Pearls and oy-sters of localization in ophthalmoparesis
Teresa Buracchio, MD and
Janet C. Rucker, MD
From the Departments of Neurology (T.B., J.C.R.) and Ophthalmology (J.C.R.), Rush University Medical Center, Chicago, IL.
Address correspondence and reprint requests to Dr. Janet C. Rucker, Department of Neurological Sciences, Rush University Medical Center, 1725 West Harrison Street, Suite 1106, Chicago, IL 60612 janet_rucker{at}rush.edu
Ocular misalignment and ophthalmoparesis result in the symptomof binocular diplopia. In the evaluation of diplopia, localizationof the ocular motility disorder is the main objective. Thisrequires a systematic approach and knowledge of the ocular motorpathways and actions of the extraocular muscles. This articlereviews the components of the ocular motor pathway and presentshelpful tools for localization and common sources of error inthe assessment of ophthalmoparesis.
Ophthalmoparesis and diplopia.
Normal eye movements share the goal of placing an object ofvisual interest on each fovea simultaneously to allow visualizationof a single, stable object. Clear and stable vision is sustainedby mechanisms that hold the object on the fovea, such as fixationand the vestibulo-ocular reflex. Absent or inadequate ocularmotility (ophthalmoplegia and ophthalmoparesis) often resultsin ocular misalignment, causing the visual symptom of binoculardiplopia. Binocular diplopia occurs when an object of visualinterest falls on the fovea in one eye and on an extrafoveallocation in the other eye. Binocular diplopia suggests dysfunctionof extraocular muscles, the neuromuscular junction, cranialnerves, cranial nerve nuclei, or internuclear and supranuclearconnections. Correct localization of the underlying lesion isthe first step to accurate diagnosis and requires a systematicapproach and knowledge of the ocular motor pathways and actionsof the extraocular muscles.
History and examination of diplopia.
When obtaining the history and examining the patient, it isimportant to determine if the diplopia is binocular or monocular.Binocular diplopia resolves with covering either eye and isthe result of ocular misalignment. Proper evaluation of binoculardiplopia should determine if it is horizontal, vertical, oroblique; worse in a particular direction of gaze; and worseat distance or near. Eye movement examination should includeassessment of ocular motility in the nine diagnostic positionsof gaze, ocular alignment (measured with the corneal light reflextest, cover test, or Maddox rod1), and comitance of any ocularmisalignment. In a comitant lesion, the amount of ocular deviationis the same regardless of gaze direction, while in an incomitantlesion, the amount of deviation varies with changes in gazedirection.
Pearls
Binocular diplopia resolves with monocular covering of eithereye, while monocular diplopia resolves with covering the affectedeye.
Visual blurring that resolves completely with monocularcoveringof either eye has the same localizing value as binoculardiplopia.
Monocular diplopia is non-neurologic in origin andis not causedby ocular misalignment. It is usually due to ocularpathologysuch as refractive error or intraocular causes suchas cataracts.2
Worsening diplopia in a particular gaze directionsuggests thatmotility in that direction is impaired.
Esodeviationis a relative medial deviation of the eyes. Exodeviationisa relative lateral deviation of the eyes. Hyperdeviationisa relative elevation of one eye.
A tropia is a visually obviousdeviation. A phoria is deviationvisible only upon interruptionof binocular fusion by coveringeither eye.
Horizontal diplopiais caused by impaired abduction or adductionof one or botheyes and vertical diplopia by impaired elevationor depression.
Diplopia worse at distance accompanies impaired abductionordivergence.
Diplopia worse at near accompanies impairedadduction or convergence.
Most neurologic ocular misalignmentsare incomitant.
Oy-sters and pitfalls
Patients with severe monocular visual loss (generally worsethan 20/200) will not experience binocular diplopia with ocularmisalignment.
Displacement or "dragging" of the fovea is arare cause of binoculardiplopia in the absence of an ocularmisalignment. It is dueto macular disease such as an epiretinalmembrane that may wrinkleor scar with subsequent distortionof the macula. This may displacethe fovea resulting in an extrafovealimage in one eye and binoculardiplopia.3,4 Monocular blurredvision or a history of maculardisease may be clues.
Cerebralpolyopia is a form of cortical visual perseverationfrom parieto-occipitalpathology. It refers to two or more visualimages persistentwith monocular covering and is often accompaniedby a homonymoushemianopia.
Extraocular muscles.
Inflammation or infiltration of individual eye muscles may causebinocular diplopia through a restrictive process. Thyroid eyedisease, idiopathic orbital inflammation (orbital pseudotumor),and malignant infiltration are the most common orbital diseasesof this type. See table 1 for a list of signs of orbital disease.
Table 1 Signs of extraocular muscle involvement in ophthalmoparesis
Pearls
Inflammation of an extraocular muscle typically results in impairedeye movement in the direction away from the muscle because itrestricts muscle movement. This is in contrast to cranial nervedysfunction in which weakness of an extraocular muscle fromdecreased innervation results in impaired motility in the directionof action of the weak muscle.
Thyroid eye disease may occurin the absence of symptoms ora previous history of thyroiddisease and even with normal thyroidstudies.
Lid retractionis common in extraocular muscle disease.
Chronic progressiveexternal ophthalmoplegia (CPEO) from extraocularmuscle myopathymay cause painless, progressive ophthalmoparesisand unilateralor bilateral ptosis.
Mitochondrial myopathy is the most commonetiology of CPEO.It may be isolated or part of a syndrome suchas Kearns-Sayre.
Oy-sters and pitfalls
External signs of orbital disease may be minimal in some patients.
Diplopia may be absent if a disease process is bilateral andsymmetric as in CPEO.
Neuromuscular junction.
Myasthenia gravis (MG) is the most common disease of the neuromuscularjunction. It may cause nearly any abnormal eye movement. Table 2lists examination findings suggestive of MG. A positive edrophoniumchloride test provides diagnostic support for MG. Edrophoniumchloride is a reversible acetylcholinesterase inhibitor thatdecreases breakdown of acetylcholine in the synaptic cleft,thereby improving neuromuscular transmission. Up to 10 mg ofedrophonium chloride is administered in small increments whilethe patient’s cardiac status is closely monitored. A positivetest demonstrates objective improvement in weakness or ptosison examination within several minutes after injection of theedrophonium. Alternatives to the edrophonium test are the icepack test and the rest test. In the ice pack test, an ice packis placed over a closed ptotic eye for 2 minutes, followed byobservation for improvement. The premise is that neuromusculartransmission is improved by cold temperatures. In the rest test,observation for improvement follows a period of 2 minutes duringwhich the eyes are closed and at rest. Standard treatments forMG may be used, but optimal treatment of ocular MG is unclear.
MG may mimic any pupil-sparingocular motility disorder.
Evaluation of eye movements in suspectedMG should include maintainedupgaze for at least 2 minutes toadequately assess for the appearanceor worsening of ptosisor downdrift of the elevated eye.
Hering’s law of equalneural innervation to both eyelidsis the basis for the findingof lid retraction and enhancedptosis. Maximal innervation tokeep a ptotic lid open resultsin excess contralateral innervationand may minimize contralateralptosis or create an appearanceof lid retraction.
In the diagnostic sign of enhanced ptosis,manual elevationof the severely ptotic lid decreases the innervationto bothlids. As a result, contralateral ptosis becomes moreprominent.
Oy-sters and pitfalls
Clostridium botulinum neurotoxin blockade of neuromuscular transmissionmay mimic the oculomotor features of MG, but unlike MG, it mayinvolve the pupil.
Miller Fisher syndrome causes demyelinationof ocular motorcranial nerve roots and may also cause diffuseophthalmoplegia,mimicking myasthenia. Diagnostic clues includethe presenceof areflexia and ataxia, although isolated ophthalmoplegiaisreported.5,6
The finding of lid retraction should promptconsideration ofcoexisting thyroid eye disease, especiallyif proptosis is present.Thyroid disease occurs with a higherincidence in MG, particularlyin the presence of acetylcholinereceptor antibodies and inpatients with ocular MG.7,8
A positiveedrophonium chloride test is useful only when a defineddeficitsuch as significant ptosis or a fixed oculomotor defectmaybe monitored for test response.
Cranial nerves.
Cranial nerve palsies result in ophthalmoparesis in the directionof action of the weak muscle. Lesions may occur anywhere alongthe course of the cranial nerve and may affect multiple cranialnerves. Cavernous sinus lesions may affect cranial nerves three,four, the first and second divisions of five, six, and sympatheticfibers. Orbital apex lesions may affect cranial nerves three,four, the first division of five, six, and the optic nerve withassociated vision loss. The association of vision loss withophthalmoparesis is critically important in localizing a lesionto the orbital apex. Inflammation (idiopathic or from systemicdisorders), malignant neoplastic infiltration, meningioma, andinternal carotid artery aneurysms are common lesions in thecavernous sinus. Lesions at the orbital apex include idiopathic(orbital pseudotumor) and systemic inflammation, infection (mucormycosisand aspergillus), and malignancy.
Third nerve (oculomotor nerve).
The third cranial nerve originates in the dorsal midbrain, exitsthe brainstem ventrally, traverses the subarachnoid space toreach the cavernous sinus, and enters the orbit via the superiororbital fissure. Just prior to entry, it divides into a superiorbranch that innervates the levator palpebrae superioris andthe superior rectus and an inferior branch that innervates theinferior and medial recti, the inferior oblique, and the irissphincter and ciliary muscles.
Pearls
In a complete pupil-involved third nerve palsy, the eye is deviateddown and out, with impaired elevation, depression, and adduction.The pupil is dilated and there is ptosis. Posterior communicatingartery (PCOM) aneurysm is the etiology until proven otherwise.Neuroimaging is indicated in these patients with CT angiography(CTA), MRI or angiography (MRI/MRA), or cerebral angiographyif other neuroimaging modalities are negative and suspicionis high.
In a complete pupil-sparing third nerve palsy, allthird nervemuscles are impaired and there is ptosis. This isvery unlikelyto be caused by a PCOM aneurysm. Microvascularischemia is acommon cause. Neuroimaging is not absolutely indicatedin thesepatients, although measurement of glucose and sedimentationrate and close observation are indicated. Neuroimaging to lookfor an underlying lesion is absolutely indicated if a presumedmicrovascular third nerve palsy fails to spontaneously resolvein 8 to 12 weeks.
The presence or absence of pupillary dysfunctionis an importantfeature in the identification of an incompletethird nerve palsy.Pupil involvement usually indicates a compressivelesion, whilesparing of the pupil is more likely ischemia.However, neuroimagingis generally recommended in these patientsgiven the morbidityand mortality risk of missing an aneurysm,particularly if thepatient is younger than 50, given the lowerrisk of an ischemiclesion in that age group.
Aberrant regenerationafter a third nerve injury causes ipsilateralelevation of theeyelid or constriction of the pupil duringadduction or depressionof the eye.
Aberrant regeneration following an acute thirdnerve palsy suggestsa compressive PCOM aneurysm or traumaticetiology.
Spontaneous aberrant regeneration without a pre-existingacutethird nerve palsy suggests a cavernous sinus meningiomaor aninternal carotid artery aneurysm.
Oy-sters and pitfalls
Primary aberrant regeneration may occur rarely with an unrupturedPCOM aneurysm.9
When a third nerve palsy follows minor headtrauma, neuroimagingis indicated to evaluate for an underlyingPCOM aneurysm.
Fourth nerve (trochlear nerve).
The trochlear nerve originates in the dorsal midbrain just inferiorto the inferior colliculus, exits the brainstem dorsally, decussateswithin the anterior medullary velum, and wraps around the midbrainto the ventral surface within the subarachnoid space. It thenenters the cavernous sinus, where it is located within the duralsinus wall. The nerve then enters the superior orbital fissureand innervates the superior oblique muscle contralateral toits nucleus of origin.
Pearls
The trochlear nerve innervates the superior oblique muscle andits primary action is intorsion of the eye. Its secondary actionis depression of the adducted eye.
Trochlear nerve dysfunctionresults in hypertropia of the affectedeye and vertical diplopia.
The hypertropia and diplopia are more prominent with downgazeand gaze in the direction contralateral to the affected side.
Diplopia is minimized when a contralateral head tilt in thedirection away from the paretic eye places the affected eyein an extorted position.
Evaluation of superior oblique functionin the setting of anoculomotor palsy with impaired adductionis challenging. Itis best assessed with the affected eye inabducted positionwhere intact intorsion during downgaze suggestspreserved superioroblique function.
Common causes of trochlearnerve lesions include congenital,trauma, infection, inflammation,ischemia, or neoplasm. Withinthe brainstem, stroke or neoplasmare common causes but seldompresent as isolated fourth nervepalsies.
The dorsal decussation near the tentorium cerebellimakes thetrochlear nerves particularly prone to traumatic injury.10
A lesion within the subarachnoid portion of the nerve mayresultfrom meningitis or a trochlear nerve schwannoma.11
Oy-sters and pitfalls
Old photographs of the patient that show a head tilt may suggestlong-standing misalignment such as that seen with congenitalfourth nerve dysfunction.
The trochlear fascicle within thebrainstem is an uncommon siteof pathology, given its shortcourse and dorsal exit. When itdoes occur, paresis of the superioroblique is contralateralto the lesion.
Another common causeof vertical diplopia is skew deviation,due to asymmetric vestibularinput into ocular motor nuclei.
Sixth nerve palsy (abducens nerve).
The abducens nerve originates in the caudal pons, exits thebrainstem ventrally, and travels in the subarachnoid space,where it ascends near the clivus. It pierces the dura and passesunder the petroclinoid (Gruber’s) ligament in Dorello’scanal, then passes through the body of the cavernous sinus (unlikethe oculomotor and trochlear nerves housed in the dural sinuswall), ultimately entering the superior orbital fissure to innervatethe lateral rectus.
Pearls
Abducens dysfunction results in ipsilateral abduction paresisand esotropia.
Meningitis may cause an abducens palsy, asmay an inflammatoryor neoplastic process of the clivus.
Theabducens nerves are prone to dysfunction from increasedor decreasedintracranial pressure. Tethering of the nerve inDorello’scanal renders it susceptible to distortion andstretch injuryfrom such alterations in intracranial pressure.12
Microvascularischemia may cause an acute-onset, isolated sixthnerve palsythat should spontaneously resolve over 8 to 12 weeks.This processis often painful and may be severe. Pain, however,may be absentand its presence is nonspecific.
Oy-sters and pitfalls
Common sixth nerve mimics include MG and restrictive medialrectus involvement in thyroid eye disease.
Additional diagnosticevaluation for other etiologies is requiredwhen a presumedmicrovascular sixth nerve palsy fails to resolvespontaneously.
Ocular motor nerve nuclei.
Ocular motor nerve nuclear lesions differ in appearance fromtheir corresponding cranial neuropathies.
Pearls
The oculomotor nucleus provides bilateral innervation to thesuperior recti and a single midline levator palpebrae subnucleusinnervates both levator muscles. Therefore, an oculomotor nuclearlesion classically causes ipsilateral ophthalmoparesis and pupildilatation with bilateral impairment of ocular elevation andbilateral ptosis.
A trochlear nuclear lesion causes a contralateralsuperior obliquepalsy and an ipsilateral Horner syndrome becauseof the proximityof the preganglionic sympathetic fibers tothe dorsally placedfourth nucleus.
An abducens nuclear lesioncauses ipsilateral horizontal gazepalsy because the abducensnucleus contains both abducens motoneuronsand interneuronsthat are destined to ascend in the contralateralmedial longitudinalfasciculus (MLF) to the contralateral oculomotormedial rectussubnucleus.
Common etiologies of ocular motor nuclear lesionsinclude demyelination,infarction, and Wernicke encephalopathy.
Oy-sters and pitfalls
Rare cases of isolated horizontal gaze palsy exist,13 but thegaze palsy is more typically accompanied by an ipsilateral facialnerve palsy because the seventh cranial nerve fascicle wrapsaround the sixth nerve nucleus.
Due to the functional divisionof the subnuclei, isolated bilateralptosis or isolated weaknessof a single muscle such as the superiorrectus are also possiblewith an oculomotor nuclear lesion.14,15
Internuclear ophthalmoplegia.
Internuclear ophthalmoplegia (INO) is caused by a lesion ofthe MLF, which carries signals from the abducens nucleus tothe contralateral medial rectus oculomotor subnucleus. The abducensnerve and MLF coordinate conjugate horizontal eye movementswith co-contraction of the ipsilateral lateral rectus and contralateralmedial rectus muscles.
Pearls
Classic signs of a unilateral INO include impaired adductionof the ipsilesional eye and abducting nystagmus of the contralateraleye.
Multiple sclerosis and microvascular brainstem ischemiaarethe most common causes of INO. The two causes may be distinguishedby age at presentation, with younger patients likely to havedemyelination and older patients ischemia.16,17
Oy-sters and pitfalls
Despite ipsilateral adduction weakness with direct motilitytesting, adduction is often intact with convergence since vergencesignals to the medial rectus motoneurons are distinct from theMLF.18
Smooth pursuit may be normal and INO diagnosed onlyby the presenceof decreased velocity of the adducting eye (adductionlag) duringsaccadic testing.19
A "pseudo-INO" may occur inMG.
Supranuclear.
Supranuclear eye movement abnormalities result from dysfunctionalcerebral, cerebellar, and brainstem afferent connections tothe ocular motor nuclei. Burst neurons in the brainstem providesudden, intense neural discharges required to initiate highvelocity saccades. Burst neurons for horizontal saccades arelocated in the pontine paramedian reticular formation (PPRF)and, for vertical saccades, in the midbrain rostral interstitialmedial longitudinal fasciculus (riMLF). A PPRF lesion causesslow or absent horizontal saccades, while a riMLF lesion causesslow or absent vertical saccades. Burst inhibition, requiredto prevent unwanted saccades from degrading vision, is providedby pontine omnipause neurons.
Pearls
A clinical hallmark of supranuclear eye movement disorders isdisproportionate involvement of saccades. Vestibular eye movementsare typically spared.
In contrast, nuclear and infranuclearlesions impair saccades,smooth pursuit, and vestibular eyemovements equally.
Progressive supranuclear palsy is a commoncause of supranucleargaze palsy, initially affecting verticalgaze to a greater extentthan horizontal.
The dorsal midbrain(Parinaud) syndrome is comprised of a supranuclearupgaze palsy,convergence-retraction nystagmus, Collier sign(lid retraction),and pupillary light-near dissociation. Themost common etiologiesare pineal gland lesions and hydrocephalus.
Gaze deviationis a common supranuclear process. The frontaleye fields (FEF)project to the contralateral PPRF. A destructivelesion (e.g.,stroke) of the FEF results in ipsiversive bilateralgaze deviation:the patient "looks at the lesion." With an irritativeFEF lesion(e.g., hemorrhage or seizure), there is contraversivedeviation:the patient "looks away from the lesion."
Oy-sters and pitfalls
A supranuclear upgaze palsy with forced downward deviation ofthe eyes ("peering at the tip of the nose") may result froma thalamic lesion; however, most of these purported thalamiclesions extend into the midbrain.20
Thalamic lesions may alsocause supranuclear thalamic esotropia,likely secondary to excessiveconvergence tone.
"Wrong way eyes" with the patient "lookingaway" from a destructivelesion may occur from thalamic pathology.21
Disclosure: The authors report no conflicts of interest.
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