RESIDENT & FELLOW SECTION Pearls and oy-sters of localization in

Section Editor Mitchell S.V. Elkind, MD, MS

Teresa Buracchio, MD ABSTRACT Janet C. Rucker, MD Ocular misalignment and ophthalmoparesis result in the symptom of binocular . In the evaluation of diplopia, localization of the ocular motility disorder is the main objective. This re- quires a systematic approach and knowledge of the ocular motor pathways and actions of the Address correspondence and . This article reviews the components of the ocular motor pathway and pre- reprint requests to Dr. Janet C. Rucker, Department of sents helpful tools for localization and common sources of error in the assessment of ophthalmo- Neurological Sciences, Rush paresis. ® 2007;69:E35–E40 University Medical Center, 1725 West Harrison Street, Suite 1106, Chicago, IL 60612 [email protected] Ophthalmoparesis and diplopia. Normal eye movements share the goal of placing an object of visual interest on each fovea simultaneously to allow visualization of a single, stable object. Clear and stable vision is sustained by mechanisms that hold the object on the fovea, such as fixation and the vestibulo- ocular reflex. Absent or inadequate ocular motility (ophthalmoplegia and ophthalmoparesis) often results in ocular misalignment, causing the visual symptom of binocular diplopia. Binocular diplopia occurs when an object of visual interest falls on the fovea in one eye and on an extrafoveal location in the other eye. Binocular diplopia suggests dysfunction of extraocular muscles, the neuromuscular junction, , cranial nerve nuclei, or internuclear and supranuclear connections. Correct localization of the underlying lesion is the first step to accurate diagnosis and requires a systematic approach and knowledge of the ocular motor pathways and actions of the extraocular muscles.

History and examination of diplopia. When obtaining the history and examining the patient, it is impor- tant to determine if the diplopia is binocular or monocular. Binocular diplopia resolves with covering either eye and is the result of ocular misalignment. Proper evaluation of binocular diplopia should determine if it is horizontal, vertical, or oblique; worse in a particular direction of gaze; and worse at distance or near. examination should include assessment of ocular motility in the nine diagnostic positions of gaze, ocular alignment (measured with the corneal light reflex test, cover test, or Maddox rod1), and comitance of any ocular misalignment. In a comitant lesion, the amount of ocular deviation is the same regardless of gaze direction, while in an incomitant lesion, the amount of devia- tion varies with changes in gaze direction.

Pearls • Binocular diplopia resolves with monocular covering of either eye, while monocular diplopia resolves with covering the affected eye. • Visual blurring that resolves completely with monocular covering of either eye has the same localizing value as binocular diplopia. • Monocular diplopia is non-neurologic in origin and is not caused by ocular misalignment. It is usually due to ocular pathology such as or intraocular causes such as .2 • Worsening diplopia in a particular gaze direction suggests that motility in that direction is impaired. • Esodeviation is a relative medial deviation of the eyes. Exodeviation is a relative lateral deviation of the eyes. Hyperdeviation is a relative elevation of one eye. • A tropia is a visually obvious deviation. A phoria is deviation visible only upon interruption of binocular fusion by covering either eye.

From the Departments of Neurology (T.B., J.C.R.) and (J.C.R.), Rush University Medical Center, Chicago, IL. Disclosure: The authors report no conflicts of interest.

Copyright © 2007 by AAN Enterprises, Inc. E35 • Horizontal diplopia is caused by impaired abduction or adduction of one or both eyes Table 1 Signs of extraocular muscle involvement in ophthalmoparesis and vertical diplopia by impaired elevation or depression. Periorbital edema • Diplopia worse at distance accompanies im- Conjunctival injection and chemosis paired abduction or divergence. Proptosis

• Diplopia worse at near accompanies im- retraction

paired adduction or convergence. (inability to close the eye completely) • Most neurologic ocular misalignments are Lid lag (higher than normal lid position in downgaze) incomitant. von Graefe sign (dynamic slowing of lid descent during eye movement from upgaze into downgaze) Oy-sters and pitfalls (from compression) • Patients with severe monocular visual loss (generally worse than 20/200) will not ex- • Chronic progressive external ophthalmoplegia perience binocular diplopia with ocular (CPEO) from extraocular muscle myopathy misalignment. may cause painless, progressive ophthalmopa- • Displacement or “dragging” of the fovea is a resis and unilateral or bilateral . rare cause of binocular diplopia in the ab- • is the most com- sence of an ocular misalignment. It is due to mon etiology of CPEO. It may be isolated or macular disease such as an epiretinal mem- part of a syndrome such as Kearns-Sayre. brane that may wrinkle or scar with subse- quent distortion of the macula. This may Oy-sters and pitfalls displace the fovea resulting in an extrafoveal • External signs of orbital disease may be min- image in one eye and binocular diplopia.3,4 imal in some patients. Monocular blurred vision or a history of • Diplopia may be absent if a disease process macular disease may be clues. is bilateral and symmetric as in CPEO. • Cerebral polyopia is a form of cortical visual perseveration from parieto-occipital pathol- Neuromuscular junction. (MG) ogy. It refers to two or more visual images per- is the most common disease of the neuromuscular sistent with monocular covering and is often junction. It may cause nearly any abnormal eye accompanied by a homonymous hemianopia. movement. Table 2 lists examination findings suggestive of MG. A positive edrophonium chlo- Extraocular muscles. Inflammation or infiltration ride test provides diagnostic support for MG. of individual eye muscles may cause binocular Edrophonium chloride is a reversible acetylcho- diplopia through a restrictive process. Thyroid linesterase inhibitor that decreases breakdown of , idiopathic orbital inflammation (or- acetylcholine in the synaptic cleft, thereby im- bital pseudotumor), and malignant infiltration proving neuromuscular transmission. Up to 10 are the most common orbital diseases of this type. mg of edrophonium chloride is administered in See table 1 for a list of signs of orbital disease. small increments while the patient’s cardiac sta- Pearls tus is closely monitored. A positive test demon- strates objective improvement in weakness or • Inflammation of an extraocular muscle typi- ptosis on examination within several minutes af- cally results in impaired eye movement in the ter injection of the edrophonium. Alternatives to direction away from the muscle because it the edrophonium test are the ice pack test and the restricts muscle movement. This is in con- rest test. In the ice pack test, an ice pack is placed trast to cranial nerve dysfunction in which over a closed ptotic eye for 2 minutes, followed by weakness of an extraocular muscle from de- observation for improvement. The premise is that creased innervation results in impaired mo- neuromuscular transmission is improved by cold tility in the direction of action of the weak temperatures. In the rest test, observation for im- muscle. provement follows a period of 2 minutes during • Thyroid eye disease may occur in the ab- which the eyes are closed and at rest. Standard sence of symptoms or a previous history of treatments for MG may be used, but optimal thyroid disease and even with normal thy- treatment of ocular MG is unclear. roid studies. • Lid retraction is common in extraocular Pearls muscle disease. • The is not involved in MG.

E36 Neurology 69 December 11, 2007 ease, especially if proptosis is present. Thy- Table 2 Examination findings in ocular MG roid disease occurs with a higher incidence

Cogan’s lid twitch Following a few seconds of in MG, particularly in the presence of acetyl- sustained downgaze, saccadic return of the eyes to central choline receptor antibodies and in patients position is accompanied by with ocular MG.7,8 initial elevation upper eyelid, twitching, and then the return • A positive edrophonium chloride test is use- of ptosis. ful only when a defined deficit such as signif- Peek sign Prolonged eye closure increases orbicularis oculi icant ptosis or a fixed oculomotor defect weakness and causes lid separation and exposure, may be monitored for test response. despite initial complete eye closure. Cranial nerves. Cranial nerve palsies result in oph-

Enhanced ptosis Increased ptosis in a less or thalmoparesis in the direction of action of the non-ptotic eyelid upon manual elevation of the more ptotic lid. weak muscle. Lesions may occur anywhere along

Lid retraction Maximal innervation to keep a the course of the cranial nerve and may affect ptotic lid open results in excess multiple cranial nerves. lesions contralateral innervation and lid retraction. may affect cranial nerves three, four, the first and Ice pack test An ice pack is placed over a second divisions of five, six, and sympathetic fi- closed ptotic eye for 2 minutes, followed by observation for bers. Orbital apex lesions may affect cranial improvement. nerves three, four, the first division of five, six, Rest test Improvement in and the optic nerve with associated vision loss. ophthalmoplegia or ptosis following a period of rest. The association of vision loss with ophthalmopa- resis is critically important in localizing a lesion to the orbital apex. Inflammation (idiopathic or • MG may mimic any pupil-sparing ocular from systemic disorders), malignant neoplastic motility disorder. infiltration, meningioma, and internal carotid ar- • Evaluation of eye movements in suspected tery aneurysms are common lesions in the cavern- MG should include maintained upgaze for at ous sinus. Lesions at the orbital apex include least 2 minutes to adequately assess for the idiopathic (orbital pseudotumor) and systemic in- appearance or worsening of ptosis or down- flammation, infection (mucormycosis and as- drift of the elevated eye. pergillus), and malignancy. • Hering’s law of equal neural innervation to both is the basis for the finding of lid Third nerve (). The third cranial retraction and enhanced ptosis. Maximal in- nerve originates in the dorsal , exits the nervation to keep a ptotic lid open results in brainstem ventrally, traverses the subarachnoid excess contralateral innervation and may space to reach the cavernous sinus, and enters the minimize contralateral ptosis or create an via the superior orbital fissure. Just prior to appearance of lid retraction. entry, it divides into a superior branch that inner- • In the diagnostic sign of enhanced ptosis, vates the levator palpebrae superioris and the su- manual elevation of the severely ptotic lid perior rectus and an inferior branch that decreases the innervation to both lids. As a innervates the inferior and medial recti, the infe- result, contralateral ptosis becomes more rior oblique, and the sphincter and ciliary prominent. muscles. Oy-sters and pitfalls Pearls • Clostridium botulinum neurotoxin blockade of neuromuscular transmission may mimic • In a complete pupil-involved third nerve the oculomotor features of MG, but unlike palsy, the eye is deviated down and out, with MG, it may involve the pupil. impaired elevation, depression, and adduc- • Miller Fisher syndrome causes demyelination tion. The pupil is dilated and there is ptosis. of ocular motor cranial nerve roots and may Posterior communicating artery (PCOM) also cause diffuse ophthalmoplegia, mimick- aneurysm is the etiology until proven other- ing myasthenia. Diagnostic clues include the wise. Neuroimaging is indicated in these pa- presence of areflexia and ataxia, although iso- tients with CT angiography (CTA), MRI or lated ophthalmoplegia is reported.5,6 angiography (MRI/MRA), or cerebral an- • The finding of lid retraction should prompt giography if other neuroimaging modalities consideration of coexisting thyroid eye dis- are negative and suspicion is high.

Neurology 69 December 11, 2007 E37 • In a complete pupil-sparing third nerve Pearls palsy, all third nerve muscles are impaired • The innervates the superior and there is ptosis. This is very unlikely to be oblique muscle and its primary action is in- caused by a PCOM aneurysm. Microvascu- torsion of the eye. Its secondary action is de- lar ischemia is a common cause. Neuroimag- pression of the adducted eye. ing is not absolutely indicated in these • Trochlear nerve dysfunction results in hy- patients, although measurement of glucose pertropia of the affected eye and vertical and sedimentation rate and close observa- diplopia. tion are indicated. Neuroimaging to look for • The and diplopia are more an underlying lesion is absolutely indicated prominent with downgaze and gaze in the if a presumed microvascular third nerve direction contralateral to the affected side. palsy fails to spontaneously resolve in 8 to 12 • Diplopia is minimized when a contralateral weeks. head tilt in the direction away from the pa- • The presence or absence of pupillary dys- retic eye places the affected eye in an ex- function is an important feature in the iden- torted position. tification of an incomplete third nerve palsy. • Evaluation of superior oblique function in Pupil involvement usually indicates a com- the setting of an oculomotor palsy with im- pressive lesion, while sparing of the pupil is paired adduction is challenging. It is best as- more likely ischemia. However, neuroimag- sessed with the affected eye in abducted ing is generally recommended in these pa- position where intact intorsion during tients given the morbidity and mortality risk downgaze suggests preserved superior of missing an aneurysm, particularly if the oblique function. • Common causes of trochlear nerve lesions patient is younger than 50, given the lower include congenital, trauma, infection, in- risk of an ischemic lesion in that age group. flammation, ischemia, or neoplasm. Within • Aberrant regeneration after a third nerve in- the brainstem, or neoplasm are com- jury causes ipsilateral elevation of the eyelid mon causes but seldom present as isolated or constriction of the pupil during adduction fourth nerve palsies. or depression of the eye. • The dorsal decussation near the tentorium • Aberrant regeneration following an acute cerebelli makes the trochlear nerves particu- third nerve palsy suggests a compressive larly prone to traumatic injury.10 PCOM aneurysm or traumatic etiology. • A lesion within the subarachnoid portion of • Spontaneous aberrant regeneration without the nerve may result from meningitis or a a pre-existing acute third nerve palsy sug- trochlear nerve schwannoma.11 gests a cavernous sinus meningioma or an internal carotid artery aneurysm. Oy-sters and pitfalls • Old photographs of the patient that show a Oy-sters and pitfalls head tilt may suggest long-standing mis- alignment such as that seen with congenital • Primary aberrant regeneration may occur fourth nerve dysfunction. rarely with an unruptured PCOM aneurysm.9 • The trochlear fascicle within the brainstem • When a third nerve palsy follows minor head is an uncommon site of pathology, given its trauma, neuroimaging is indicated to evaluate short course and dorsal exit. When it does for an underlying PCOM aneurysm. occur, paresis of the superior oblique is con- Fourth nerve (trochlear nerve). The trochlear nerve tralateral to the lesion. originates in the dorsal midbrain just inferior to • Another common cause of vertical diplopia the inferior colliculus, exits the brainstem dor- is skew deviation, due to asymmetric vestib- sally, decussates within the anterior medullary ve- ular input into ocular motor nuclei. lum, and wraps around the midbrain to the (). The abducens ventral surface within the subarachnoid space. It nerve originates in the caudal pons, exits the then enters the cavernous sinus, where it is lo- brainstem ventrally, and travels in the subarach- cated within the dural sinus wall. The nerve then noid space, where it ascends near the clivus. It enters the superior orbital fissure and innervates pierces the dura and passes under the petroclinoid the contralateral to its (Gruber’s) ligament in Dorello’s canal, then nucleus of origin. passes through the body of the cavernous sinus

E38 Neurology 69 December 11, 2007 (unlike the oculomotor and trochlear nerves nal fasciculus (MLF) to the contralateral oc- housed in the dural sinus wall), ultimately enter- ulomotor medial rectus subnucleus. ing the superior orbital fissure to innervate the • Common etiologies of ocular motor nuclear lateral rectus. lesions include demyelination, infarction, and . Pearls Oy-sters and pitfalls • Abducens dysfunction results in ipsilateral abduction paresis and . • Rare cases of isolated horizontal gaze palsy • Meningitis may cause an abducens palsy, as exist,13 but the gaze palsy is more typically may an inflammatory or neoplastic process accompanied by an ipsilateral facial nerve of the clivus. palsy because the seventh cranial nerve fasci- • The abducens nerves are prone to dysfunc- cle wraps around the sixth nerve nucleus. tion from increased or decreased intracranial • Due to the functional division of the subnu- pressure. Tethering of the nerve in Dorello’s clei, isolated bilateral ptosis or isolated canal renders it susceptible to distortion and weakness of a single muscle such as the supe- stretch injury from such alterations in intra- rior rectus are also possible with an oculo- cranial pressure.12 motor nuclear lesion.14,15 • Microvascular ischemia may cause an acute- Internuclear ophthalmoplegia. Internuclear oph- onset, isolated sixth nerve palsy that should thalmoplegia (INO) is caused by a lesion of the spontaneously resolve over 8 to 12 weeks. MLF, which carries signals from the abducens nu- This process is often painful and may be se- cleus to the contralateral medial rectus oculomo- vere. Pain, however, may be absent and its tor subnucleus. The abducens nerve and MLF presence is nonspecific. coordinate conjugate horizontal eye movements Oy-sters and pitfalls with co-contraction of the ipsilateral lateral rec- tus and contralateral medial rectus muscles. • Common sixth nerve mimics include MG and restrictive medial rectus involvement in Pearls thyroid eye disease. • Classic signs of a unilateral INO include im- • Additional diagnostic evaluation for other paired adduction of the ipsilesional eye and ab- etiologies is required when a presumed mi- ducting of the contralateral eye. crovascular sixth nerve palsy fails to resolve • and microvascular brain- spontaneously. stem ischemia are the most common causes of INO. The two causes may be distin- Ocular motor nerve nuclei. Ocular motor nerve nuclear lesions differ in appearance from their guished by age at presentation, with younger corresponding cranial neuropathies. patients likely to have demyelination and older patients ischemia.16,17 Pearls Oy-sters and pitfalls • The oculomotor nucleus provides bilateral • Despite ipsilateral adduction weakness with innervation to the superior recti and a single direct motility testing, adduction is often in- midline levator palpebrae subnucleus inner- tact with convergence since vergence signals vates both levator muscles. Therefore, an oc- to the medial rectus motoneurons are dis- ulomotor nuclear lesion classically causes tinct from the MLF.18 ipsilateral ophthalmoparesis and pupil dila- • Smooth pursuit may be normal and INO di- tation with bilateral impairment of ocular agnosed only by the presence of decreased elevation and bilateral ptosis. velocity of the adducting eye (adduction lag) • A trochlear nuclear lesion causes a contralat- during saccadic testing.19 eral superior oblique palsy and an ipsilateral • A “pseudo-INO” may occur in MG. Horner syndrome because of the proximity of the preganglionic sympathetic fibers to the Supranuclear. Supranuclear eye movement abnor- dorsally placed fourth nucleus. malities result from dysfunctional cerebral, cere- • An abducens nuclear lesion causes ipsilateral bellar, and brainstem afferent connections to the horizontal gaze palsy because the abducens ocular motor nuclei. Burst neurons in the brain- nucleus contains both abducens motoneu- stem provide sudden, intense neural discharges rons and interneurons that are destined to required to initiate high velocity saccades. Burst ascend in the contralateral medial longitudi- neurons for horizontal saccades are located in the

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