Diplopia Supranuclear and Nuclear Causes.12

7/24/2019 Diplopia Supranuclear and Nuclear Causes.12

1/18

DIPLOPIA

SUPRANUCLEAR ANDNUCLEAR CAUSESJanet C. Rucker

ABSTRACT

When evaluating a patient with diplopia, it is critical to differentiate monocular dip-lopia (diplopia present in one eye) from binocular diplopia (diplopia resolves withclosure of either eye). Binocular diplopia is typically related to ocular misalignmentand often has a neurologic cause. Although the supranuclear ocular motor systemis primarily associated with generation of bilateral eye movements, certain supra-nuclear processes can cause ocular misalignment and binocular diplopia. Skewdeviation, the most common supranuclear cause of diplopia, presents with binocu-lar vertical diplopia due to a hypertropia and full ductions in each eye. Oculomotornuclear lesions have distinct clinical characteristics related to the unique anatomyof the third cranial nerve nuclei, which may present with combinations, includingbilateral ptosis and contralateral or bilateral ocular elevation deficits. Trochlear nu-clear lesions clinically appear identical to fascicular or trochlear axonal lesions, butabducens nuclear lesions produce ipsilesional gaze palsies rather than unilateralcranial nerve VI palsies.

Continuum Lifelong Learning Neurol 2009;15(4):150167.

When evaluating a patient for diplo-pia (doubling of vision), the first ques-tion asked of the patient should beOne eye or two? In other words,does the diplopia resolve completely

when the patient covers either eye, oris it still present with one or the othereye closed? Some patients may not beable to answer this question, and it ishelpful to perform a quick assessment

by asking the patient whose diplopiais currently present to cover each eyein turn early in the course of the evalu-ation. When the diplopia resolves com-pletely with coverage of either eye, itis binocular diplopia. When the diplo-pia persists upon coverage of one orthe other eye, it is monocular diplopia.

Monocular diplopia, generally non-neurologic in origin, is often due to ei-ther an eye problem, such as a cataractor an uncorrected need for glasses, orto nonphysiologic causes (Table 10-1).The second image often appears shad-owlike or ghostlike (at times overlap-ping) rather than as a clear and distinctimage. Another clue to an uncorrectedneed for glasses (refractive error) as

the cause of monocular diplopia is re-solution of the diplopia when the pa-tient views through a pinhole with theaffected eye. Patients with monoculardiplopia should be sent for ophthal-mic consultation and generally do notrequire further neurologic evaluationor imaging.

150

Relationship Disclosure: Dr Rucker has nothing to disclose.Unlabeled Use of Products/Investigational Use Disclosure: Dr Rucker has nothing to disclose.

KEY POINTS

A When the

diplopia resolves

completely

with coverageof either eye,

it is binocular

diplopia. When

the diplopia

persists upon

coverage of one

or the other eye,

it is monocular

diplopia.

A Monocular

diplopia,

generallynon-neurologic

in origin, is often

due to either an

eye problem,

such as a

cataract or an

uncorrected

need for glasses,

or to

nonphysiologic

causes.

Copyright # 2009, American Academy of Neurology. All rights reserved.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


2/18

Binocular diplopia is very likely causedby a relative misalignment of the eyesfrom a supranuclear, cranial nerve nu-cleus, internuclear, cranial nerve, neuro-muscular junction, or extraocular mus-cle problem (Table 10-1). The fovea,located temporal to the optic nerve,is the area of the retina with the high-est density of photoreceptors and thehighest visual acuity. Each time we lookat an object, all of our eye movementsshare the goal of placing and maintain-ing the object of visual interest on thefovea in each eye to ensure visualiza-tion of a single stable object. When theeyes are relatively misaligned, a visual

image falls on the fovea in one eye andon an extrafoveal location in the op-posite eye, creating binocular diplopia(Figure 10-1). Accompanying ophthal-moparesis or ophthalmoplegia may ormay not be obvious on examination.Particularly challenging to the neurolo-gist is when eye movements appear tobe full, but the patient reports persis-tent binocular diplopia. Assessment ofocular alignment is the only tool avail-able for localization of the diplopia in

151

TABLE 10-1 Monocular Versus Binocular Diplopia

" Causes of Monocular Diplopia

Eye problem (eg, refractive error, cataract)

Nonphysiologic

Cerebral polyopia (bilateral, very rare)

" Causes of Binocular Diplopia

Ocular misalignment from lesions of the following:

Supranuclear (eg, skew deviation)

Cranial nerve nuclei (eg, abducens nucleus)

Internuclear (eg, internuclear ophthalmoplegia)

Cranial nerve (eg, abducens nerve palsy)Neuromuscular junction (eg, myasthenia gravis)

Extraocular muscle disease (eg, thyroid eye disease)

Dragged fovea from retinal wrinkle (very rare)

FIGURE 10-1

Solid black lines

represent normal ocularalignment with which

the telephone image falls on each foveasimultaneously and a single telephoneis viewed. Inward deviation of the lefteye (represented by the dashed curvedarrow) results in binocular diplopia becausethe image of the telephone falls on anextrafoveal location in the left eye (dashedlines).

Adapted with permission from Leigh RJ, Zee DS. Theneurology of eye movements. 3rd ed. New York:Oxford University Press, 1999:337. Reprinted withpermission from Rucker JC. Oculomotor disorders.Semin Neurol 2007;27(3):245.

KEY POINT

A Binocular

diplopia is very

likely due

to a relativemisalignment

of the eyes.

Continuum Lifelong Learning Neurol 2009;15(4)



3/18

that setting. It is also important to keepin mind that, while binocular diplopiais the most common symptom with an

ocular misalignment, frank diplopia isnot always present, and visual blur thatresolves completely with covering eithereye can also be a manifestation of anocular misalignment (binocular blur).It is also essential to recognize that pa-tients with poor vision in one or botheyes may have an ocular misalignmentbut fail to experience binocular diplopia.

When binocular diplopia is confirmedby history, additional historical featuresmay assist with localization and/or eti-

ology, and careful examination oftendiscloses the nature of the problem.

Very rare exceptions to the above de-scriptions of binocular and monoculardiplopia exist. Binocular diplopia is re-

ported with a retinal problem in oneeye, such as retinal wrinkling called anepiretinal membrane, due to disruptionor dragging of the fovea and maculafrom their usual location (Figure 10-2)(Barton, 2004). As a result, a relativemisalignment of the foveae and binoc-ular diplopia occur in the absence of atrue neurologic ocular misalignment.One clue to this diagnosis is the pres-ence of metamorphopsia (straight linesappear bent) with Amsler grid test-

ing. Given the subtlety of these retinalchanges, ophthalmic consultation with

152

FIGURE 10-2 Ophthalmoscopic views in three patients with binocular diplopia attributedto retinal wrinkling with foveal displacement. Top, Left eye of patient 1.Middle, Right eye of patient 2. Bottom, Right eye of patient 3. Enlarged

higher-contrast views of the macular region are provided in the middle images. Thin darkstreaks are visible in the perimacular region of all cases. On the rightare drawings of thewrinkles superimposed on a threshold black-and-white version of the middle images, to aidin illustration.

Reprinted with permission from Barton JJ. Retinal diplopia associated with macular wrinkling. Neurology2004;63(5):926. Copyright # 2004, AAN Enterprises, Inc. All rights reserved.


"SUPRANUCLEAR AND NUCLEAR



4/18

pharmacologic pupil dilation and care-ful examination of the foveal regionshould be considered in patients with

binocular diplopia and distorted orblurred monocular vision or a historyof retinal disease.

Cerebral polyopia is extremely rare;it constitutes an exception to the gen-eral statement that monocular diplopia

is non-neurologic and is due to an eye ornonphysiologic problem. Cerebral poly-opia is visualization of multiple images

that persists in each eye with monoc-ular closure or pinhole (Figure 10-3)(Bender, 1945). Occasionally, cerebral dip-lopia occurs with only two images seen.Cerebral polyopia-diplopia is causedby posterior cerebral lesions affecting

153

FIGURE 10-3 The palinopsias. A, A room as correctlyobserved. B, Perseveration: each red circlemarks a successive fixation point. In other

words, the patient looks at the real lamp shade on the left,and when the patient shifts gaze to two different pointsin the right hemifield, a percept of the lampshade persists.C, Illusory visual spread: the pattern of the furniture fabriccoverings spreads beyond their true boundaries to otherobjects. D, Polyopia: the lampshade is repeated in rowsand columns.

Reprinted with permission from ffytche DH, Howard RJ. The perceptualconsequences of visual loss: positive pathologies of vision. Brain 1999;122(pt 7):1248.

KEY POINTS

A Supranuclear

eye movement

problems

result fromdysfunction of

the supranuclear

or premotor

afferent neural

pathways from

the cerebral

hemispheres,

cerebellum,

and brainstem

into the final

common

pathway of eye

movements.

A Many

supranuclear

ocular motor

disorders

predominately

affect one type

of dynamic eye

movement,

such as the fast

saccades we use

to jump our eyes

quickly fromone target to

another, and

they typically

affect the eye

movement

symmetrically.




5/18

the visual pathways and is typically ac-companied by other neurologic symp-toms and signs referable to these areas,

such as homonymous hemianopia. Itis a disorder of higher cortical visualfunction and a subtype of visual persev-eration. Other types of visual persev-eration include visual afterimages andillusory visual spread (Figure 10-3).

SUPRANUCLEAR CAUSES OFBINOCULAR DIPLOPIA

Supranuclear eye movement problemsresult from dysfunction of the supranu-clear or premotor afferent neural path-

ways from the cerebral hemispheres,

cerebellum, and brainstem into the finalcommon pathway of eye movements.This final common pathway consists of

the ocular motor cranial nerve nucleiand nerves, neuromuscular junction,and extraocular muscle. Separate ana-tomic supranuclear pathways exist forthe different types of eye movements,such as saccades, smooth pursuit, andthe vestibulo-ocular reflex, and a greatdeal is now known about how theseneural networks govern eye movements(Buttner and Buttner-Ennever, 2006;Leigh and Zee, 2006).

While the specific focus of this sec-

tion is restricted to binocular diplopiafrom supranuclear problems, it is im-portant to note that many supranuclearocular motor disorders predominatelyaffect one type of dynamic eye move-ment, such as the fast saccades we useto jump our eyes quickly from one tar-get to another, and that they typicallyaffect the range of eye movement sym-metrically (Figure 10-4) (Video Seg-ment 60), or not at all. As a result,

visual symptoms may frequently be

minimized by the symmetry of theprocess. Supranuclear eye movementproblems may be incidentally notedand diagnostically helpful in a visuallyasymptomatic patient with multifocalneurologic disease. On the other hand,

vague visual symptoms, such as visualblurring, may occur but are nonlocaliz-ing. Binocular diplopia will occur only

when the two eyes are affected differ-ently, causing an ocular misalignment.

Diplopia may also be more commonwhen the deficits have acute onset, suchas with infarction. Lesions affecting su-pranuclear pathways in the cerebralhemispheres (frontal and parietal eyefields) rarely cause diplopia and are notfurther addressed here.

Vertical Gaze Palsy

Saccadic. Brainstem control centers forvertical eye movements reside primar-ily in the midbrain. In order to generate

154

FIGURE 10-4 A characteristic supranuclear gaze palsyaffecting saccades to a greater extentthan smooth pursuit with sparing of the

vestibular-ocular reflex. This patient does not report binoculardiplopia, given the symmetry of the process.A, The maximumextent of downward movement of the eyes with followingof a smoothly moving target (smooth pursuit) is to thehorizontal midline. B, Downward saccades are completelyeliminated. This picture shows the eyes stuck in upgazefollowing a fast vertical upward eye movement (verticalsaccade). The patient is unable to even saccade back downto midline. C, The ability of the vestibulo-ocular reflex toovercome the downgaze palsy is demonstrated.

KEY POINT

A Lesions of

burst neurons

(especially

when bilateral)result in

slowed or

absent vertical

saccades.





6/18

fast saccadic eye movements, specialburst neurons must discharge vigor-ously and send a signal to the appro-

priate cranial nerve nuclei. For verticalsaccades, these burst neurons are lo-cated in the rostral interstitial mediallongitudinal fasciculus (riMLF) just ros-tral to the oculomotor (cranial nerve III)nucleus (Figure 10-5). A few are lo-cated in the nearby interstitial nucleusof Cajal (INC) (Buttner and Buttner-Ennever, 2006; Horn and Buttner-Ennever, 1998). Lesions of these burstneurons (especially when bilateral) re-sult in slowed or absent vertical saccades

(Table 10-2). Such lesions are mostlikely to result in binocular vertical dip-lopia when they are acute in onset,such as with infarction or acute demy-elination, and when they affect the eyesasymmetrically. In addition, in the acutesetting, all vertical eye movements maybe affected.

A sudden-onset vertical supranucleargaze palsy with or without diplopia inan older patient is characteristic of amidbrain infarction, either in combina-tion with a disturbance of conscious-ness or cognition or in combination

with more widespread infarction fromtop-of-the basilar syndrome. The for-mer usually results from small vesselinvolvement supplying the posterome-dial thalami and riMLF. Top-of-the basi-lar infarction is usually caused by anembolus at the bifurcation point of thebasilar into the posterior cerebral arter-ies; variable midbrain, superior cerebel-

lar, thalamic, and often occipital andtemporal lobe infarction occurs withresultant supranuclear vertical gaze pal-sies, somnolence, delirium, and homon-

ymous hemianopia. The blood supplyto the riMLFs is via the thalamic-subthalamic paramedian arteries (alsocalled paramedian thalamic arteries),

with origin from the proximal posteriorcerebral artery. In 20% of the population,a common trunk off the posterior cere-bral artery provides bilateral riMLF per-

fusion via a single thalamic-subthalamicartery, the artery of Percheron (Percheron,1973). An infarct in the territory of this

single vessel results in bilateral para-median thalamic and mesencephalic in-farctions (Figure 10-6) (Matheus andCastillo, 2003).

Each riMLF projects only unilaterallyto motor neurons for eye depressionand bilaterally to motor neurons for ele-

vation. riMLF lesions therefore tendto have a greater effect on downgazethan on upgaze (Moschovakis et al,1991a; Moschovakis et al, 1991b). Mostof what we know about vertical sac-

cadic control is from animal experiments.

155

FIGURE 10-5 Sagittal brainstem drawing showing ocularmotor-related nuclei. Within the midbrain,premotor vertical saccade burst neurons

are located within the rostral interstitial medial longitudinalfasciculus (riMLF) and interstitial nucleus of Cajal (INC).The shadedregion is the paramedian pontine reticularformation (PPRF) containing premotor horizontal saccadeburst neurons, with an arrowshowing the general locationof these neurons.

PC = posterior commissure; SC = superior colliculus,III = oculomotor nucleus; IIIn = oculomotor nerve;IV = trochlear nucleus; VI = abducens nucleus;VIn = abducens nerve; MLF = medial longitudinal fasciculus;IO = inferior olive; XII = hypoglossal nerve.

Drawing based on Buttner U, Bu ttner-Ennever JA. Present concepts ofoculomotor organization. Prog Brain Res 2006;151:142.

KEY POINT

A An infarct in

the territory

of the single

thalamic-subthalamic

artery results

in bilateral

paramedian

thalamic and

mesencephalic

infarctions.




7/18

These data suggest that unilateral riMLFlesions should cause only a minimal def-icit of downward saccades; however,human case reports suggest much moreextensive deficits of vertical ocularmotility (Figure 10-7). It is likely that

the lesions in some of these humancases involve structures other than theriMLF, such as the INC, because bilateralINC lesions have the potential to im-pair all vertical eye movements. A su-pranuclear forced downward deviationof the eyes (peering at the tip of thenose) has been attributed to thalamiclesions (most notably infarction or hem-orrhage), but most of these lesions likelyextend to the midbrain and affect theriMLF (Choi et al, 2004).

Unilateral or monocular vertical supra-nuclear palsies are difficult to understandbased on physiologic and anatomicknowledge of supranuclear neural path-

ways, but they are occasionally reported(Onofrj et al, 2004). The variant of a

monocular elevation palsy, sometimestermed double elevator palsy, has re-ceived much attention as a supranu-clear problem; it is important to keepin mind, however, that this term de-scribes only what is seen on examina-tion and does not localize the cause ofthe elevation deficit. Any problem caus-ing limitation of elevation of one eyecould be termed double elevator palsy.The potential causes also include my-opathic (eg, thyroid eye disease causing

156

TABLE 10-2 Supranuclear Causes of Diplopia

Supranuclear Disorder Affected Structure Clinical Appearance

Vertical saccadic gazepalsy

Midbrain: rostral interstitial mediallongitudinal fasciculus (riMLF) andinterstitial nucleus of Cajal (INC)

Slow or absent vertical saccades forupward or downward eye movements,unilateral or bilateral

Dorsal midbrain syndrome(Parinaud syndrome)

Midbrain: posterior commissure Supranuclear upgaze palsyPupillary light-near dissociationConvergence-retraction nystagmusEyelid retraction (Collier sign)

Skew deviation Supranuclear connections betweenotolith vestibular organs and ocularmotor cranial nerve nuclei

Lesions may occur peripherally or

anywhere from medulla to midbrain

Vertical misalignment of the eyes,comitant or incomitant

For lesions below the pontine

decussation of the pathway, the eye on

the side of the lesion is the lower eye

For lesions above the pontine decussa-

tion of the pathway, the eye on the

side of the lesion is the higher eye

Horizontal saccadicgaze palsy

Pons: paramedian pontine reticularformation (PPRF)

Slow or absent horizontal saccades inthe direction ipsilateral to the lesion

One-and-a-half syndrome Pons: unilateral PPRF orabducens nucleus and mediallongitudinal fasciculus (MLF)

Absent horizontal gaze in the directionipsilateral to the lesion (from PPRFor abducens nucleus involvement)

Impaired adduction of the ipsilateral

eye (from MLF involvement)

Supranuclear esotropia Thalamus or upper midbrain Inward deviation of the eyes with orwithout abduction impairment





8/18

restriction of elevation from inferiorrectus involvement), neuromuscularjunction (eg, ocular myasthenia gravis),

and neuropathic (eg, partial third nervepalsy affecting the elevator musclessuperior rectus and inferior oblique).

Dorsal midbrain syndrome.A veryspecific type of supranuclear verticalgaze palsy occurs in the dorsal mid-brain syndrome (also called Parinaud syn-drome). A supranuclear upgaze palsyaccompanies other features that variablyinclude pupillary light-near dissociation,

vergence dysfunction, convergence-retraction nystagmus, and eyelid retrac-

tion (Collier sign) in the dorsal midbrainsyndrome (Table 10-2) (Video Seg-ments 61 to 63). The supranucleargaze palsy is likely caused by involve-ment of fibers projecting to theposteriorcommissure (Figure 10-5) from theINC. Although any dorsal midbrain le-sion may cause this syndrome, pinealgland lesions (Figure 10-8) and hydro-cephalus are the most common etiolo-gies, as the pineal gland and cerebralaqueduct are located just dorsal to thedorsal midbrain.

Skew DeviationSkew deviation, a common supranu-clear cause of vertical diplopia, is anacquired vertical misalignment of theeyes due to a lesion of the supra-nuclear pathways connecting the ves-tibular apparatus to the vertical ocularmotor cranial nerve nuclei and finalcommon pathway for eye movements

(Table 10-2) (Brodsky et al, 2006).Although vertical diplopia from theskew deviation is the most prominentsymptom, the patient may exhibit atriad of findings, including a path-ologic head tilt and inappropriatetorsional rotation of both eyes, in ad-dition to the skew deviation. This con-stellation is termed the ocular tiltreaction (OTR).

In order to understand skew devia-tion and the OTR, a basic familiarity

with the vestibular system is necessary.Each time the head is moved, signalsare sent via the vestibular apparatus to

the appropriate ocular motor cranialnerve nuclei to elicit a compensatorymovement of the eyes in an equal butopposite direction. This allows stablegaze during head movements, such asduring ambulation. Within the inner ear,the vestibular apparatus is comprisedof the semicircular canals and the oto-lith organs, the utricle and saccule. Thesemicircular canals sense angular accel-eration of the head, whereas the oto-lith organs sense linear acceleration. In

lateral-eyed animals, the otolith organsalso mediate a physiologic OTR in re-sponse to tilting of the head or wholebody from side to side that has thefollowing components: (1) rolling or tor-sional movement of the eyes, (2) verticaldeviation of the eyes, and (3) a compen-satory head tilt. Although the OTR servesan important physiologic role in lateral-eyed animals, such as fish or rabbits whoneed it to maintain their eyes in the hor-izontal planewithside-to-side movements,it is largely unnecessary in front-eyedanimals such as humans. In pathologicconditions when a lesion is present along

157

KEY POINT

A A supranuclear

upgaze palsy

accompanies

other featuresthat variably

include pupillary

light-near

dissociation,

vergence

dysfunction,

convergence-

retraction

nystagmus, and

eyelid retraction

(Collier sign)

in the dorsal

midbrain

syndrome.

FIGURE 10-6 Axial fluid-attenuated inversion recoveryMRI images demonstrate medial inferiorthalamic (right) and medial superior

midbrain (left) infarcts in the vascular distribution of the arteryof Percheron.

Reprinted with permission from Matheus MG, Castillo M. Imaging of acutebilateral paramedian thalamic and mesencephalic infarcts. AJNR Am JNeuroradiol 2003;24(10):2006.




9/18

158

FIGURE 10-7 Complete bilateral supranuclear vertical gaze palsy presumably secondaryto toxoplasmosis.A, Gaze straight ahead.B, Impaired upward eye movementson attempted upgaze. Note development of esotropia (eyes turned inward)

with attempted upgaze. C, Impaired downward eye movements on attempted downgaze.D, Intact right gaze. E, Intact left gaze. F, (T2-weighted axial MRI) and (G) (fluid-attenuatedinversion recovery axial MRI) show the causative lesion in the midbrain (white arrows).

Courtesy of Dr Michael Lee, University of Minnesota, Minneapolis, MN.

FIGURE 10-8 Noncontrasted T1-weighted sagittal (A, C) and axial (B) MRI scans showinghyperintense pineal gland pathology in three women who presented withheadaches and/or dorsal midbrain syndrome. The pineal lesion in each case

is a pineal gland papillary tumor, a new diagnostic entity recognized in the 2007 WorldHeath Organization Classification of Tumors of the Nervous System.

Reprinted with permission from Chang AH, Fuller GN, Debnam JM, et al. MR imaging of papillary tumor of the pinealregion. AJNR Am J Neuroradiol 2008;29(1):188.

KEY POINT

A Skew deviation,

a common

supranuclear

cause of verticaldiplopia, is an

acquired vertical

misalignment of

the eyes caused

by a lesionof the

supranuclear

pathways

connecting

the vestibular

apparatus to the

vertical ocular

motor cranial

nerve nuclei.





10/18

the supranuclearutricular pathways, per-versions of this OTR may occur.

Skew deviation used to be consid-

ered a diagnosis of exclusion that wasnot localizable beyond a lesion some-where in the posterior fossa. Much hasbeen learned about skew deviation inthe recent past; it is now known thatthe skew deviation does have localizing

value and that careful examination canreliably identify a skew deviation. Thedirection of the head tilt and torsionalrotational movement of the eyes is anextremely important feature in accu-rate diagnosis. With the OTR, the head

and the superior poles of both eyes ro-tate toward the lower eye (Figures 10-9and10-10).

Neural signals from one utricle proj-ect to the ipsilateral vestibular nucleiand then decussate within the ponsand ascend within the medial longitu-dinal fasciculus (MLF) (see section oninternuclear ophthalmoplegia [INO] fordetails regarding the anatomy and clini-cal appearance of lesions of the MLF).

A lesion anywhere along this pathwaymay result in a skew deviation andOTR (Figure 10-9). In addition, thereare many interconnecting pathwaysbetween the vestibular system and thecerebellum; thus, cerebellar lesions mayalso cause skew deviation. In the brain-stem, with lesions at or below the levelof the decussation, the eye on the sideof the lesion will be the lower eye(Brandt and Dieterich, 1994). With le-sions above the level of the pontine

decussation, the eye on the side of thelesion will be the higher eye (ipsi-lesional hypertropia). The presence ofthese ascending utricular pathways

within the MLF makes skew deviationa common finding in combination withan INO (see section on INO for de-tailed description of the clinical appear-ance of an INO) (Case 10-1) (VideoSegment 64) (Frohman et al, 2008).

The vertical ocular misalignment witha skew deviation may be comitant (the

same size in all directions of gaze; eg,3-prism diopter right hypertropia in allpositions of gaze) or incomitant (variable

in size with gaze directional changes;eg, 3-prism diopter hypertropia in rightgaze converting to 3-prism diopter lefthypertropia in left gaze). Alternation of

which eye is the higher eye with dif-ferent gaze positions is also sometimesseen, with a distinctive and peculiar syn-drome of alternating skew on lateral gazeconsisting of a right hypertropia (righteye higher) on right gaze, and a lefthypertropia (left eye higher) on left gaze.

From a practical standpoint, bed-

side neurologic examination with an

159FIGURE 10-9 Pathways from the otoliths and vertical

semicircular canals to the oculomotornuclei and supranuclear vertical gaze

control centers (riMLF and INC). Note the decussation of thesepathways at the level of the pons. The ocular tilt reaction isdepicted schematically on therightin relation to the level ofthe lesion. Note that with lesions below the decussation, theeye contralateral to the lesion is the higher eye, and withlesions above the decussation the eye ipsilateral to the lesion isthe higher eye.

riMLF = rostral interstitial medial longitudinal fasciculus;INC = interstitial nucleus of Cajal; III = oculomotor nucleus;IV = trochlear nucleus; VI = abducens nucleus; VIII = vestibularnuclei; Vim = ventralis intermedius; Vce = ventral caudalisexternus.

Reprinted with permission from Brandt T, Dieterich M. Vestibular syndromesin the roll plane: topographic diagnosis from brainstem to cortex. AnnNeurol 1994;36(3):337347. Copyright # 1994, John Wiley & Sons, Inc.

KEY POINT

A Neural signals

from one utricle

project to the

ipsilateralvestibular nuclei

and then

decussate within

the pons and

ascend within

the medial

longitudinal

fasciculus

(MLF). A lesion

anywhere along

this pathway

may result in a

skew deviation.




11/18

undilated fundus makes it difficult todetect torsional rotation of the fundus,although this can be measured withMaddox rods or dilated fundus pho-tography. Skew deviation should beconsidered when a vertical ocular mis-alignment does not conform to the pat-tern expected for a trochlear (cranialnerve IV) palsy (and extraocular muscleor neuromuscular junction pathophysi-ologies can be ruled out). In other

words, skew deviation rather thantrochlear palsy is suspected when the

vertical diplopia and ocular misalign-ment are not worsened by downgaze,gaze in the direction contralateral to theside with the higher eye, and uponipsidirectional head tilt (eg, a righttrochlear nerve palsy produces a righthypertropia, worse on left gaze, leftand downgaze, and right head tilt).

Horizontal Saccadic Gaze Palsy

Brainstem control centers for horizontaleye movements reside primarily in the

pons. For horizontal saccades, the sac-cadic burst neurons are located in theparamedian pontine reticular formation(PPRF) just rostral to the abducens (cra-nial nerve VI) nucleus (Figure 10-5).Lesions of these burst neurons result inslowed or absent horizontal saccadesipsilateral to the lesion (eg, a rightPPRF lesion affecting the right saccadicburst neurons will impair or abolishsaccades to the right) (Table 10-2).

Acute lesions may deviate the eyes inthe contralateral direction. Bilateral le-

sions result in absent horizontal gazeor a selective loss of horizontal sac-cades. Lesions of the PPRF are mostlikely to result in binocular horizontaldiplopia when they are acute in onset,such as with infarction or acute demy-elination; however, such lesions oftenaffect the eyes symmetrically and thusdo not cause diplopia. As stated ear-lier, the MLF originates in the ponsand decussates before ascending tothe midbrain; a unilateral pontine

160

KEY POINTS

A The vertical

ocular

misalignment

with a skewdeviation may

be comitant or

incomitant.

A Burst neurons for

horizontal

saccades are

located in the

paramedian

pontine reticular

formation (PPRF)

just rostral to

the abducens(cranial nerve VI)

nucleus. Lesions

of these burst

neurons result

in slowed or

absent

horizontal

saccades

ipsilateral

to the lesion.

A The MLF

originates in thepons and

decussates

before ascending

to the midbrain;

a unilateral

pontine lesion

involving the

PPRF and the

adjacent

decussating MLF

produces the

one-and-a-half

syndrome.

FIGURE 10-10 Fundus photographs showing the torsional movements of the eyes in apatient with a skew deviation and ocular tilt reaction. Normally, the fovealregion of the eye is at the same horizontal level as the optic disc. In the right

eye fundus photograph (OD, leftside of figure), the eye is intorted (upper pole of the eye rotatedin toward the nose or toward the left shoulder) with the macular-disc line rotated clockwise

(according to the examiner). In the left eye fundus photograph (OS,rightside of figure), the eye isextorted (upper pole of the eye rotated out away from the nose or toward the left shoulder)with the macular-disc line rotated clockwise (again, according to the examiner). These fundusphotos and the torsional movements in them correspond to the lateralization of the pathwaysdepicted in Figure 10-8 and in the patient in Case 10-1. In other words, this represents thetorsional directions of the eyes with a lesion in the left medulla below the level of otolithpathway decussation or a lesion in the right pons or midbrain above the level of otolithpathway decussation.

Reprinted with permission from Frohman TC, Galetta S, Fox R, et al. Pearls and oy-sters: the medial longitudinalfasciculus in ocular motor physiology. Neurology 2008;70(17):e5767. Review. Copyright # 2008, AAN Enterprises,Inc. All rights reserved.





12/18

161

Case 10-1A 66-year-old woman with no past medical history (although she had not seen a doctor in

many years) presented with new-onset binocular oblique diplopia. She was found to behypertensive, diabetic, and to have hyperlipidemia. No other neurologic symptoms were present.Her diplopia was worse on left gaze and when viewing near targets.

Examination revealed full vertical and rightward (Figure 10-11A) eye movements but impairedadduction of the right eye (Figure 10-11B) and abducting nystagmus of the left eye characteristicfor a right INO (Video Segment 64). An accompanying outward deviation (exotropia) of the eyes waspresent (Figure 10-11C) (Video Segment 64).In addition, there was a large verticalmisalignment of the eyes with the right eyehigher than the left eye (right hypertropia)(Figure 10-11C) (Video Segment 64). Thisvertical misalignment was the same size

in all gaze directions (comitant).MRI of the brain with diffusion-weightedimaging and gadolinium was unremarkableother than for chronic small vesselischemic changes. No acute brainstemlesions were seen. The patient wasdiagnosed with an acute brainsteminfarction and started on low-doseaspirin following a negative evaluation forembolic stroke.

Comment. The patients ocular motilityfindings are a right INO in combinationwith a skew deviation. The lesion based

on the examination findings is knownto be the right MLF, somewhere betweenthe left abducens nucleus and the rightoculomotor nucleus (see section onINO for more details). Because ascendingpathways from the utricle within thevestibular apparatus travel within theMLF, skew deviation is often found incombination with an INO. As expectedfor a skew deviation at this level (abovethe pontine decussation [Figure 10-9]),the right eye (ipsilateral to the rightMLF lesion) is higher than the left eye.

Despite the absence of an identifiableacute pontine or midbrain lesion on MRI,the diagnosis is acute infarction of theMLF that is likely due to small vesseldisease. The patients age and her newlyidentified vascular risk factors supportthis diagnosis. If she were in her twentieswithout vascular risk factors, demyelinationwould be the most likely etiology. MRI is frequently negative with small vessel infarctionscausing isolated ocular motility problems. The prognosis for spontaneous visual recovery isexcellent in this setting.

FIGURE 10-11




13/18

lesion involving the PPRF and theadjacent decussating MLF producesthe one-and-a-half syndrome (see sec-

tion on INO for details regarding theanatomy and clinical appearance oflesions of the MLF). The PPRF lesioncauses an ipsilateral horizontal gazepalsy, and the MLF lesion causes an ip-silateral INO with impaired ipsilateraladduction; eg, with a right pontine le-sion affecting the right PPRF and theright MLF that originated from the leftpons and decussated already, the pa-tient will have absent right horizontalgaze (no abduction of the right eye or

adduction of the left eye) from PPRFinvolvement and impaired adduction ofthe right eye from MLF involvement. Theonly remaining horizontal eye move-ment is abduction of the left eye; thusone and a half of the horizontal eyemovements are impaired. The one-and-a-half syndrome may also occur from alesion affecting the abducens (cranialnerve VI) nucleus and the MLF. It isfurther discussed in the section on nu-clear causes of diplopia with a figureand video example.

Supranuclear Esotropia

Inward deviation of the eyes (esotropia)and binocular horizontal diplopia of su-pranuclear origin may occur with thal-amic, midbrain, or cerebellar lesions(Table 10-2) (Video Segment 61)(Gomez et al, 1988; Pullicino et al,2000). As this mimics an abducens (cra-nial nerve VI) lesion, it is sometimes

termed pseudoabducens palsy. This phe-nomenon is poorly understood, as arethe brainstem supranuclear pathwaysmediating convergence of the eyes;however, thalamic esotropia and mid-brain pseudoabducens palsy are gener-ally attributed to excessive convergencetone. This supranuclear esotropia maybe accompanied by unilateral or bilaterallimitation of abduction, usually affectingsome eye movements (such as saccadesor smooth pursuit) and sparing others

(such as the vestibulo-ocular reflex), asis characteristic of supranuclear ocularmotility deficits.

NUCLEAR CAUSES OFBINOCULAR DIPLOPIA

Lesions of the ocular motor cranialnerve nuclei are rare and have a dif-ferent clinical appearance than theirrespective cranial nerve lesions wheninvolving the oculomotor (cranial nerveIII) or abducens (cranial nerve VI) nu-clei. Brainstem lesions may be causedby any etiology; they are often ische-mic or demyelinating but may also

be due to hemorrhage, infection, neo-plasm, or necrosis such as in Wernickeencephalopathy. As with skew devia-tion, when the ocular nuclear deficitoccurs in isolation, it may be radio-graphically silent.

Oculomotor (Cranial Nerve III)Nuclei

Paired oculomotor nuclei are located inthe dorsal midbrain at the level of thesuperior colliculus (Figure 10-5). Eachnucleus contains inferior and medialrectus and inferior oblique subnucleiproviding ipsilateral innervation, a su-perior rectus subnucleus providing in-nervation to the contralateral superiorrectus, and an Edinger-Westphal nu-cleus providing parasympathetic pre-ganglionic output to the iris sphincterand ciliary muscles (Figure 10-12).

A single midline caudal subnucleusprovides innervation to both levator

palpebrae superioris muscles. An ocu-lomotor nuclear lesion may result inbilateral ptosis from bilateral levatorpalpebrae superioris involvement if thesingle midline nucleus is involved. Con-tralateral or bilateral ocular elevation de-ficits may also occur (Case 10-2). Thecontralateral elevation deficit is due tothe crossed innervation of the superiorrectus subnucleus. If this and the fi-bers that originated in the contralat-eral superior rectus subnucleus and

162

KEY POINTS

A Inward deviation

of the eyes

(esotropia)

and binocularhorizontal

diplopia of

supranuclear

origin may

occur with

thalamic,

midbrain,

or cerebellar

lesions.

A An oculomotor

nuclear lesion

may result inbilateral ptosis

from bilateral

levator

palpebrae

superioris

involvement

if the single

midline nucleus

is involved.

Contralateral

or bilateral

ocular elevation

deficits mayalso occur due

to the crossed

innervation of

the superior

rectus

subnucleus.





14/18

decussated already are involved, bilat-eral elevation deficits occur. Ipsilateral

weakness of the medial or inferior recti

and/or the inferior oblique musclesand ipsilateral pupillary enlargementmay result from a nuclear lesion. A verysmall focal nuclear lesion may causeisolated bilateral ptosis or isolated weak-ness of a single muscle (Kwon et al,2003; Rabadi and Beltmann, 2005; Saekiet al, 2000).

Trochlear (Cranial Nerve IV)Nuclei

Paired trochlear nuclei are located inthe dorsal midbrain just below the levelof the inferior colliculus (Figure 10-5).Differentiating a trochlear nuclear le-sion from a trochlear nerve lesion isclinically difficult, given the identicalappearance of the superior oblique

weakness. The affected eye is elevated,and the patient experiences verticaldiplopia worst in downgaze with theeye adducted. A resting head tilt in thedirection away from the affected eye

and chin-down head position are com-mon. This minimizes diplopia by plac-ing the affected eye in an extortedpositionin other words, in the oppo-site direction of action of the superioroblique, which is an intorter of the eye.

A trochlear nuclear lesion is identifiedwhen the weak superior oblique mus-cle is contralateral to the lesioned nu-cleus (Figure 10-15), as the trochlearnerve fascicles decussate immediatelyafter their dorsal exit from the midbrain.

In addition, other brainstem signs, suchas a Horner syndrome ipsilateral to thebrainstem lesion and contralateral tothe superior oblique weakness, mayalso accompany a trochlear nuclearlesion.

Abducens (Cranial Nerve VI)Nuclei

Paired abducens nuclei are located inthe caudal dorsal pons (Figure 10-5).

The fascicle of the facial nerve wrapsaround the nucleus, creating the facialgenu, a protrusion along the dorsal sur-

face of the pons. The abducens nucleuscontains two neuronal populations: (1)motor neurons that form the abducensnerve for lateral rectus innervation and(2) interneurons that decussate imme-diately at the level of the pons and thenascend in the contralateral MLF to thecontralateral medial rectus. The MLFfacilitates horizontal conjugate gaze inthe direction ipsilateral to the abducensnucleus of origin. In contrast to anabducens nerve palsy, which causes uni-

lateral abduction weakness, an abducensnuclear palsy results in an ipsilateralconjugate horizontal gaze palsy. Ipsilat-eral lower motor neuron facial weak-ness is nearly always present, although

163

FIGURE 10-12 The anatomy of the oculomotor nucleusin the rhesus monkey. Note the singlecentral caudal nucleus for bilateral levator

palpebrae superioris innervation and the contralateralsubnucleus for superior rectus innervation.

CCN = central caudal nucleus; DN = dorsal nucleus;IC = intermediate nucleus; IV = trochlear nucleus; VN = ventralnucleus; R = right; L = left.

Reprinted with permission from Leigh RJ, Zee DS. The neurology of eyemovements. New York: Oxford University Press, 2006; and Warwick R.Representation of the extra-ocular muscles in the oculomotor nuclei ofthe monkey. J Comp Neurol 1953;98:449503. Copyright # 1953,John Wiley & Sons, Inc.

KEY POINT

A A trochlear

nuclear lesion

is identified

when theweak superior

oblique muscle

is contralateral

to the lesioned

nucleus, as the

trochlear

nerve fascicles

decussate

immediately

after their

dorsal exit from

the midbrain.




15/18

164

Case 10-2

A 61-year-old woman with a history of epiglottic cancer and hypertension had binocularvertical diplopia upon awakening from an uneventful tracheostomy and direct laryngoscopywith biopsy for laryngeal stenosis and chronic hoarseness. Examination revealed impairedelevation of the right eye, depression of the left eye, adduction of the left eye, and elevationof the adducted left eye (Figure 10-13). She also had very subtle impairment of elevationof the left eye in an abducted position(not seen well in the motilityphotographs). MRI of the brain revealedincreased signal on fluid-attenuatedinversion recovery images suggestive ofan acute infarction affecting the rostralmidbrain (Figure 10-14A and B).

Comment.The patients ocularmotility examination revealed bilateralabnormalities, with the majority offindings in the left eye, in combinationwith isolated elevation impairment of theright eye. This combination should raisesuspicion for a nuclear oculomotor palsy,especially with postoperative diplopiawhen an infarct is the most likely clinicalscenario. Myasthenia gravis, which canmimic any ocular motility pattern and be acutely unmasked by surgical anesthetics, would be themost important disease in the pre-MRI differential diagnosis. The specific muscles that are weak inthis patient, proven to have a very rostral midbrain infarction on the left, include the right

superior rectus, left inferior rectus, left medial rectus, and left inferior obliqueall muscles whoseinnervationoriginatesin the leftoculomotornucleus. Mildweaknessof the leftsuperior rectus(as evidencedby mildweakness of

the abductedleft eye thatwas not wellvisualizedon thephotographs)suggestsinvolvement ofthe superior rectus fibers from the right oculomotor superior rectus subnucleus. These crossingfibers pass very close to the contralateral subnucleus and can often be involved in an oculomotornuclear palsy.

Case courtesy of Dr M. Tariq Bhatti, Duke Eye Center, Durham, NC.

FIGURE 10-14 Courtesy of Dr M. Tariq Bhatti, Duke Eye Center, Durham, NC.

FIGURE 10-13 Courtesy of Dr M. Tariq Bhatti, Duke Eye Center,Durham, NC.





16/18

a few cases lacking this have been re-ported (Miller et al, 2002).

A unilateral pontine lesion involv-ing the abducens nucleus and the MLF

that originated in the contralateral ponsand already decussated may cause theone-and-a-half syndrome (see section onINO for details regarding the anatomy

165

FIGURE 10-15 A nuclear trochlear palsy in a 28-year-old patient with binocular verticaldiplopia due to weakness of the right superior oblique muscle with a lesionin the left dorsal midbrain (white arrows) that resolved spontaneously after

1 month. It was presumed to be a demyelinating lesion A, T2-weighted axial MRI showingthe hyperintense lesion (white arrow).B, Gadolinium-enhanced axial MRI showing enhancementof the lesion (white arrow).

Courtesy of Dr Gregory Van Stavern, Washington University, St. Louis, MO.

KEY POINT

A In contrast to

an abducens

nerve palsy,

which causesunilateral

abduction

weakness,

an abducens

nuclear palsy

results in an

ipsilateral

conjugate

horizontal

gaze palsy.

FIGURE 10-16 Right one-and-a-half-syndrome.A, The resting position of the eyes.B, Attempts to elicit rightward eye movements disclose a complete righthorizontal gaze palsy from involvement of the right abducens nucleus.

C, Upon left gaze, impaired adduction of the right eye is present with intact abduction of theleft eye from a right internuclear ophthalmoplegia. D, Axial CT scan at the level of the ponsreveals a right dorsal pontine hyperdensity due to hemorrhage.




17/18

and clinical appearance of lesions ofthe MLF). The abducens nuclear lesioncauses an ipsilateral horizontal gaze

palsy, and the MLF lesion causes anipsilateral INO with impaired ipsilat-eral adduction. An example of lateral-ization follows: With a right pontinelesion affecting the right abducensnucleus and the right MLF that origi-nated from the left pons and de-cussated already, the patient willhave absent right horizontal gaze (noabduction of the right eye or adduc-tion of the left eye) from abducensnuclear involvement and impaired

adduction of the right eye from MLFinvolvement. The only remaining hor-izontal eye movement is abduction of

the left eye; thus one and a half of thehorizontal eye movements are impaired(Figure 10-16) (Video Segment 65).

An exotropia (outward deviation of theeyes) is often present. This exotropiais sometimes called paralytic pontineexotropia and will cause binocular hori-zontal diplopia (Sharpe et al, 1974).One-and-a-half syndrome also occursfrom a lesion affecting the PPRF (seethe section on supranuclear horizontalsaccadic palsy) and the MLF.

REFERENCES

Barton JJ. Retinal diplopia associated with macular wrinkling. Neurology 2004;63(5):925927.

Bender MB. Polyopia and monocular diplopia of cerebral origin. Arch Neurol Psychiatry1945;54:323338.

Brandt T, Dieterich M. Vestibular syndromes in the roll plane: topographic diagnosisfrom brainstem to cortex. Ann Neurol 1994;36(3):337347.

Brodsky MC, Donahue SP, Vaphiades M, Brandt T. Skew deviation revisited. SurvOphthalmol 2006;51(2):105128.

Buttner U, Buttner-Ennever JA. Present concepts of oculomotor organization. ProgBrain Res 2006;151:142.

Choi KD, Jung DS, Kim JS. Specificity of peering at the tip of the nose for a diagnosisof thalamic hemorrhage. Arch Neurol 2004;61(3):417422.

Frohman TC, Galetta S, Fox R, et al. Pearls and oy-sters: the medial longitudinal fasciculusin ocular motor physiology. Neurology 2008;70(17):e57e67.

Gomez CR, Gomez SM, Selhorst JB. Acute thalamic esotropia. Neurology 1988;33(11):17591762.

Horn AK, Buttner-Ennever JA. Premotor neurons for vertical eye movements in therostral mesencephalon of monkey and human: histologic identification by parvalbumin

staining. J Comp Neurol 1998;392(4):413427.

Kwon JH, Kwon SU, Ahn HS, et al. Isolated superior rectus palsy due to contralateralmidbrain infarction. Arch Neurol 2003;60(11):16331635.

Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed. New York: Oxford UniversityPress, 2006.

166





18/18

Matheus MG, Castillo M. Imaging of acute bilateral paramedian thalamic andmesencephalic infarcts. AJNR Am J Neuroradiol 2003;24(10):20052008.

Miller NR, Biousse V, Hwang T, et al. Isolated acquired unilateral horizontal gaze

paresis from a putative lesion of the abducens nucleus. J Neuroophthalmol 2002;22(3):204207.

Moschovakis AK, Scudder CA, Highstein SM. Structure of the primate oculomotor burstgenerator: I. medium-lead burst neurons with upward on-directions. J Neurophysiol1991a;65(2):203217.

Moschovakis AK, Scudder CA, Highstein SM, Warren JD. Structure of the primateoculomotor burst generator: II. medium-lead burst neurons with downwardon-directions. J Neurophysiol 1991b;65(2):218229.

Onofrj M, Iacono D, Luciano AL, et al. Clinically evidenced unilateral dissociationof saccades and pursuit eye movements. J Neurol Neurosurg Psychiatry 2004;75(7):10481050.

Percheron G. The anatomy of the arterial supply of the human thalamus and its use forthe interpretation of the thalamic vascular pathology. Z Neurol 1973;205(1):113.

Pullicino P, Lincoff N, Truax BT. Abnormal vergence with upper brainstem infarcts:

pseudoabducens palsy. Neurology 2000;55(3):352358.

Rabadi MH, Beltmann MA. Midbrain infarction presenting isolated medial rectusnuclear palsy. Am J Med 2005;118(8):836837.

Saeki N, Yamaura A, Sunami K. Bilateral ptosis with pupil sparing because of a discretemidbrain lesion: magnetic resonance imaging evidence of topographic arrangementwithin the oculomotor nerve. J Neuroophthamol 2000;20(2):130134.

Sharpe JA, Rosenberg MA, Hoyt WF, Daroff RB. Paralytic pontine exotropia: a sign ofacute unilateral pontine gaze palsy and internuclear ophthalmoplegia. Neurology1974;24(11):10761081.

SUGGESTED ADDITONAL RESOURCE

The Neuro-Ophthalmology Virtual Education Library at http://library.med.utah.edu/NOVEL/.

167

Documents

Diplopia Supranuclear and Nuclear Causes.12