Diplopia Due to Ocular Motor Cranial due...Diplopia Due to Ocular Motor Cranial Neuropathies Wayne...

Diplopia Due toOcular Motor CranialNeuropathies

Wayne T. Cornblath, MD, FAAN

ABSTRACTPurpose of Review: Determining which cranial nerve(s) is (are) involved is a criticalstep in appropriately evaluating a patient with diplopia.Recent Findings: New studies have looked at the various etiologies of cranial nervepalsies in the modern imaging era. The importance of the C-reactive protein test inevaluating the possibility of giant cell arteritis has recently been emphasized.Summary: Dysfunction of the oculomotor (third), trochlear (fourth), or abducens (sixth)cranial nerve will produce ocular misalignment and resultant binocular diplopia or binocularblur. A misalignment in the vertical plane of as small as 200 2m is enough to producediplopia. Diagnosing diplopia from a cranial nerve abnormality requires an understanding ofstructure (the anatomy of the cranial nerves from nucleus to muscle), function (themovements controlled by the cranial nerves), possible etiologies, and exceptions to the rules.

Continuum (Minneap Minn) 2014;20(4):966–980.

ANATOMYThe third cranial nerve (oculomotor)starts in the midbrain as combinedmidline nuclei divided into subnucleiwith a few anatomic quirks that arehelpful to know. The superior rectussubnuclei innervate the contralateraleye. The central caudal nucleus is asingle nucleus that innervates bothlevator palpebrae superioris muscles.

These nuclei are located in a dorsal,midline position. Thus, both eyes canbe affected with a single nuclear lesion.

The fascicle of the third nerve projectsanteriorly, passing by the reticular forma-tion, red nucleus, substantia nigra, andcorticospinal tracts to enter the subarach-noid space via the interpeduncular fossa.In the subarachnoid space, the pupillaryfibers are located in the superior andmedial portion of the nerve. The thirdnerve passes by the posterior communi-cating artery, edge of the tentorium, anduncus before entering the upper lateral

wall of the cavernous sinus. The thirdnerveenters thesuperiorportionof thecavernoussinus; it then splits into a superior andinferiordivisionas it enters theorbit throughthe superior orbital fissure. The superiordivision supplies the superior rectus andlevator palpebrae superioris muscles. Theinferior division supplies the medial rectus,inferior rectus, and inferior oblique and, viathe ciliary ganglion, innervates the pupillarysphincter and ciliary body.

The fourth cranial nerve (trochlear)nucleus is ventral to the cerebral aque-duct at the pontomesencephalic junction.The axons for each nerve then exit thebrainstem dorsally (the only cranial nerveto do so) at the level of the inferiorcolliculus, where they decussate. Thenerve then runs around the cerebralpeduncle and enters the lateral wall ofthe cavernous sinus just below the thirdnerve, entering the orbit through thesuperior orbital fissure and innervating thesuperior oblique muscle. The fourth nerve

Address correspondence toDrWayneT.Cornblath,Universityof Michigan, W. K. Kellogg EyeCenter, 1000 Wall St, Ann Arbor,MI 48105, [email protected].

Relationship Disclosure:Dr Cornblath reports nodisclosure.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Cornblath reports nodisclosure.

* 2014, American Academyof Neurology.

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has the longest course and fewest axonsof the ocular motor nerves. With thedecussation, the fourth nerve nucleusinnervates the contralateral superioroblique muscle.

The sixth cranial nerve (abducens)nucleus is in the dorsal pons on the floorof the fourth ventricle adjacent to thefacial nerve nucleus. The sixth nervenucleus contains neurons that produceinternuclear neurons to innervate thecontralateral medial rectus muscle viathe medial longitudinal fasciculus. Thesixth nerve nucleus along with the fibersfrom the facial nucleus form the facialcolliculus. The axons from the sixth nervenucleus run ventrally and caudally, lateralto the corticospinal tract, and exit at thepontomedullary junction. The sixth nervethen runs along the clivus until it piercesthe dura at the Dorello canal, goes overthe petrous ridge, and enters the cavern-ous sinus. In the cavernous sinus, thesixth nerve is in the middle, just lateral tothe carotid artery andmedial to the fourthnerve. The sympathetic fibers to the pupilandMuellermuscle are on the sixth nervefor a short distance in the cavernoussinus. The sixth nerve enters the orbitthrough the superior orbital fissure andinnervates the lateral rectus muscle.

FUNCTIONThe sixth cranial nerve (lateral rectus)abducts the eye, and the medial rectus(third nerve) adducts the eye. Thesuperior and inferior recti and obliquemuscles move the eye in more thanone direction, with primary, secondary,and tertiary actions (Table 9-1).The superior rectus (third nerve) ele-vates and intorts the eye with theinferior rectus (third nerve) depressingand extorting the eye. The superioroblique (fourth nerve) depresses andintorts the eye with the inferioroblique (third nerve) elevating andextorting the eye.

Both oblique muscles abduct theeye. The levator palpebrae super-ioris (third nerve) primarily elevatesthe eyelid, with the Mueller muscleproviding about 2 mm of eyelidelevation.

DIAGNOSIS: LOCALIZATIONIn localizing cranial nerve palsies, cer-tain anatomic features can be helpful tolimit the possible locations. The firstconsideration is whether a single cra-nial nerve (isolated) is involved, and, inthe case of the third nerve, whetherfeatures that localize to the nucleus or

KEY POINTS

h Diagnosing diplopiafrom a cranial nerveabnormality requires anunderstanding ofstructure (the anatomyof the cranial nervesfrom nucleus to muscle),function (the movementscontrolled by the cranialnerves), the possibleetiologies, and exceptionsto the rules.

h Both the superior andinferior oblique musclesabduct the eye. Thelevator palpebraesuperioris (third nerve)primarily elevates theeyelid, with the Muellermuscle providing about2 mm of eyelid elevation.

TABLE 9-1 Extraocular Muscle Innervation and Action

Muscle Innervation Actiona

Superior rectus Oculomotor nerve(superior branch)

Elevation, intorsionb, adduction

Inferior rectus Oculomotor nerve(inferior branch)

Depression, extorsionc; adduction

Medial rectus Oculomotor nerve(inferior branch)

Abduction

Lateral rectus Abducens nerve Adduction

Superior oblique Trochlear nerve Intorsionb, depression, abduction

Inferior oblique Oculomotor nerve(inferior branch)

Extorsionc, elevation, abduction

a Primary action appears in bold.b Intorsion is the inward rotation of the upper pole of the vertical meridian of the eye.c Extorsion is the outward rotation of the upper pole of the vertical meridian of the eye.

967Continuum (Minneap Minn) 2014;20(4):966–980 www.ContinuumJournal.com


superior and inferior divisions arepresent. The next consideration iswhether multiple cranial nerves areinvolved, and, finally, whether otherneurologic symptoms (eg, hemiparesis,ataxia) are present.

Third Nerve PalsyNuclear lesions in the third nerve willproduce either bilateral ptosis or noptosis due to involvement or lack ofinvolvement of the single subnucleuscontrolling the levator. Similarly, oneor both pupils can be either involvedor normal because of the rostral loca-tion of the paired Edinger-Westphalnuclei. Because of the crossed supe-rior rectus subnuclei, a nuclear lesionwill have either bilateral dysfunction,from involvement of the subnucleiand crossing fibers, or contralateralsuperior rectus dysfunction, frominvolvement of the crossing fibersonly. Fascicular lesions of the thirdnerve can be associated with hemi-paresis, ataxia, or tremor from involve-ment of adjacent corticospinal tracts,red nucleus, brachium conjunctivum,and cerebellar peduncles. Cavernoussinus lesions can produce third nervepalsies in combination with fourth,fifth (trigeminal) (V1, V2), and/orsixth nerve palsies. In the orbit,either the superior or inferior divisionof the third nerve can be involved.However, divisional third nerve palsiescan occasionally be mimicked bycompressive lesions prior to the orbit.

Fourth Nerve PalsyIsolated nuclear lesions of the fourthnerve are rare and give rise to contra-lateral palsies caused by the decussa-tion. A nuclear fourth nerve palsy canalso include ipsilateral internuclearophthalmoplegia and Horner syn-drome or contralateral afferent pupil-lary defect from involvement of themedial longitudinal fasciculus, de-scending oculosympathetic fibers, orpupillary axons in the brachium of thesuperior colliculus. Cavernous sinuslesions can produce fourth nervepalsies in combination with third, fifth(V1, V2), and/or sixth nerve palsies.

Sixth Nerve PalsyIn the brainstem, a nuclear lesion of thesixth nerve produces a gaze palsy due tothe neurons innervating the contralateralmedial rectus. A fascicular lesion pro-duces an isolated abduction deficit. Sixthnerve nuclear lesions can damage theadjacent medial longitudinal fasciculusand produce a one-and-a-half syndrome.Fascicular lesions can be accompaniedby hemiparesis, sensory change, or facialnerve palsy from involvement of thecoriticospinal tract, medial lemniscus, orseventh nerve fascicle. A single clivuslesion, metastasis, or primary tumor canproduce unilateral or bilateral sixth nervepalsies, as illustrated inCase 9-1. In thepetrous ridge, the fifth and sixthcranial nerves can both be affected,typically by infection. Cavernous sinuslesions can produce sixth nerve palsies

Case 9-1A 51-year-old man presented for evaluation of horizontal, binoculardiplopia that had been present for 2 weeks. He was a marathon runnerwith no vascular risk factors and no family history of vascular disease.On examination he had a right abduction deficit consistent with a rightsixth nerve palsy. Neuroimaging was obtained and read as normal.Further review, however, showed that the normal high signal, from fat(Figure 9-1A), in the clivus marrow space was absent (Figure 9-1B), indicating

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Ocular Motor Cranial Neuropathies


a metastatic process replacing the fat and compressing the sixth nerve inthe Dorello canal. Further evaluation revealed other asymptomatic bonylesions, and an eventual diagnosis of metastatic prostate cancer was made.

Comment. In this case, knowledge of the path of the sixth nerve allowsa focused review of the MRI and discovery of the abnormality causingthe nerve palsy.

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FIGURE 9-1 Panel A shows normal high signal in the clivus (arrow)on a T1-weighted MRI sagittal MRI of a healthyindividual. In panel B, the normal high signal, from fat, in

the clivus marrow space is absent in the T1-weighted sagittal MRI of thepatient in Case 9-1 (arrow), indicating a metastatic process replacing thefat and compressing the sixth nerve in the Dorello canal.



in combination with third, fourth, and/or fifth (V1, V2) nerve palsies. Thecombination of a unilateral Hornersyndrome and sixth nerve palsy alsolocalizes to the cavernous sinus, asillustrated in Case 9-2.

Third, Fourth, and SixthNerve PalsyWith multiple cranial nerve palsies, fourpossibilities, or localizations, exist. Thefirst possibility, as already noted, is a

cavernous sinus location that involvesthe third, fourth, and sixth nerves andfirst and second division of the fifth(trigeminal) nerve (V1, V2), or variouscombinations. The second possibility formultiple cranial nerve involvement is aCSF-based process affecting the nerves inthe subarachnoid space. The third possi-bility is a neuromuscular junction pro-cess, which can mimic a multiple cranialnerve process. The fourth possibility isan inflammatory cranial neuropathy.

KEY POINT

h Cavernous sinus lesionscan produce sixth nervepalsies in combinationwith third, fourth,and/or fifth (V1, V2)nerve palsies. Thecombination of aunilateral Hornersyndrome and sixthnerve palsy also localizesto the cavernous sinus.

Case 9-2An 86-year-old man reported diplopia that had gradually worsened over the past 3 months. He hadno other neurologic complaints. Past medical history included resection of multiple squamous cellcarcinomas from his face. Examination showed an abduction deficit on the left, along with left ptosisand miosis (Figure 9-2). Testing with cocaine eye drops showed increase in anisocoria with minimaldilation on the left, indicating a left Horner syndrome (Figure 9-3). The combination of sixth nervepalsy and Horner syndrome indicated a cavernous sinus localization. The history of slow progressionover months indicated a compressive or infiltrative lesion. The history of squamous cell carcinomaindicated perineural spread of the squamous cell carcinoma from the skin through the superior orbitalnerve to the cavernous sinus as the etiology. This was confirmed on imaging (Figure 9-4A, B) andbiopsy (Figure 9-4C).

FIGURE 9-2 Examination of the patient in Case 9-2. Normal right gaze (A), left ptosis and miosis (B), and abductiondeficit on left gaze (C).

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FIGURE 9-3 Testing with cocaine eye drops showedincrease in anisocoria with minimal dilation onthe left, indicating a left Horner syndrome.




DIAGNOSIS: ETIOLOGYIn general, the same processes affecteach of the cranial nerves: ischemia,compression, trauma, inflammation,and neuromuscular junction disorders;but differences exist in how common

certain etiologies are for each nerve andwhen multiple nerves are involved. Inaddition, some conditions are unique tocertain nerves, ie, decompensated con-genital fourth nerve palsy or aneurysmalthird nerve palsy. This section includes

Comment. In this case the observation of two distinct neurologicfindings, a sixth nerve palsy and a Horner syndrome, lead to a singleanatomic location, the sixth nerve in the cavernous sinus, and to a focusedevaluation and eventual diagnosis.

FIGURE 9-4 Imaging and biopsy of the patient in Case 9-2.A, Fullness of left cavernous sinus on axial CT(arrow). B, Enlarged superior orbital nerve oncoronal CT (arrow). C, Lid crease incision andbiopsy of enlarged superior orbital nerve seenon CT (arrow).

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discussion on the features common tocranial nerves III, IV, and VI and thefeatures specific to each nerve.

When evaluating any cranial nervepalsy, several questions need to beanswered:

1. Are any other neurologic signsor symptoms present? As notedearlier in this article, involvementof the nucleus or fascicular portionof the nerve typically is associatedwith other neurologic symptoms.

2. Is a history of trauma present?Third, fourth, and sixth cranialnerve palsies can result fromtrauma, with only minor headtrauma needed to produce afourth nerve palsy.1

3. What is the age of the patient?Ischemic cranial nerve palsies occurin patients older than 50 years or inyounger patients with significantvascular risk factors.

4. Are any symptoms of giant cellarteritis (eg, new-onset headache,jaw claudication, polymyalgiarheumatica symptoms, fatigue, nightsweats, weight loss, fever) present?In this author’s experience, 15% ofpatients with biopsy-proven giantcell arteritis presentedwith diplopia.

5. Has significant variability in thediplopia occurred, particularly timeswith and without diplopia in thecourse of a day? Myasthenia graviswill vary, frequently with no diplopiaupon awakening or after a period ofrest. Thyroid eye disease will typicallyproduce diplopia that is worse uponawakening and can resolve later inthe day because of orbital congestionwhen supine.

Pain can be severe in ischemic cranialneuropathies and in aneurysmal thirdnerve palsy or can be absent in either.Given this variability, the presence orabsence of pain is much less useful thanthe other features discussed and there-

fore is not mentioned in the listing ofhistorical features. In most patients,diplopia is a binary symptom, eitherpresent or absent. Thus, the onset ofthe diplopia offers no distinction be-tween acute (ischemic) or slow (com-pressive) etiologies. Occasionally,patients with a compressive lesion willnote an increased area in which they seedouble, ie, double on left gaze becomingdouble in left, primary, and right gazeover several months.

Third Nerve PalsyIn evaluating an isolated third nerve palsy,four additional factors need to be consid-ered when deciding on the etiology:

1. Is the pupil involved, ie, largerthan the other pupil and lessreactive? Pupillary involvement isconsidered to be the hallmark ofcompressive third nerve palsies(rule of the pupil) and relates to thelocation of the fibers serving thepupil on the outside of the nerve.2

2. The extent of involvement ofthe motor function needs to beevaluated. Are elevation, depression,adduction, and complete ptosisabsent? Or are these functionspartially affected? This observationis critical because the rule of thepupil only applies in the presenceof complete motor involvement.Incomplete motor involvementand a normal pupil can be seenwith an aneurysmal or othercompressive third nerve palsyearly on, as illustrated in Case 9-3.With progression,motor involvementcan become complete and thepupil becomes involved.3 There is,of course, an exception to the ruleof the pupil. In up to 25% ofischemic third nerve palsieswith complete motor involvement,up to 2 mm of anisocoria can bepresent with the pupil still reactive.4

KEY POINTS

h The onset of the diplopiaoffers no distinctionbetween acute (ischemic)or slow (compressive)etiologies. Occasionally,patients with acompressive lesion willnote an increased area inwhich they see double,ie, double on left gazebecoming double in left,primary, and right gazeover several months.

h Incomplete motorinvolvement and anormal pupil can be seenwith an aneurysmal orother compressive thirdnerve palsy early on.With progression, motorinvolvement can becomecomplete and the pupilbecomes involved.




Case 9-3A 63-year-old woman had 2 weeks of diplopia without headache or other neurologic complaints.She also had hypertension, diabetes mellitus, and a 60 pack-year smoking history. Examination showedmild right ptosis along with mild elevation, depression, and adduction deficits with equally roundand reactive pupils, consistent with a partial third nerve palsy with pupil sparing (Figure 9-5). Whileshe did have significant vascular risk factors and a normal pupil, because her third nerve palsy wasincomplete meant the rule of the pupil did not apply, and evaluation for an aneurysmal third nervepalsy was undertaken. Subsequent CT angiography showed a posterior communicating arteryaneurysm (Figure 9-6).

Comment. Aneurysmal third nerve palsy is a neuro-ophthalmic emergency where the decisionmaking is driven by careful evaluation of the pupil and extraocular motility. Pain, age, and vascularrisk factors do not play a role here.

FIGURE 9-5 Examination of the patient in Case 9-3. A, Upgaze with slight limitation ofelevation in the right eye. B, Right gaze. C, Primary gaze with right ptosis andpseudoretraction on left. D, Left gaze with decreased adduction of right eye.E, Downgaze with slight limitation of depression in the right eye.

FIGURE 9-6 Reconstruction of CT angiography showing rightposterior communicating artery aneurysm (arrow).



3. Does the third nerve palsy affectonly the superior division or inferiordivision? This divisional patternwould indicate an orbital process.

4. Are any signs of aberrantregeneration present? Aberrantregeneration consists of anexpected gaze movementproducing an unexpected oraberrant response. Commonexamples include eyelid elevationwith adduction and ptosis withabduction; adduction withattempted downgaze; or pupillaryconstriction with elevation,depression, or adduction, asillustrated in Case 9-4. Aberrantregeneration is seen either after atraumatic third nerve palsy or witha long-standing third nerve palsyfrom a compressive etiology,so-called primary aberrantregeneration.5 Meningioma isthe most common cause ofprimary aberrant regeneration,but aneurysms can also cause this.

Fourth Nerve PalsyIn addition to the usual factors affectingcranial nerves, the fourth cranial nervecan also produce diplopia from decom-pensation of a long-standing or congen-ital fourth nerve palsy. This can occur atany age and can be seen with nopreceding factors or after trauma ormedical illness. A decompensated, con-genital fourth nerve palsy has a numberof historical and examination featuresto distinguish it from other recentlyacquired causes of fourth nerve palsy.When asked, patients with a decom-pensated, congenital fourth nerve palsywill frequently recall brief episodes ofvertical diplopia in the past, usuallyassociated with excessive fatigue oralcohol use. Patients frequently havelong-standing head tilt to the sideopposite the palsy as a method toreduce symptoms. Review of old pho-

tographs can show this head tilt manyyears prior to the development ofsymptomatic diplopia. Some patientshave facial asymmetry with the side ofthe face opposite the head tilt beingslightly smaller.6 While these featuresare variably present, the sine qua nonfor diagnosing a decompensated, con-genital fourth nerve palsy is increasedvertical fusional amplitudes or a greaterthan average ability to fuse two verticallymisaligned images into a single image.The normal range for vertical fusionalamplitudes is 1 to 4 prism diopters;patients with a decompensated, con-genital fourth nerve palsy typicallyhave 6 or more prism diopters ofvertical fusional amplitude. This ismeasured with a prism bar and canbe done by neurologists with access toprisms or by neuro-ophthalmologistsand ophthalmologists.

Sixth Nerve PalsyLike the third and fourth nerves, thereare special circumstances for an isolatedsixth nerve palsy. Alterations in intracra-nial pressure can produce a sixth nervepalsy, either unilateral or bilateral, fromshift of the brain down. With highintracranial pressure, there is associatedpapilledema. With low intracranial pres-sure, spontaneous or after lumbarpuncture, there will be no other exam-ination findings.

Etiologies by IncidenceWhen reviewing the frequency of thecauses of isolated third, fourth, and sixthnerve palsy, several large series are com-monly referenced. A number of thesestudies, however, raise issues. Somestudies have been done prior to modernimaging, some are retrospective or hos-pital based versus outpatient based, andsome from tertiary centers are prone toreferral bias. With these caveats in mind,Table 9-2 and Table 9-3 give an idea ofthe prevalence of various etiologies by




Case 9-4A 45-year-old woman presented with diplopia on upgaze noted recently. She had no history of traumaand no significant past medical, social, or family history. Examination showed mild left ptosis inprimary gaze, decreased adduction in right gaze, dilated left pupil in left gaze, adduction of the lefteye in upgaze, and left eyelid retraction in downgaze (Figure 9-7). This combination of findingsindicated primary aberrant regenerationof the left thirdnerve. Fibers intended for the leftmedial rectus hadregrown to innervate the pupil and physiologically decrease their innervation on left gaze, leading to pupildilation. Fibers intended for the left inferior rectus had regrown to innervate the levator, leading to eyelidretraction on downgaze. Fibers intended for the left superior rectus had regrown to innervate the medialrectus, leading to adduction on upgaze. The presence of aberrant regeneration without a history of trauma

raised a concern for a compressive lesion of thethird nerve, typically either cavernous sinusmeningioma or long-standing aneurysm.Imaging revealed a cavernous sinus meningioma(Figure 9-8).

Comment. The presence of aberrantregeneration indicates either a traumatic thirdnerve palsy months or years earlier ora long-standing compressive lesion. In thepresence of aberrant regeneration, the ruleof the pupil or concern for neuromuscularjunction disorders no longer applies.

FIGURE 9-7 Examination of the patient in Case 9-4. A, Upgaze showing lack of elevation of the left eye and adduction of theleft eye. B, Right gaze showing slight limitation of adduction of the left eye. C, Primary gaze showing left ptosis. D,Left gaze showing dilation of the left pupil. E, Downgaze showing left eyelid retraction.

FIGURE 9-8 Axial contrast-enhanced T1-weighted MRIshowing a large enhancing cavernous sinusmeningioma on the left.



cranial nerve in adults and children.7Y10

Of note is that in the third nerve palsyseries myasthenia gravis is included inthe ‘‘other’’ category.

Causes of Multiple CranialNerve PalsiesWhen multiple cranial neuropathies arepresent, two initial questions should beasked:

1. Are the involved nerves in asingle anatomic localization, eg,left third, fourth, and sixth nervepalsies from a left cavernous sinusprocess?

2. Is any sensory involvement present?Myasthenia gravis or Miller-Fisher

syndrome can affect multiple cranialnervesbutwill havenosensory findings.

The cranial nerves in the cavernoussinus can be compromised by either aprimary cavernous sinus process, such asmeningioma, carotid artery aneurysm,cavernous sinus thrombosis, or idiopathicinflammation (Tolosa-Hunt syndrome),or an adjacent process. Processes adjacentto the cavernous sinus can also affect thecranial nerves in the cavernous sinus.Possibilities include pituitary adenoma,sphenoid wing meningioma, giant aneu-rysm, and craniopharyngioma.

In the subarachnoid space, multiplenerves, on one or both sides, can beaffected by carcinomatous meningitis,

KEY POINT

h Processes adjacent tothe cavernous sinus,such as pituitaryadenoma, sphenoidwing meningioma, giantaneurysm, andcraniopharyngioma, canalso affect the cranialnerves in the cavernoussinus.

TABLE 9-2 Etiology of Adult Isolated Cranial Nerve Palsya

Etiology Cranial Nerve III Cranial Nerve IV Cranial Nerve VI

Ischemic 49% 23% 45%

Aneurysmal 9% 0% 0%

Tumor 7% 1% 2%

Congenital 0% 38% 0%

Trauma 6% 29% 15%

Myasthenia gravis 0% 0% 1%

Multiple sclerosis 3% 0% 7.5%

Other 16% 1% 22%

Undetermined 10% 8% 7.5%a Data fromBerlit P, J Neurol Sci7; Mollan SP, et al, Eye (London),8 www.nature.com/eye/journal/v23/n3/full/eye200824a.html; Patel SV, et al, Ophthalmology,9 www.aaojournal.org/article/S0161-6420(03)01184-9/abstract.

TABLE 9-3 Etiology of Pediatric Isolated Cranial Nerve Palsya

Etiology Cranial Nerve III Cranial Nerve IV Cranial Nerve VI

Tumor 12.5% 1% 17%

Congenital 50% 38% 8%

Trauma 25% 29% 25%

Postviral 0% 0% 17%

Other 0% 1% 0%

Undetermined 12.5% 8% 33%a Data from Holmes JM, et al, Am J Ophthalmol,10 www.ajo.com/article/S0002-9394(98)00424-3/abstract.




http://www.nature.com/eye/journal/v23/n3/full/eye200824a.html

http://www.nature.com/eye/journal/v23/n3/full/eye200824a.html

http://www.aaojournal.org/article/S0161-6420(03)01184-9/abstract

http://www.aaojournal.org/article/S0161-6420(03)01184-9/abstract

http://www.ajo.com/article/S0002-9394(98)00424-3/abstract

tuberculosis or other chronic infec-tions, and sarcoidosis.

Myasthenia gravis and Lambert-Eatonmyasthenic syndrome can produceweakness simulating multiple unilateralor bilateral cranial nerve palsies. Finally,Miller-Fisher syndrome can producemultiple unilateral or bilateral cranialnerve palsies.

MIMICS AND EXCEPTIONSNow that the rules have been reviewed,this section will include discussion ofthe exceptions to the rules.

In patients with previous strabismussurgery, the evaluation of motility tolocalize to an involved cranial nervebecomes very difficult without knowl-edge of both the surgery done and thepostoperative alignment. Unfortunately,

given the common situation of surgeryat a young age (eg, age 2) and evaluationwith new symptoms at an older age (eg,age 60), the previous data are frequentlyunavailable.

Strabismus, or congenital ocularmisalignment, can produce an esotropiaor exotropia potentially misdiagnosed asa cranial neuropathy. Features of thehistory and examination, however, candistinguish strabismus from cranial neu-ropathy. A history of patching, eyeexercises as a child, or eyeglasses wornonly when young suggest a long-standingproblem. Typically, patients with strabis-mus have developed suppression at ayoung age and will not report diplopiadespite obvious ocularmisalignment. Onexamination, strabismus is comitant, ie,the misalignment is equal in all gazes, as

KEY POINT

h In patients with previousstrabismus surgery, theevaluation of motility tolocalize to an involvedcranial nerve becomesvery difficult withoutknowledge of both thesurgery done and thepostoperative alignment.Unfortunately, given thecommon situation ofsurgery at a young age(eg, age 2) and evaluationwith new symptoms at anolder age (eg, age 60),the previous data arefrequently unavailable.

TABLE 9-4 Evaluation of Cranial Nerve Palsy

b Cranial nerves (CN) III, IV,a VI: Isolated 950 years of age

CN III: Incomplete or pupil involvement, perform urgent CT angiography/MRangiography; if negative, obtain erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP). Follow-up: Reexamine at 4 weeks and if no betterobtain acetylcholine receptor antibodies and directed CN imaging. Considerlumbar puncture and single-fiber EMG.

CN III (pupil sparing, otherwise complete), IV, VI: ESR/CRP done at initialevaluation; if negative then follow up as below.

Acetylcholine receptor antibodies at onset if any variability.

Follow-up: Reexamine at 4 weeks and if no better obtain acetylcholinereceptor antibodies and directed CN imaging. Consider lumbar puncture andsingle-fiber EMG.

b CN III, IV a, VI: Isolated G50 years of age

CN III: Incomplete or pupil involvement, perform urgent CT angiography/MRangiography.

CN III (pupil sparing, otherwise complete), IV, VI: Perform directed CNimaging, obtain acetylcholine receptor antibodies/single-fiber EMG andlumbar puncture.

CN III, IV, VI: Single CN palsy with other neurologic features: perform directedimaging depending on other features, anti-GQ1b if any areflexia or ataxia.

CN III, IV, VI (more than one nerve involved): Perform directed imagingto cavernous sinus, skull base, and CN; obtain lumbar puncture,acetylcholine receptor antibodies/single-fiber EMG if no sensoryinvolvement is present.

a CN IV with features of congenital decompensation, no evaluation needed.



compared with the incomitant mis-alignment seen in acquired cranial neu-ropathies. Undiagnosed strabismus canbe first noticed at a later age.

Of course, patients with congenitalstrabismus can develop acquired cranialnerve palsies. In this setting, a complaintof diplopia is typical because the newmisalignment brings the eyes out of thelong-established zone of suppression.The pattern of misalignment can bedifficult to discern until one recognizesthe combination of an incomitant andcomitant disorder, eg, an incomitanthypertropia from an acquired fourthnerve palsy on top of a congenital,comitant esotropia.

Duane syndrome is a mimickerof cranial nerve palsy with severalfeatures that can prevent confusion, asillustrated inCase 9-5. Duane syndromecan produce an inability to abduct(type 1); inability to adduct (type 2);or inability to abduct and adduct(type 3), mimicking sixth nerve palsy,third nerve palsy, or a combination ofboth. Four features help distinguishDuane syndrome from cranial nerve

palsy: (1) Duane syndrome is congenital,and most patients have suppressionand do not report diplopia despiteobvious misalignment. (2) In primarygaze most patients are aligned despitemarked limitations in abduction oradduction. This contrasts with cranialnerve palsies, in which marked limita-tions of movement produce misalign-ment in virtually all gaze positions,including primary gaze. (3) Duanesyndrome frequently shows narrowingof the palpebral fissure with adduction,and (4) retraction of the globe (bestviewed from the side) occurs withadduction.11

Internuclear ophthalmoplegia (INO)can be confused with a partial thirdnerve palsy, but several features distin-guish them:1. As with patients with Duane

syndrome, patients with an INOare aligned in primary despitelarge adduction deficits. Theexception to this rule is patientswith bilateral INOs who areexophoric, termed wall-eyedbilateral INO or WEBINO.

KEY POINTS

h Patients with congenitalstrabismus can developacquired cranial nervepalsies. The pattern ofmisalignment can bedifficult to discern untilone recognizes thecombination of anincomitant andcomitant disorder, eg,an incomitanthypertropia from anacquired fourth nervepalsy on top of acongenital, comitantesotropia.

h Duane syndrome canproduce an inability toabduct (type 1); inabilityto adduct (type 2); orinability to abduct andadduct (type 3),mimicking sixth nervepalsy, third nerve palsy,or a combination ofboth.

Case 9-5A27-year-oldwomanwas sent for evaluation of a sixth nerve palsy after a fall fromahorse. She reported noloss of consciousness but did see stars. She had no complaints of diplopia. Upon examination, she hadabsence of abduction on left gaze. She had normal alignment in primary gaze and narrowing of the leftpalpebral fissure (Figure 9-9) on right gaze. All of these findings were consistent with a congenital Duanesyndrome. No further evaluation was needed.

Comment. This case demonstrates typical findings of an adult with Duane syndrome.

FIGURE 9-9 Examination of the patient in Case 9-5. A, Right gaze showing narrowed palpebral fissure in the left eye.B, Primary gaze showing normal alignment. C, Left gaze showing very limited abduction of the left eye.




2. Patients with INOs have no othersigns of third nerve dysfunction,and a complete adduction deficitwithout other third nerve findingsis extraordinarily rare.

3. Patients with an INO can have anassociated skew deviation, withthe higher eye being on the sideof the INO, that would not beseen with a third nerve palsy.

EVALUATIONThe decision on testing rests on threefeatures: (1) Is more than one cranialnerve involved? (2) Is the patient youn-ger or older than 50 years? (3) Whichnerve is involved? All cases with multiplecranial nerve palsies or single cranialnerve palsies in patients younger thanage 50 need evaluation (Table 9-4).Exceptions to the age rule exist, how-ever. Occasionally a patient youngerthan age 50 will already have previoussignificant vascular disease. When thethird cranial nerve is the involved nerve,special circumstances apply. An incom-plete or pupil-involved third nerve palsyrequires urgent evaluation for the pos-sibility of an aneurysm regardless of age.The author’s institution favors CT angi-ography (CTA) done the same day apatient is seen as a fast, effective tool todetermine whether an aneurysm ispresent. Others prefer magnetic reso-nance angiography (MRA) or digitalsubtraction angiography.12 The author’sargument for CTA is the ease ofobtaining the test, the speed of the test,and the fact that motion artifact that candegrade an MRA is rarely an issue. Onceobtained, the image must be correctlyinterpreted. In one series, eight of17 studies that showed an aneurysmwere initially read as normal. When thepatient was seen at a tertiary center, thepreviously conducted studies werereviewed, and an aneurysmwas found.13

In evaluating an isolated cranial nervepalsy in the patient older than age 50

(excluding partial or pupil-involved thirdnerve palsies mentioned earlier) eryth-rocyte sedimentation rate (ESR) andC-reactive protein (CRP) should bedrawn. If test results are abnormal ora high level of clinical suspicion ispresent, the diagnosis of giant cellarteritis should be pursued.14 Verticalfusional amplitudes should be mea-sured in fourth nerve palsy to diag-nose a decompensated congenitalfourth nerve palsy that needs noadditional evaluation. The diagnosisat this point, assuming normal ESRand CRP, is that of a nonarteriticischemic cranial nerve palsy, whichshould recover during the next 1 to12 months. Some disagreement existson the need to image these patientsimmediately to confirm the diagnosisof ischemic cranial nerve palsy (byruling out a compressive or inflam-matory lesion) versus following thepatients and obtaining imaging at 4 to6 weeks if the expected recovery,typically partial at that point in time,has not occurred.9,15,16 This authorfavors following patients and imagingat 4 to 6 weeks if no recovery hasoccurred. In patients in whom a lesion isfound at 4 to 6 weeks, typically the delayhas no affect on prognosis, and theincidence of a compressive lesion absenta history of cancer is quite low. Anacetylcholine receptor antibody titershould be drawn at onset if a history ofsignificant variability is present, or at 4to 6 weeks if the expected improvementhas not occurred. A rest test can also bedone to evaluate for myasthenia gravis.The patient is rested for 30 minutes andevaluated for changes, either improve-ment of the prerest ocular motilityabnormality or development of a newabnormality (ie, right hypertropiachanging to a left hypertropia with rest),or 2 mm or more improvement inptosis. If positive, the rest test is highlysuggestive for myasthenia gravis.17 If

KEY POINTS

h In primary gaze mostpatients with Duanesyndrome are aligneddespite markedlimitations in abductionor adduction. Thiscontrasts with cranialnerve palsies, in whichmarked limitations ofmovement producemisalignment in virtuallyall gaze positions,including primary gaze.

h An incomplete orpupil-involved thirdnerve palsy requiresurgent evaluation forthe possibility of ananeurysm regardless ofage. CT angiographydone the same day thepatient is seen is a fast,effective tool todetermine whether ananeurysm is present.



imaging is normal and further worsen-ing occurs, lumbar puncture lookingfor neoplasm, inflammation, or infec-tion can be done.

SUMMARYThe anatomy and physiology of theocular motor system is well described,and examination of the ocular motorsystem can be quite precise and quan-tifiable. This combination of under-standing and examination ability allowfor accurate diagnosis of ocular motilityabnormalities (eg, third nerve palsy).Then, by following the rules describedabove, as well as understanding theexceptions, diagnostic testing can beappropriately utilized and the cause ofthe ocular motor abnormality found.

REFERENCES1. Hoya K, Kirino T. Traumatic trochlear nerve

palsy following minor occipital impactVfourcase reports. Neurol Med Chir (Tokyo)2000;40(7):358Y360.

2. Trobe JD. Third nerve palsy and the pupil.Footnotes to the rule. Arch Ophthalmol1988;106(5):601Y602.

3. Kissel JT, Burde RM, Klingele TG, Zeiger HE.Pupil-sparing oculomotor palsies with internalcarotid-posterior communicating arteryaneurysms. Ann Neurol 1983;13(2):149Y154.

4. Dhume KU, Paul KE. Incidence of pupillaryinvolvement, course of anisocoria andophthalmoplegia in diabetic oculomotornerve palsy. Indian J Ophthalmol 2013;61(1):13Y17.

5. Schatz NJ, Savino PJ, Corbett JJ. Primaryaberrant aculomotor regeneration. A signof intracavernous meningioma. Arch Neurol1977;34(1):29Y32.

6. Wilson ME, Hoxie J. Facial asymmetry insuperior oblique muscle palsy. J PediatrOphthalmol Strabismus 1993;30(5):315Y318.

7. Berlit P. Isolated and combined pareses ofcranial nerves III, IV and VI. A retrospectivestudy of 412 patients. J Neurol Sci 1991;103(1):10Y15.

8. Mollan SP, Edwards JH, Price A, et al.Aetiology and outcomes of adult superioroblique palsies: a modern series. Eye (Lond)2009;23(3):640Y644.

9. Patel SV, Mutyala S, Leske DA, et al.Incidence, associations, and evaluation of sixthnerve palsy using a population-basedmethod.Ophthalmology 2004;111(2):369Y375.

10. Holmes JM, Mutyala S, Maus TL, et al.Pediatric third, fourth, and sixth nervepalsies: a population-based study. Am JOphthalmol 1999;127(4):388Y392.

11. Yuksel D, Orban de Xivry JJ, Lefevre P.Review of the major findings about Duaneretraction syndrome (DRS) leading to anupdated form of classification. Vision Res.2010;50(23):2334Y2347.

12. Vaphiades MS, Cure J, Kline L. Managementof intracranial aneurysm causing a thirdcranial nerve palsy: MRA, CTA or DSA?Semin Ophthalmol 2008;23(3):143Y150.

13. Elmalem VI, Hudgins PA, Bruce BB, et al.Underdiagnosis of posterior communicatingartery aneurysm in noninvasive brainvascular studies. J Neuroophthalmol2011;31(2):103Y109.

14. Kermani TA, Schmidt J, Crowson CS, et al.Utility of erythrocyte sedimentation rateand C-reactive protein for the diagnosis ofgiant cell arteritis. Semin Arthritis Rheum2012;41(6):866Y871.

15. Murchison AP, Gilbert ME, Savino PJ.Neuroimaging and acute ocular motormononeuropathies: a prospective study.Arch Ophthalmol 2011;129(3):301Y305.

16. Chou KL, Galetta SL, Liu GT, et al. Acuteocular motor mononeuropathies: prospectivestudy of the roles of neuroimaging andclinical assessment. J Neurol Sci 2004;219(1Y2):35Y39.

17. Odel JG, Winterkorn JM, Behrens MM.The sleep test for myasthenia gravis.A safe alternative to Tensilon. J ClinNeuroophthalmol 1991;11(4):288Y292.




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