

Local or distant metastasis

 

Pituitary apoplexy

 

Meningeal carcinomatosis or lymphomatosis

 

 

INFECTION

Mucormycosis or other fungal infection

 

Herpes zoster

 

Tuberculosis

 

Bacterial sinusitis, mucocele, periostitis

 

Syphilis

 

 

INFLAMMATION

Sarcoid

 

Wegener’s granulomatosis

 

Tolosa–Hunt syndrome

 

Orbital pseudotumor

 

GIANT CELL ARTERITIS

ISCHEMIC

Diabetes

 

Hypertension

 

OPHTHALMOPLEGIC MIGRAINE

 

 

 

Bilateral Ophthalmoplegia.

Neuroimaging that includes the course of each nerve involved on each side is required for patients who have bilateral simultaneous ophthalmoplegia without obvious cause. If negative, CSF examination is carried out and serologic evaluation for collagen vascular disease, arteritis, syphilis, and Lyme disease is obtained.

DIFFERENTIAL DIAGNOSIS

Numerous disorders that affect ocular motility may mimic and appear identically to a cranial neuropathy. These processes include restrictive ophthalmopathies, such as thyroid disease; neuromuscular diseases, such as myasthenia or botulism; and polyneuropathies, such as the Miller–Fisher variant of the Guillain–Barré syndrome.

The major examination technique used to exclude a restrictive process is the forced duction examination, in which a forceps or cotton-tipped swab is used to overcome the ductional deficit in the eye. A positive sign of restriction is when the deficit cannot be overcome because of resistance. Another sign of restrictive disease is an elevation of intraocular pressure when the eye moves in the direction of the restriction.

Isolated Cranial Neuropathies

ISOLATED SIXTH CRANIAL NERVE PALSY.

The differential diagnosis of a sixth nerve paresis includes Duane’s retraction syndrome, thyroid or other restrictive ophthalmopathy, myasthenia gravis, spasm of the near reflex, or breakdown of a previous esophoria.

Duane’s syndrome is a congenital abnormality that occurs in three different forms. All three forms include narrowing of the palpebral fissure and retraction of the globe when the eye is adducted. Type I consists of an abduction deficit that mimics a sixth nerve paresis, type II consists of an adduction deficit, and type III includes both an abduction and adduction deficit ( Fig. 199-11 ). Pathologically, abnormal development of the cells of the abducens nucleus and innervation of the lateral rectus by branches of the oculomotor nuclei occurs. During adduction, co-firing of the medial and lateral recti produces retraction of the globe. Patients who have Duane’s syndrome do not usually experience diplopia. Duane’s syndrome is bilateral in 18% of cases and familial in 10%. [59] [60]

 

 

 

 

Figure 199-11 Duane’s syndrome (type III). A, Abduction deficit. B, Adduction deficit, retraction of globe, and narrowing of palpebral fissure on adduction of the right eye.

 

1333

Spasm of the near reflex most often is seen as a nonorganic, functional disorder in patients who have psychogenic disease or in malingerers. It presents with an abduction deficit that arises from substitution of convergence for lateral gaze. The diagnosis is made by finding the other features of the near reflex, mainly miosis, on attempted lateral gaze. Ductions tested with the other eye covered usually are normal. Spasm of the near reflex is seen rarely in organic conditions.[61]

Restrictive ophthalmopathy most often results from thyroid disease. If not already present, the patient soon develops other orbital signs, such as proptosis, injection, chemosis, lid retraction and lag, and has a positive forced duction test. Other restrictive processes of the medial rectus include trauma and orbital myositis.

Myasthenia may be differentiated on history and examination by the features of fatigability and variability. Evaluation using a Tensilon test, acetylcholine receptor antibody, and electromyogram establishes the diagnosis.

Patients who have congenital esophoria or compensated esotropia may give a history consistent with sixth nerve palsy, as a result of worsening of the previous deviation, often in times of stress or infection. Features that favor this diagnosis include a relatively comitant deviation and the establishment of an ocular deviation when photographs of the patient at a younger age are reviewed.

Infants who have congenital esotropia may have cross-fixation that mimics a sixth nerve paresis. This may be seen with latent nystagmus, as part of the nystagmus blockage syndrome. Evaluation after patching one eye for days or performing the Doll’s head maneuver demonstrate normal abduction.[35]

ISOLATED FOURTH CRANIAL NERVE PALSY.

The differential diagnosis of isolated fourth nerve paresis includes myasthenia gravis, thyroid ophthalmopathy and other orbital restrictive processes, Brown’s syndrome, skew deviation, and overaction of the inferior oblique muscle associated with congenital strabismus. Thyroid ophthalmopathy is present most often with other orbital signs and features of restriction, as noted above for sixth nerve paresis.[62] Myasthenia gravis can be differentiated by its fatigability and variability. Skew deviation, a supranuclear vertical deviation that results from brainstem disease, is often associated with other neurological findings that are not present with an isolated fourth nerve paresis. Skew deviation may have a comitant or incomitant pattern of deviation and does not exactly fit with the three-step pattern of a fourth nerve paresis. The ocular tilt reaction, a form of skew deviation that most closely mimics a fourth nerve paresis, appears with hypotropia, head tilt towards the hypotropic eye, and conjugate torsion towards the hypotropic eye.[63] In addition, excyclotorsion may not be present with myasthenia, skew deviation, and thyroid disease, but is invariably present with an isolated fourth nerve paresis.

Brown’s syndrome causes diplopia because of an elevation deficit in adduction, in which the involved eye is hypotropic; forced duction test is positive. When congenital, this syndrome results from a short or tethered superior oblique tendon, but the acquired syndrome may be a result of tenosynovitis, adhesions, metastasis, or trauma.[1] [35] Brown’s syndrome actually mimics an inferior oblique paresis; the latter may be differentiated by concomitant overaction of the superior oblique muscle, an A-pattern horizontal deviation, and a negative forced duction test. Patients affected by overaction of the inferior oblique muscle have a deviation greatest in adduction in upgaze.

ISOLATED THIRD CRANIAL NERVE PALSY.

The differential diagnosis of isolated third nerve palsy is not as lengthy as for fourth and sixth nerve palsies because of the many structures innervated by the third nerve and the characteristic findings. Nonetheless, if no pain or pupil involvement exists, myasthenia gravis must be considered. Restrictive ophthalmopathy may mimic parts of a third nerve paresis, but does not involve the pupil, more often presents with lid retraction than ptosis if thyroid ophthalmopathy is the cause, and often has other orbital findings. A supranuclear lesion may involve ptosis and an elevation deficit, but usually has other associated deficits that involve midbrain and diencephalic structures.

Nonisolated Cranial Neuropathies

It is important in the diagnosis of simultaneous palsies of the motor nerves of the eye to differentiate these from oculoparesis that arises from orbital inflammatory disease, such as Graves’ ophthalmopathy or orbital pseudotumor, ocular myopathies (such as chronic progressive external ophthalmoplegia), disorders of neuromuscular transmission (such as myasthenia gravis or botulism), and polyneuropathies (such as the Miller–Fisher variant of Guillain–Barré syndrome). Demyelinating disease, basilar artery ischemia or aneurysm, skull base tumors, Wernicke’s encephalopathy, and supranuclear gaze palsies also must be included in the differential diagnosis of nonisolated cranial neuropathies.[34]

TREATMENT

Aside from treatment for the specific cause of the cranial neuropathy, the symptoms of diplopia must be treated. Acutely, occlusion of either eye using a patch or opaque tape over glasses is the best treatment, particularly in patients who are expected to recover. With chronic diplopia, prism therapy is helpful for a subgroup of patients, especially when the deviation is not very incomitant. Eventually, with chronic, stable deviations, strabismus surgery ( Chapter 81 ) may be useful.

Botulinum toxin injections are used by some clinicians early on, particularly for fourth or sixth nerve paresis, to promote earlier fusion while recovery takes place. Ultimate recovery is similar with or without botulinum treatment.[64] Botulinum toxin is also a treatment option for a chronic cranial nerve paresis. For instance, in a fourth nerve paresis, it may be injected into the ipsilateral inferior oblique or the contralateral inferior rectus.

Nonisolated Cranial Neuropathies

The Tolosa–Hunt syndrome is exquisitely sensitive to corticosteroids—pain resolves almost immediately and ophthalmoplegia resolves subacutely with 60–80?mg/day of prednisone. However, recurrences may not respond as well.

Direct internal carotid artery to cavernous sinus fistulas are treated by occlusion carried out by an interventional neuroradiologist, with balloon occlusion of the connection between the carotid artery and cavernous sinus. Occasionally, neurosurgery is required, with occlusion of the carotid artery both above and below the site of the fistula.

Dural arteriovenous fistulas may be followed clinically if no threat to vision exists. In over 50% of patients, the fistula spontaneously thrombosis and resolves, particularly after angiography.[58] In addition, the patient may be trained to perform occlusion of the carotid artery intermittently during the day by the application of pressure using the finger tips (provided no serious cerebrovascular disease is present); this may allow for spontaneous thrombosis to occur. On some occasions, spontaneous thrombosis may be associated with retinal vein occlusions and visual loss. In cases in which a threat to vision occurs, selective arteriography with occlusion of the feeder vessels is performed by an interventional radiologist.

Miscellaneous Disorders

Superior oblique myokymia often spontaneously remits, but may recur after months or years. The treatment of choice is carbamazepine; alternatives include baclofen and clonazepam.[35] For patients who do not respond or do not tolerate medication, surgery (a superior oblique tenectomy and inferior oblique weakening procedure) may be helpful.[65] Ocular neuromyotonia often responds to treatment with carbamazepine.

 

1334

 

 

REFERENCES

 

1. Brodsky MC, Baker RS, Hamed LM, eds. Pediatric neuro-ophthalmology. New York: Springer-Verlag; 1996.

 

2. Holmes JM, Mutyala S, Maus TL, et al. Pediatric third, fourth, and sixth nerve palsies: A population-based study. Am J Ophthalmol 1999;127:388–92.

 

3. Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 1992;114:568–74.

 

4. Moster ML, Savino PJ, Sergott RC, et al. Isolated sixth-nerve palsies in younger adults. Arch Ophthalmol. 1984;102:1328–30.

 

5. Sakalas R, Harbinson JW, Vines FS, Becker DP. Chronic sixth nerve palsy. An initial sign of basisphenoid tumors. Arch Ophthalmol. 1975;93:186–90.

 

6. Savino PJ, Hilliker JK, Casell GH, Schatz NJ. Chronic sixth nerve palsies. Are they really harbingers of serious intracranial disease? Arch Ophthalmol. 1982; 100:1442–4.

 

7. Currie J, Lubin JH, Lessell S. Chronic isolated abducens paresis from tumors at the base of the brain. Arch Neurol. 1983;40:226–9.

 

8. Galetta S, Smith JL. Chronic isolated sixth nerve palsies. Arch Neurol. 1989; 46:79–82.

 

9. Knox DL, Clark DB, Schuster FF. Benign VI nerve palsies in children. Pediatrics. 1967;40:560–3.

 

10. Volpe NJ, Lessell S. Remitting sixth nerve palsy in skull base tumors. Arch Ophthalmol. 1993;111:1391–5.

 

11. Shrader EC, Schlezinger NS. Neuro-ophthalmologic evaluation of abducens nerve paralysis. Arch Neurol. 1960;63:108–14.

 

12. Rucker CW. The causes of paralysis of the third, fourth and sixth cranial nerves. Am J Ophthalmol. 1966;61:353–8.

 

13. Johnston AC. Etiology and treatment of abducens paralysis. Trans Pacific Coast Oto-ophthalmol Soc. 1968;49:259–77.

 

14. Keane JR. Bilateral sixth nerve palsy. Analysis of 125 cases. Arch Neurol. 1976;33:681–3.

 

15. Rush JA, Younge BR. Paralysis of cranial nerves III, IV, and VI. Cause and prognosis in 1,000 cases. Arch Ophthalmol. 1981;99:76–9.

 

16. Tiffin PAC, MacEwen CJ, Criag EA, Clayton G. Acquired palsy of the oculomotor, trochlear and abducens nerves. Eye. 1996;10:377–84.

 

17. Richards BW, Jones FR, Younge BR. Causes and prognosis in 4278 cases of paralysis of the oculomotor, trochlear and abducens cranial nerves. Am J Ophthalmol 1992;113:489-96.

 

18. Archambault P, Wise JS, Rosen J, Polomeno RC, Auger N. Herpes zoster ophthalmoplegia. Report of six cases. J Clin Neuro Ophthalmol. 1988;8:185–91.

 

19. Khawn E, Scott AB, Jampolsky A. Acquired superior oblique palsy. Diagnosis and management. Arch Ophthalmol. 1967;77:761–8.

 

20. Burger LJ, Kalvin NH, Smith JL. Acquired lesions of the fourth cranial nerve. Brain. 1970;93:567–74.

 

21. Younge BR, Sutula F. Analysis of trochlear nerve palsies. Diagnosis, etiology and treatment. Mayo Clin Proc. 1977;52:11–18.

 

22. Goldstein JE, Cogan DG. Diabetic ophthalmoplegia with special reference to the pupil. Arch Ophthalmol. 1960;64:144–52.

 

23. Green WR, Hackett ER, Schlezinger NS. Neuro-ophthalmologic evaluation of oculomotor nerve paralysis. Arch Ophthalmol. 1964;72:154–67.

 

24. Miller NR. Solitary oculomotor nerve palsy in childhood. Am J Ophthalmol. 1977;83:106–11.

 

25. Harley R. Paralytic strabismus in children. Etiologic incidence and management of the third, fourth and sixth nerve palsies. Ophthalmology. 1980;87:24–43.

 

26. Kissel JT, Burde RM, Klingele TG, Zeigler HE. Pupil-sparing oculomotor palsies with internal carotid–posterior communicating artery aneurysms. Ann Neurol. 1983;13:149–54.

 

27. Newman SA. Disorders of ocular motility. In: Slamovits TL, Burde R, eds. Textbook of ophthalmology. Neuro-ophthalmology, London: Mosby–Yearbook Europe; 1997.

 

28. Friedman AP, Harter DH, Merritt HH. Ophthalmoplegia migraine. Arch Neurol. 1962;7:82–9.

 

29. Sebag J, Sadun AA. Aberrant regeneration of the third nerve to the iris sphincter following penetrating orbital trauma. Arch Neurol. 1983;40:762–5.

 

30. Schatz NJ, Savino PJ, Corbett JJ. Primary aberrant oculomotor regeneration. A sign of intracavernous meningioma. Arch Neurol. 1977;34:29–32.

 

31. Cox TA, Wurster JB, Godfrey WA. Primary aberrant oculomotor regeneration due to intracranial aneurysm. Arch Neurol. 1979;36:507–71.

 

32. Friedman DI, Wright K, Sadun AA. Oculomotor palsy with cyclic spasms. Neurology. 1989;39:1263–4.

 

33. Derakhshan I. Superior branch palsy of the oculomotor nerve with spontaneous recovery. Ann Neurol. 1978;4:478–9.

 

34. Sergott RC, Glaser JS, Berger LJ. Simultaneous, bilateral diabetic ophthalmoplegia. Report of two cases and discussion of differential diagnosis. Ophthalmology. 1984;91:18–22.

 

35. Leigh RJ, Zee DS. In: Plum F, Gilman S, Martin JB, et al, eds. The neurology of eye movements, ed 2. Philadelphia: FA Davis; 1991.

 

36. Kline LB. The Tolosa–Hunt syndrome. Surv Ophthalmol. 1982;27:79–95.

 

37. Jefferson G. Concerning injuries, aneurysms and tumors involving the cavernous sinus. Trans Ophthalmol Soc UK. 1953;73:117–52.

 

38. Thomas JE, Yos E. The parasellar syndrome: Problems in determining etiology. Mayo Clin Proc. 1970;45:617–23.

 

39. Kline LB. Cavernous sinus/orbital apex syndrome. In: Tusa RJ, Newman SA, eds. Neuro-ophthalmological disorders. New York: Marcel Dekker, 1995:291–8.

 

40. Keane JR. Cavernous sinus syndrome. Analysis of 151 cases. Arch Neurol. 1996; 53:967–71.

 

41. Tolosa E. Periarteritic lesions of the carotid siphon with the clinical features of a carotid infraclinoid aneurysm. J Neurol Neurosurg Psychiatry. 1954;17:300–2.

 

42. Hunt WE, Meagher JN, LeFever HE, Zeman W. Painful ophthalmoplegia. Its relation to indolent inflammation of the cavernous sinus. Neurology. 1961;11:56–62.

 

43. Miller N, ed. Walsh and Hoyt’s neuro-ophthalmology, vol 2, ed 4. Williams and Wilkins: Baltimore; 1985.

 

44. Miller EA, Savino PJ, Schatz NJ. Bilateral sixth-nerve palsy. A rare complication of water-soluble contrast myelography. Arch Ophthalmol. 1982; 100:603–4.

 

45. Morrow MJ, Sharpe JA, Ranalli PJ. Superior oblique myokymia associated with a posterior fossa tumor: oculographic correlation with an idiopathic case. Neurology. 1990;40:367–70.

 

46. Shults WT, Hoyt WF, Behrens M, et al. Ocular neuromyotonia. A clinical description of six patients. Arch Ophthalmol. 1986;104:1028–34.

 

47. Lessell S, Lessell IM, Rizzo JF III. Ocular neuromyotonia after radiation therapy. Am J Ophthalmol. 1986;102:766–70.

 

48. Newman SA. Clinical challenges. Gaze-induced strabismus. Surv Ophthalmol. 1993;38:303–9.

 

49. Moster ML. Complications of cancer therapies. In: Miller N, Newman NJ, eds. Walsh and Hoyt’s neuro-ophthalmology, ed 5. Baltimore: Williams and Wilkins; 1997.

 

50. Chrousos GA, Dipaola F, Kattah JC, Laws ER. Paresis of the abducens nerve after trivial head injury. Am J Ophthalmol. 1993;116:387–8.

 

51. Walter KA, Newman NJ, Lessell S. Oculomotor palsy from minor head trauma: initial sign of intracranial aneurysm. Neurology 1994;44:148–50.

 

52. O’Connor PS, Tredici TJ, Green RP. Pupil-sparing third nerve palsies caused by aneurysm. Am J Ophthalmol. 1983;95:395–7.

 

53. Bartleson JD, Trautmann JC, Sundt TM. Minimal oculomotor nerve paresis secondary to unruptured intracranial aneurysm. Arch Neurol. 1986;43:1015–20.

 

54. McFadzean RM, Teasdale EM. Computerized tomography angiography in isolated third nerve palsies. Jl Neurosurg 1998:88:679–84.

 

55. Jacobson DM, Trobe JD. The emerging role of magnetic resonance angiography in the management of patients with third cranial nerve palsy. Am J Ophthalmol 1999;128:94–6.

 

56. Branley MG, Wright KW, Borchert MS. Third nerve palsy due to cerebral artery aneurysm in a child. Aust NZ Jl Ophth 1992;20:137–40.

 

57. Ohara MA, Anderson RT, Brown D. Magnetic resonance imaging in ophthalmoplegic migraine of children. J AAPOS 2001;5:307–10.

 

58. Golnik KC. Cavernous sinus arteriovenous fistula. In: Tusa RJ, Newman SA, eds. Neuro-ophthalmologic disorders. New York: Marcel Dekker, 1995:317–27.

 

59. Raab E. Clinical features of Duane’s syndrome. J Pediatr Ophthalmol Strabismus. 1986;23:64–8.

 

60. DeRespinis PA, Caputo AR, Wagner RS, Guo S. Major review. Duane’s retraction syndrome. Surv Ophthalmol. 1993;38:257–88.

 

61. Moster ML, Hoenig EM. Spasm of the near reflex associated with metabolic encephalopathy. Neurology. 1989;39:150.

 

62. Moster ML, Bosley TM, Slavin ML, Rubin SE. Thyroid ophthalmology presenting as superior oblique paresis. J Clin Neuro Ophthalmol. 1992;12:94–7.

 

63. Donahue SP, Lavin PJM, Hamed LM. Tonic ocular tilt reaction simulating a superior oblique palsy. Arch Ophthalmol 1999;117:347–52.

 

64. Holmes JM, Beck RW, Kip KE, et al. Botulinum toxin treatment versus conservative management in acute traumatic sixth nerve palsy or paresis. J AAPOS 2000;4:145–9.

 

65. Palmer EA, Shults WT. Superior oblique myokymia: preliminary results of surgical treatment. J Pediatr Ophthalmol Strabismus. 1984;21:96–101.