KEY POINTS

150

When the
diplopia resolves
completely
with coverage
of either eye,
it is binocular
diplopia. When
the diplopia
persists upon
coverage of one
or the other eye,
it is monocular
diplopia.
Monocular
diplopia,
generally
non-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.

DIPLOPIA
SUPRANUCLEAR AND
NUCLEAR CAUSES
Janet C. Rucker

ABSTRACT
When evaluating a patient with diplopia, it is critical to differentiate monocular diplopia (diplopia present in one eye) from binocular diplopia (diplopia resolves with
closure of either eye). Binocular diplopia is typically related to ocular misalignment
and often has a neurologic cause. Although the supranuclear ocular motor system
is primarily associated with generation of bilateral eye movements, certain supranuclear processes can cause ocular misalignment and binocular diplopia. Skew
deviation, the most common supranuclear cause of diplopia, presents with binocular vertical diplopia due to a hypertropia and full ductions in each eye. Oculomotor
nuclear lesions have distinct clinical characteristics related to the unique anatomy
of the third cranial nerve nuclei, which may present with combinations, including
bilateral ptosis and contralateral or bilateral ocular elevation deficits. Trochlear nuclear lesions clinically appear identical to fascicular or trochlear axonal lesions, but
abducens nuclear lesions produce ipsilesional gaze palsies rather than unilateral
cranial nerve VI palsies.
Continuum Lifelong Learning Neurol 2009;15(4):150167.

When evaluating a patient for diplopia (doubling of vision), the first question asked of the patient should be
One eye or two? In other words,
does the diplopia resolve completely
when the patient covers either eye, or
is it still present with one or the other
eye closed? Some patients may not be
able to answer this question, and it is
helpful to perform a quick assessment
by asking the patient whose diplopia
is currently present to cover each eye
in turn early in the course of the evaluation. When the diplopia resolves completely with coverage of either eye, it
is binocular diplopia. When the diplopia persists upon coverage of one or
the other eye, it is monocular diplopia.

Monocular diplopia, generally nonneurologic in origin, is often due to either an eye problem, such as a cataract
or an uncorrected need for glasses, or
to nonphysiologic causes (Table 10-1).
The second image often appears shadowlike or ghostlike (at times overlapping) rather than as a clear and distinct
image. Another clue to an uncorrected
need for glasses (refractive error) as
the cause of monocular diplopia is resolution of the diplopia when the patient views through a pinhole with the
affected eye. Patients with monocular
diplopia should be sent for ophthalmic consultation and generally do not
require further neurologic evaluation
or imaging.

Relationship Disclosure: Dr Rucker has nothing to disclose.

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

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

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

KEY POINT

TABLE 10-1

"

Monocular Versus Binocular Diplopia

Causes of Monocular Diplopia

Eye problem (eg, refractive error, cataract)
Nonphysiologic

Binocular
diplopia is very
likely due
to a relative
misalignment
of the eyes.

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)

Binocular diplopia is very likely caused

by a relative misalignment of the eyes
from a supranuclear, cranial nerve nucleus, internuclear, cranial nerve, neuromuscular junction, or extraocular muscle problem (Table 10-1). The fovea,
located temporal to the optic nerve,
is the area of the retina with the highest density of photoreceptors and the
highest visual acuity. Each time we look
at an object, all of our eye movements
share the goal of placing and maintaining the object of visual interest on the
fovea in each eye to ensure visualization of a single stable object. When the
eyes are relatively misaligned, a visual
image falls on the fovea in one eye and
on an extrafoveal location in the opposite eye, creating binocular diplopia
(Figure 10-1). Accompanying ophthalmoparesis or ophthalmoplegia may or
may not be obvious on examination.
Particularly challenging to the neurologist is when eye movements appear to
be full, but the patient reports persistent binocular diplopia. Assessment of
ocular alignment is the only tool available for localization of the diplopia in

151
Solid black lines
represent normal ocular
alignment with which
the telephone image falls on each fovea
simultaneously and a single telephone
is viewed. Inward deviation of the left
eye (represented by the dashed curved
arrow) results in binocular diplopia because
the image of the telephone falls on an
extrafoveal location in the left eye (dashed
lines).

FIGURE 10-1

Adapted with permission from Leigh RJ, Zee DS. The

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

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" SUPRANUCLEAR AND NUCLEAR

that setting. It is also important to keep

in mind that, while binocular diplopia
is the most common symptom with an
ocular misalignment, frank diplopia is
not always present, and visual blur that
resolves completely with covering either
eye can also be a manifestation of an
ocular misalignment (binocular blur).
It is also essential to recognize that patients with poor vision in one or both
eyes may have an ocular misalignment
but fail to experience binocular diplopia.
When binocular diplopia is confirmed
by history, additional historical features
may assist with localization and/or etiology, and careful examination often
discloses the nature of the problem.

Very rare exceptions to the above descriptions of binocular and monocular

diplopia exist. Binocular diplopia is reported with a retinal problem in one
eye, such as retinal wrinkling called an
epiretinal membrane, due to disruption
or dragging of the fovea and macula
from their usual location (Figure 10-2)
(Barton, 2004). As a result, a relative
misalignment of the foveae and binocular diplopia occur in the absence of a
true neurologic ocular misalignment.
One clue to this diagnosis is the presence of metamorphopsia (straight lines
appear bent) with Amsler grid testing. Given the subtlety of these retinal
changes, ophthalmic consultation with

152

Ophthalmoscopic views in three patients with binocular diplopia attributed

to 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 dark
streaks are visible in the perimacular region of all cases. On the right are drawings of the
wrinkles superimposed on a threshold black-and-white version of the middle images, to aid
in illustration.

FIGURE 10-2

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

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pharmacologic pupil dilation and careful examination of the foveal region

should be considered in patients with
binocular diplopia and distorted or
blurred monocular vision or a history
of retinal disease.
Cerebral polyopia is extremely rare;
it constitutes an exception to the general statement that monocular diplopia

is non-neurologic and is due to an eye or

nonphysiologic problem. Cerebral polyopia is visualization of multiple images
that persists in each eye with monocular closure or pinhole (Figure 10-3)
(Bender, 1945). Occasionally, cerebral diplopia occurs with only two images seen.
Cerebral polyopia-diplopia is caused
by posterior cerebral lesions affecting

KEY POINTS

Supranuclear
eye movement
problems
result from
dysfunction of
the supranuclear
or premotor
afferent neural
pathways from
the cerebral
hemispheres,
cerebellum,
and brainstem
into the final
common
pathway of eye
movements.
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 from
one target to
another, and
they typically
affect the eye
movement
symmetrically.

153

The palinopsias. A, A room as correctly

observed. B, Perseveration: each red circle
marks 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 points
in the right hemifield, a percept of the lampshade persists.
C, Illusory visual spread: the pattern of the furniture fabric
coverings spreads beyond their true boundaries to other
objects. D, Polyopia: the lampshade is repeated in rows
and columns.

FIGURE 10-3

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

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" SUPRANUCLEAR AND NUCLEAR

KEY POINT

Lesions of
burst neurons
(especially
when bilateral)
result in
slowed or
absent vertical
saccades.

the visual pathways and is typically accompanied by other neurologic symptoms and signs referable to these areas,
such as homonymous hemianopia. It
is a disorder of higher cortical visual
function and a subtype of visual perseveration. Other types of visual perseveration include visual afterimages and
illusory visual spread (Figure 10-3).
SUPRANUCLEAR CAUSES OF
BINOCULAR DIPLOPIA
Supranuclear eye movement problems
result from dysfunction of the supranuclear or premotor afferent neural pathways from the cerebral hemispheres,

154

A characteristic supranuclear gaze palsy

affecting saccades to a greater extent
than smooth pursuit with sparing of the
vestibular-ocular reflex. This patient does not report binocular
diplopia, given the symmetry of the process. A, The maximum
extent of downward movement of the eyes with following
of a smoothly moving target (smooth pursuit) is to the
horizontal midline. B, Downward saccades are completely
eliminated. This picture shows the eyes stuck in upgaze
following a fast vertical upward eye movement (vertical
saccade). The patient is unable to even saccade back down
to midline. C, The ability of the vestibulo-ocular reflex to
overcome the downgaze palsy is demonstrated.

FIGURE 10-4

cerebellum, and brainstem into the final

common pathway of eye movements.
This final common pathway consists of
the ocular motor cranial nerve nuclei
and nerves, neuromuscular junction,
and extraocular muscle. Separate anatomic supranuclear pathways exist for
the different types of eye movements,
such as saccades, smooth pursuit, and
the vestibulo-ocular reflex, and a great
deal is now known about how these
neural networks govern eye movements
(Bu
ttner and Bu
ttner-Ennever, 2006;
Leigh and Zee, 2006).
While the specific focus of this section is restricted to binocular diplopia
from supranuclear problems, it is important to note that 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 from one target to another, and that they typically
affect the range of eye movement symmetrically (Figure 10-4) (Video Segment 60), or not at all. As a result,
visual symptoms may frequently be
minimized by the symmetry of the
process. Supranuclear eye movement
problems may be incidentally noted
and diagnostically helpful in a visually
asymptomatic patient with multifocal
neurologic disease. On the other hand,
vague visual symptoms, such as visual
blurring, may occur but are nonlocalizing. Binocular diplopia will occur only
when the two eyes are affected differently, causing an ocular misalignment.
Diplopia may also be more common
when the deficits have acute onset, such
as with infarction. Lesions affecting supranuclear pathways in the cerebral
hemispheres (frontal and parietal eye
fields) rarely cause diplopia and are not
further addressed here.
Vertical Gaze Palsy
Saccadic. Brainstem control centers for
vertical eye movements reside primarily in the midbrain. In order to generate

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fast saccadic eye movements, special

burst neurons must discharge vigorously and send a signal to the appropriate cranial nerve nuclei. For vertical
saccades, these burst neurons are located in the rostral interstitial medial
longitudinal fasciculus (riMLF) just rostral to the oculomotor (cranial nerve III)
nucleus (Figure 10-5). A few are located in the nearby interstitial nucleus
of Cajal (INC) (Bu
ttner and Bu
ttnerEnnever, 2006; Horn and Bu
ttnerEnnever, 1998). Lesions of these burst
neurons (especially when bilateral) result in slowed or absent vertical saccades
(Table 10-2). Such lesions are most
likely to result in binocular vertical diplopia when they are acute in onset,
such as with infarction or acute demyelination, and when they affect the eyes
asymmetrically. In addition, in the acute
setting, all vertical eye movements may
be affected.
A sudden-onset vertical supranuclear
gaze palsy with or without diplopia in
an older patient is characteristic of a
midbrain infarction, either in combination with a disturbance of consciousness or cognition or in combination
with more widespread infarction from
top-of-the basilar syndrome. The former usually results from small vessel
involvement supplying the posteromedial thalami and riMLF. Top-of-the basilar infarction is usually caused by an
embolus at the bifurcation point of the
basilar into the posterior cerebral arteries; variable midbrain, superior cerebellar, thalamic, and often occipital and
temporal lobe infarction occurs with
resultant supranuclear vertical gaze palsies, somnolence, delirium, and homonymous hemianopia. The blood supply
to the riMLFs is via the thalamicsubthalamic paramedian arteries (also
called paramedian thalamic arteries),
with origin from the proximal posterior
cerebral artery. In 20% of the population,
a common trunk off the posterior cerebral artery provides bilateral riMLF per-

fusion via a single thalamic-subthalamic

artery, the artery of Percheron (Percheron,
1973). An infarct in the territory of this
single vessel results in bilateral paramedian thalamic and mesencephalic infarctions (Figure 10-6) (Matheus and
Castillo, 2003).
Each riMLF projects only unilaterally
to motor neurons for eye depression
and bilaterally to motor neurons for elevation. riMLF lesions therefore tend
to have a greater effect on downgaze
than on upgaze (Moschovakis et al,
1991a; Moschovakis et al, 1991b). Most
of what we know about vertical saccadic control is from animal experiments.

KEY POINT

An infarct in
the territory
of the single
thalamicsubthalamic
artery results
in bilateral
paramedian
thalamic and
mesencephalic
infarctions.

155
Sagittal brainstem drawing showing ocular
motor-related nuclei. Within the midbrain,
premotor vertical saccade burst neurons
are located within the rostral interstitial medial longitudinal
fasciculus (riMLF) and interstitial nucleus of Cajal (INC).
The shaded region is the paramedian pontine reticular
formation (PPRF) containing premotor horizontal saccade
burst neurons, with an arrow showing the general location
of 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.

FIGURE 10-5

Drawing based on Buttner U, Buttner-Ennever JA. Present concepts of

oculomotor organization. Prog Brain Res 2006;151:142.

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" SUPRANUCLEAR AND NUCLEAR

TABLE 10-2

Supranuclear Causes of Diplopia

Supranuclear Disorder

Affected Structure

Clinical Appearance

Vertical saccadic gaze

palsy

Midbrain: rostral interstitial medial

longitudinal fasciculus (riMLF) and
interstitial nucleus of Cajal (INC)

Slow or absent vertical saccades for

upward or downward eye movements,
unilateral or bilateral

Dorsal midbrain syndrome Midbrain: posterior commissure

(Parinaud syndrome)

Supranuclear upgaze palsy

Pupillary light-near dissociation
Convergence-retraction nystagmus
Eyelid retraction (Collier sign)

Skew deviation

Vertical misalignment of the eyes,

comitant or incomitant

Supranuclear connections between

otolith vestibular organs and ocular
motor cranial nerve nuclei
Lesions may occur peripherally or
anywhere from medulla to midbrain

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 decussation of the pathway, the eye on the
side of the lesion is the higher eye

Horizontal saccadic
gaze palsy

Pons: paramedian pontine reticular

formation (PPRF)

Slow or absent horizontal saccades in

the direction ipsilateral to the lesion

One-and-a-half syndrome

Pons: unilateral PPRF or

abducens nucleus and medial
longitudinal fasciculus (MLF)

Absent horizontal gaze in the direction

ipsilateral to the lesion (from PPRF
or abducens nucleus involvement)
Impaired adduction of the ipsilateral
eye (from MLF involvement)

Supranuclear esotropia

156

Thalamus or upper midbrain

These data suggest that unilateral riMLF

lesions should cause only a minimal deficit of downward saccades; however,
human case reports suggest much more
extensive deficits of vertical ocular
motility (Figure 10-7). It is likely that
the lesions in some of these human
cases involve structures other than the
riMLF, such as the INC, because bilateral
INC lesions have the potential to impair all vertical eye movements. A supranuclear forced downward deviation
of the eyes (peering at the tip of the
nose) has been attributed to thalamic
lesions (most notably infarction or hemorrhage), but most of these lesions likely
extend to the midbrain and affect the
riMLF (Choi et al, 2004).

Inward deviation of the eyes with or

without abduction impairment

Unilateral or monocular vertical supranuclear palsies are difficult to understand

based on physiologic and anatomic
knowledge of supranuclear neural pathways, but they are occasionally reported
(Onofrj et al, 2004). The variant of a
monocular elevation palsy, sometimes
termed double elevator palsy, has received much attention as a supranuclear problem; it is important to keep
in mind, however, that this term describes only what is seen on examination and does not localize the cause of
the elevation deficit. Any problem causing limitation of elevation of one eye
could be termed double elevator palsy.
The potential causes also include myopathic (eg, thyroid eye disease causing

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restriction of elevation from inferior

rectus involvement), neuromuscular
junction (eg, ocular myasthenia gravis),
and neuropathic (eg, partial third nerve
palsy affecting the elevator muscles
superior rectus and inferior oblique).
Dorsal midbrain syndrome. A very
specific type of supranuclear vertical
gaze palsy occurs in the dorsal midbrain syndrome (also called Parinaud syndrome). A supranuclear upgaze palsy
accompanies other features that variably
include pupillary light-near dissociation,
vergence dysfunction, convergenceretraction nystagmus, and eyelid retraction (Collier sign) in the dorsal midbrain
syndrome (Table 10-2) (Video Segments 61 to 63). The supranuclear
gaze palsy is likely caused by involvement of fibers projecting to the posterior
commissure (Figure 10-5) from the
INC. Although any dorsal midbrain lesion may cause this syndrome, pineal
gland lesions (Figure 10-8) and hydrocephalus are the most common etiologies, as the pineal gland and cerebral
aqueduct are located just dorsal to the
dorsal midbrain.
Skew Deviation
Skew deviation, a common supranuclear cause of vertical diplopia, is an
acquired vertical misalignment of the
eyes due to a lesion of the supranuclear pathways connecting the vestibular apparatus to the vertical ocular
motor cranial nerve nuclei and final
common pathway for eye movements
(Table 10-2) (Brodsky et al, 2006).
Although vertical diplopia from the
skew deviation is the most prominent
symptom, the patient may exhibit a
triad of findings, including a pathologic head tilt and inappropriate
torsional rotation of both eyes, in addition to the skew deviation. This constellation is termed the ocular tilt
reaction (OTR).
In order to understand skew deviation and the OTR, a basic familiarity

with the vestibular system is necessary.

Each time the head is moved, signals
are sent via the vestibular apparatus to
the appropriate ocular motor cranial
nerve nuclei to elicit a compensatory
movement of the eyes in an equal but
opposite direction. This allows stable
gaze during head movements, such as
during ambulation. Within the inner ear,
the vestibular apparatus is comprised
of the semicircular canals and the otolith organs, the utricle and saccule. The
semicircular canals sense angular acceleration of the head, whereas the otolith organs sense linear acceleration. In
lateral-eyed animals, the otolith organs
also mediate a physiologic OTR in response to tilting of the head or whole
body from side to side that has the
following components: (1) rolling or torsional movement of the eyes, (2) vertical
deviation of the eyes, and (3) a compensatory head tilt. Although the OTR serves
an important physiologic role in lateraleyed animals, such as fish or rabbits who
need it to maintain their eyes in the horizontal plane with side-to-side movements,
it is largely unnecessary in front-eyed
animals such as humans. In pathologic
conditions when a lesion is present along

KEY POINT

A supranuclear
upgaze palsy
accompanies
other features
that variably
include pupillary
light-near
dissociation,
vergence
dysfunction,
convergenceretraction
nystagmus, and
eyelid retraction
(Collier sign)
in the dorsal
midbrain
syndrome.

157

Axial fluid-attenuated inversion recovery

MRI images demonstrate medial inferior
thalamic (right) and medial superior
midbrain (left) infarcts in the vascular distribution of the artery
of Percheron.

FIGURE 10-6

Reprinted with permission from Matheus MG, Castillo M. Imaging of acute

bilateral paramedian thalamic and mesencephalic infarcts. AJNR Am J
Neuroradiol 2003;24(10):2006.

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" SUPRANUCLEAR AND NUCLEAR

KEY POINT

Skew deviation,
a common
supranuclear
cause of vertical
diplopia, is an
acquired vertical
misalignment of
the eyes caused
by a lesion of the
supranuclear
pathways
connecting
the vestibular
apparatus to the
vertical ocular
motor cranial
nerve nuclei.

Complete bilateral supranuclear vertical gaze palsy presumably secondary

to toxoplasmosis. A, Gaze straight ahead. B, Impaired upward eye movements
on 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-attenuated
inversion recovery axial MRI) show the causative lesion in the midbrain (white arrows).

FIGURE 10-7

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

158

Noncontrasted T1-weighted sagittal (A, C ) and axial (B) MRI scans showing
hyperintense pineal gland pathology in three women who presented with
headaches 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 World
Heath Organization Classification of Tumors of the Nervous System.

FIGURE 10-8

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

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the supranuclear utricular pathways, perversions of this OTR may occur.

Skew deviation used to be considered a diagnosis of exclusion that was
not localizable beyond a lesion somewhere in the posterior fossa. Much has
been learned about skew deviation in
the recent past; it is now known that
the skew deviation does have localizing
value and that careful examination can
reliably identify a skew deviation. The
direction of the head tilt and torsional
rotational movement of the eyes is an
extremely important feature in accurate diagnosis. With the OTR, the head
and the superior poles of both eyes rotate toward the lower eye (Figures 10-9
and 10-10).
Neural signals from one utricle project to the ipsilateral vestibular nuclei
and then decussate within the pons
and ascend within the medial longitudinal fasciculus (MLF) (see section on
internuclear ophthalmoplegia [INO] for
details regarding the anatomy and clinical appearance of lesions of the MLF).
A lesion anywhere along this pathway
may result in a skew deviation and
OTR (Figure 10-9). In addition, there
are many interconnecting pathways
between the vestibular system and the
cerebellum; thus, cerebellar lesions may
also cause skew deviation. In the brainstem, with lesions at or below the level
of the decussation, the eye on the side
of the lesion will be the lower eye
(Brandt and Dieterich, 1994). With lesions above the level of the pontine
decussation, the eye on the side of the
lesion will be the higher eye (ipsilesional hypertropia). The presence of
these ascending utricular pathways
within the MLF makes skew deviation
a common finding in combination with
an INO (see section on INO for detailed description of the clinical appearance of an INO) (Case 10-1) (Video
Segment 64) (Frohman et al, 2008).
The vertical ocular misalignment with
a skew deviation may be comitant (the

same size in all directions of gaze; eg,

3-prism diopter right hypertropia in all
positions of gaze) or incomitant (variable
in size with gaze directional changes;
eg, 3-prism diopter hypertropia in right
gaze converting to 3-prism diopter left
hypertropia in left gaze). Alternation of
which eye is the higher eye with different gaze positions is also sometimes
seen, with a distinctive and peculiar syndrome of alternating skew on lateral gaze
consisting of a right hypertropia (right
eye higher) on right gaze, and a left
hypertropia (left eye higher) on left gaze.
From a practical standpoint, bedside neurologic examination with an

KEY POINT

Neural signals
from one utricle
project to the
ipsilateral
vestibular 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.

159
Pathways from the otoliths and vertical
semicircular canals to the oculomotor
nuclei and supranuclear vertical gaze
control centers (riMLF and INC). Note the decussation of these
pathways at the level of the pons. The ocular tilt reaction is
depicted schematically on the right in relation to the level of
the lesion. Note that with lesions below the decussation, the
eye contralateral to the lesion is the higher eye, and with
lesions above the decussation the eye ipsilateral to the lesion is
the higher eye.
riMLF = rostral interstitial medial longitudinal fasciculus;
INC = interstitial nucleus of Cajal; III = oculomotor nucleus;
IV = trochlear nucleus; VI = abducens nucleus; VIII = vestibular
nuclei; Vim = ventralis intermedius; Vce = ventral caudalis
externus.

FIGURE 10-9

Reprinted with permission from Brandt T, Dieterich M. Vestibular syndromes

in the roll plane: topographic diagnosis from brainstem to cortex. Ann
Neurol 1994;36(3):337347. Copyright # 1994, John Wiley & Sons, Inc.

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" SUPRANUCLEAR AND NUCLEAR

KEY POINTS

160

The vertical
ocular
misalignment
with a skew
deviation may
be comitant or
incomitant.
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.
The MLF
originates in the
pons 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.

Fundus photographs showing the torsional movements of the eyes in a

patient with a skew deviation and ocular tilt reaction. Normally, the foveal
region of the eye is at the same horizontal level as the optic disc. In the right
eye fundus photograph (OD, left side of figure), the eye is intorted (upper pole of the eye rotated
in 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, right side of figure), the eye is
extorted (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 fundus
photos and the torsional movements in them correspond to the lateralization of the pathways
depicted in Figure 10-8 and in the patient in Case 10-1. In other words, this represents the
torsional directions of the eyes with a lesion in the left medulla below the level of otolith
pathway decussation or a lesion in the right pons or midbrain above the level of otolith
pathway decussation.

FIGURE 10-10

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

undilated fundus makes it difficult to

detect torsional rotation of the fundus,
although this can be measured with
Maddox rods or dilated fundus photography. Skew deviation should be
considered when a vertical ocular misalignment does not conform to the pattern expected for a trochlear (cranial
nerve IV) palsy (and extraocular muscle
or neuromuscular junction pathophysiologies can be ruled out). In other
words, skew deviation rather than
trochlear palsy is suspected when the
vertical diplopia and ocular misalignment are not worsened by downgaze,
gaze in the direction contralateral to the
side with the higher eye, and upon
ipsidirectional head tilt (eg, a right
trochlear nerve palsy produces a right
hypertropia, worse on left gaze, left
and downgaze, and right head tilt).
Horizontal Saccadic Gaze Palsy
Brainstem control centers for horizontal
eye movements reside primarily in the

pons. For horizontal saccades, the saccadic burst neurons are located in the
paramedian pontine reticular formation
(PPRF) just rostral to the abducens (cranial nerve VI) nucleus (Figure 10-5).
Lesions of these burst neurons result in
slowed or absent horizontal saccades
ipsilateral to the lesion (eg, a right
PPRF lesion affecting the right saccadic
burst neurons will impair or abolish
saccades to the right) (Table 10-2).
Acute lesions may deviate the eyes in
the contralateral direction. Bilateral lesions result in absent horizontal gaze
or a selective loss of horizontal saccades. Lesions of the PPRF are most
likely to result in binocular horizontal
diplopia when they are acute in onset,
such as with infarction or acute demyelination; however, such lesions often
affect the eyes symmetrically and thus
do not cause diplopia. As stated earlier, the MLF originates in the pons
and decussates before ascending to
the midbrain; a unilateral pontine

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Case 10-1
A 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 be
hypertensive, 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 impaired
adduction of the right eye (Figure 10-11B) and abducting nystagmus of the left eye characteristic
for a right INO (Video Segment 64). An accompanying outward deviation (exotropia) of the eyes was
present (Figure 10-11C) (Video Segment 64).
In addition, there was a large vertical
misalignment of the eyes with the right eye
higher than the left eye (right hypertropia)
(Figure 10-11C) (Video Segment 64). This
vertical misalignment was the same size
in all gaze directions (comitant).
MRI of the brain with diffusion-weighted
imaging and gadolinium was unremarkable
other than for chronic small vessel
ischemic changes. No acute brainstem
lesions were seen. The patient was
diagnosed with an acute brainstem
infarction and started on low-dose
aspirin following a negative evaluation for
embolic stroke.
Comment. The patients ocular motility
findings are a right INO in combination
with a skew deviation. The lesion based
on the examination findings is known
to be the right MLF, somewhere between
the left abducens nucleus and the right
oculomotor nucleus (see section on
INO for more details). Because ascending
pathways from the utricle within the
vestibular apparatus travel within the
MLF, skew deviation is often found in
combination with an INO. As expected
for a skew deviation at this level (above
the pontine decussation [Figure 10-9]),
the right eye (ipsilateral to the right
MLF lesion) is higher than the left eye.
Despite the absence of an identifiable
acute pontine or midbrain lesion on MRI,
the diagnosis is acute infarction of the
MLF that is likely due to small vessel
disease. The patients age and her newly
identified vascular risk factors support
this diagnosis. If she were in her twenties FIGURE 10-11
without vascular risk factors, demyelination
would be the most likely etiology. MRI is frequently negative with small vessel infarctions
causing isolated ocular motility problems. The prognosis for spontaneous visual recovery is
excellent in this setting.

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161

" SUPRANUCLEAR AND NUCLEAR

KEY POINTS

162

Inward deviation
of the eyes
(esotropia)
and binocular
horizontal
diplopia of
supranuclear
origin may
occur with
thalamic,
midbrain,
or cerebellar
lesions.
An oculomotor
nuclear lesion
may result in
bilateral ptosis
from bilateral
levator
palpebrae
superioris
involvement
if the single
midline nucleus
is involved.
Contralateral
or bilateral
ocular elevation
deficits may
also occur due
to the crossed
innervation of
the superior
rectus
subnucleus.

lesion involving the PPRF and the

adjacent decussating MLF produces
the one-and-a-half syndrome (see section on INO for details regarding the
anatomy and clinical appearance of
lesions of the MLF). The PPRF lesion
causes an ipsilateral horizontal gaze
palsy, and the MLF lesion causes an ipsilateral INO with impaired ipsilateral
adduction; eg, with a right pontine lesion affecting the right PPRF and the
right MLF that originated from the left
pons and decussated already, the patient will have absent right horizontal
gaze (no abduction of the right eye or
adduction of the left eye) from PPRF
involvement and impaired adduction of
the right eye from MLF involvement. The
only remaining horizontal eye movement is abduction of the left eye; thus
one and a half of the horizontal eye
movements are impaired. The one-anda-half syndrome may also occur from a
lesion affecting the abducens (cranial
nerve VI) nucleus and the MLF. It is
further discussed in the section on nuclear causes of diplopia with a figure
and video example.
Supranuclear Esotropia
Inward deviation of the eyes (esotropia)
and binocular horizontal diplopia of supranuclear origin may occur with thalamic, midbrain, or cerebellar lesions
(Table 10-2) (Video Segment 61)
(Gomez et al, 1988; Pullicino et al,
2000). As this mimics an abducens (cranial nerve VI) lesion, it is sometimes
termed pseudoabducens palsy. This phenomenon is poorly understood, as are
the brainstem supranuclear pathways
mediating convergence of the eyes;
however, thalamic esotropia and midbrain pseudoabducens palsy are generally attributed to excessive convergence
tone. This supranuclear esotropia may
be accompanied by unilateral or bilateral
limitation of abduction, usually affecting
some eye movements (such as saccades
or smooth pursuit) and sparing others

(such as the vestibulo-ocular reflex), as

is characteristic of supranuclear ocular
motility deficits.
NUCLEAR CAUSES OF
BINOCULAR DIPLOPIA
Lesions of the ocular motor cranial
nerve nuclei are rare and have a different clinical appearance than their
respective cranial nerve lesions when
involving the oculomotor (cranial nerve
III) or abducens (cranial nerve VI) nuclei. Brainstem lesions may be caused
by any etiology; they are often ischemic or demyelinating but may also
be due to hemorrhage, infection, neoplasm, or necrosis such as in Wernicke
encephalopathy. As with skew deviation, when the ocular nuclear deficit
occurs in isolation, it may be radiographically silent.
Oculomotor (Cranial Nerve III)
Nuclei
Paired oculomotor nuclei are located in
the dorsal midbrain at the level of the
superior colliculus (Figure 10-5). Each
nucleus contains inferior and medial
rectus and inferior oblique subnuclei
providing ipsilateral innervation, a superior rectus subnucleus providing innervation to the contralateral superior
rectus, and an Edinger-Westphal nucleus providing parasympathetic preganglionic output to the iris sphincter
and ciliary muscles (Figure 10-12).
A single midline caudal subnucleus
provides innervation to both levator
palpebrae superioris muscles. An oculomotor nuclear lesion may result in
bilateral ptosis from bilateral levator
palpebrae superioris involvement if the
single midline nucleus is involved. Contralateral or bilateral ocular elevation deficits may also occur (Case 10-2). The
contralateral elevation deficit is due to
the crossed innervation of the superior
rectus subnucleus. If this and the fibers that originated in the contralateral superior rectus subnucleus and

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decussated already are involved, bilateral elevation deficits occur. Ipsilateral

weakness of the medial or inferior recti
and/or the inferior oblique muscles
and ipsilateral pupillary enlargement
may result from a nuclear lesion. A very
small focal nuclear lesion may cause
isolated bilateral ptosis or isolated weakness of a single muscle (Kwon et al,
2003; Rabadi and Beltmann, 2005; Saeki
et al, 2000).
Trochlear (Cranial Nerve IV)
Nuclei
Paired trochlear nuclei are located in
the dorsal midbrain just below the level
of the inferior colliculus (Figure 10-5).
Differentiating a trochlear nuclear lesion from a trochlear nerve lesion is
clinically difficult, given the identical
appearance of the superior oblique
weakness. The affected eye is elevated,
and the patient experiences vertical
diplopia worst in downgaze with the
eye adducted. A resting head tilt in the
direction away from the affected eye
and chin-down head position are common. This minimizes diplopia by placing the affected eye in an extorted
positionin other words, in the opposite direction of action of the superior
oblique, which is an intorter of the eye.
A trochlear nuclear lesion is identified
when the weak superior oblique muscle is contralateral to the lesioned nucleus (Figure 10-15), as the trochlear
nerve fascicles decussate immediately
after their dorsal exit from the midbrain.
In addition, other brainstem signs, such
as a Horner syndrome ipsilateral to the
brainstem lesion and contralateral to
the superior oblique weakness, may
also accompany a trochlear nuclear
lesion.
Abducens (Cranial Nerve VI)
Nuclei
Paired abducens nuclei are located in
the caudal dorsal pons (Figure 10-5).

The fascicle of the facial nerve wraps

around the nucleus, creating the facial
genu, a protrusion along the dorsal surface of the pons. The abducens nucleus
contains two neuronal populations: (1)
motor neurons that form the abducens
nerve for lateral rectus innervation and
(2) interneurons that decussate immediately at the level of the pons and then
ascend in the contralateral MLF to the
contralateral medial rectus. The MLF
facilitates horizontal conjugate gaze in
the direction ipsilateral to the abducens
nucleus of origin. In contrast to an
abducens nerve palsy, which causes unilateral abduction weakness, an abducens
nuclear palsy results in an ipsilateral
conjugate horizontal gaze palsy. Ipsilateral lower motor neuron facial weakness is nearly always present, although

KEY POINT

A trochlear
nuclear lesion
is identified
when the
weak superior
oblique muscle
is contralateral
to the lesioned
nucleus, as the
trochlear
nerve fascicles
decussate
immediately
after their
dorsal exit from
the midbrain.

163

The anatomy of the oculomotor nucleus

in the rhesus monkey. Note the single
central caudal nucleus for bilateral levator
palpebrae superioris innervation and the contralateral
subnucleus for superior rectus innervation.
CCN = central caudal nucleus; DN = dorsal nucleus;
IC = intermediate nucleus; IV = trochlear nucleus; VN = ventral
nucleus; R = right; L = left.

FIGURE 10-12

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

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" SUPRANUCLEAR AND NUCLEAR

Case 10-2

164

A 61-year-old woman with a history of epiglottic cancer and hypertension had binocular
vertical diplopia upon awakening from an uneventful tracheostomy and direct laryngoscopy
with biopsy for laryngeal stenosis and chronic hoarseness. Examination revealed impaired
elevation of the right eye, depression of the left eye, adduction of the left eye, and elevation
of the adducted left eye (Figure 10-13). She also had very subtle impairment of elevation
of the left eye in an abducted position
(not seen well in the motility
photographs). MRI of the brain revealed
increased signal on fluid-attenuated
inversion recovery images suggestive of
an acute infarction affecting the rostral
midbrain (Figure 10-14A and B).
Comment. The patients ocular
motility examination revealed bilateral
abnormalities, with the majority of
findings in the left eye, in combination
with isolated elevation impairment of the
right eye. This combination should raise
suspicion for a nuclear oculomotor palsy,
especially with postoperative diplopia
of Dr M. Tariq Bhatti, Duke Eye Center,
FIGURE 10-13 Courtesy
Durham, NC.
when an infarct is the most likely clinical
scenario. Myasthenia gravis, which can
mimic any ocular motility pattern and be acutely unmasked by surgical anesthetics, would be the
most important disease in the pre-MRI differential diagnosis. The specific muscles that are weak in
this 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 whose
innervation
originates
in the left
oculomotor
nucleus. Mild
weakness
of the left
superior rectus
(as evidenced
by mild
weakness of
the abducted
left eye that
was not well
visualized
on the
photographs)
FIGURE 10-14 Courtesy of Dr M. Tariq Bhatti, Duke Eye Center, Durham, NC.
suggests
involvement of
the superior rectus fibers from the right oculomotor superior rectus subnucleus. These crossing
fibers pass very close to the contralateral subnucleus and can often be involved in an oculomotor
nuclear palsy.
Case courtesy of Dr M. Tariq Bhatti, Duke Eye Center, Durham, NC.

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KEY POINT

In contrast to
an abducens
nerve palsy,
which causes
unilateral
abduction
weakness,
an abducens
nuclear palsy
results in an
ipsilateral
conjugate
horizontal
gaze palsy.

A nuclear trochlear palsy in a 28-year-old patient with binocular vertical

diplopia due to weakness of the right superior oblique muscle with a lesion
in 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 showing
the hyperintense lesion (white arrow). B, Gadolinium-enhanced axial MRI showing enhancement
of the lesion (white arrow).

FIGURE 10-15

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

a few cases lacking this have been reported (Miller et al, 2002).
A unilateral pontine lesion involving the abducens nucleus and the MLF

that originated in the contralateral pons

and already decussated may cause the
one-and-a-half syndrome (see section on
INO for details regarding the anatomy

165

Right one-and-a-half-syndrome. A, The resting position of the eyes.

B, Attempts to elicit rightward eye movements disclose a complete right
horizontal 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 the
left eye from a right internuclear ophthalmoplegia. D, Axial CT scan at the level of the pons
reveals a right dorsal pontine hyperdensity due to hemorrhage.

FIGURE 10-16

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" SUPRANUCLEAR AND NUCLEAR

and clinical appearance of lesions of

the MLF). The abducens nuclear lesion
causes an ipsilateral horizontal gaze
palsy, and the MLF lesion causes an
ipsilateral INO with impaired ipsilateral adduction. An example of lateralization follows: With a right pontine
lesion affecting the right abducens
nucleus and the right MLF that originated from the left pons and decussated already, the patient will
have absent right horizontal gaze (no
abduction of the right eye or adduction of the left eye) from abducens
nuclear involvement and impaired

adduction of the right eye from MLF

involvement. The only remaining horizontal eye movement is abduction of
the left eye; thus one and a half of the
horizontal eye movements are impaired
(Figure 10-16) (Video Segment 65).
An exotropia (outward deviation of the
eyes) is often present. This exotropia
is sometimes called paralytic pontine
exotropia and will cause binocular horizontal diplopia (Sharpe et al, 1974).
One-and-a-half syndrome also occurs
from a lesion affecting the PPRF (see
the section on supranuclear horizontal
saccadic 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 Psychiatry
1945;54:323338.
Brandt T, Dieterich M. Vestibular syndromes in the roll plane: topographic diagnosis
from brainstem to cortex. Ann Neurol 1994;36(3):337347.
Brodsky MC, Donahue SP, Vaphiades M, Brandt T. Skew deviation revisited. Surv
Ophthalmol 2006;51(2):105128.
Buttner U, Buttner-Ennever JA. Present concepts of oculomotor organization. Prog
Brain Res 2006;151:142.
Choi KD, Jung DS, Kim JS. Specificity of peering at the tip of the nose for a diagnosis
of thalamic hemorrhage. Arch Neurol 2004;61(3):417422.

166

Frohman TC, Galetta S, Fox R, et al. Pearls and oy-sters: the medial longitudinal fasciculus
in 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 the
rostral 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 contralateral
midbrain infarction. Arch Neurol 2003;60(11):16331635.
Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed. New York: Oxford University
Press, 2006.

Continuum Lifelong Learning Neurol 2009;15(4)

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

Matheus MG, Castillo M. Imaging of acute bilateral paramedian thalamic and

mesencephalic 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 burst
generator: I. medium-lead burst neurons with upward on-directions. J Neurophysiol
1991a;65(2):203217.
Moschovakis AK, Scudder CA, Highstein SM, Warren JD. Structure of the primate
oculomotor burst generator: II. medium-lead burst neurons with downward
on-directions. J Neurophysiol 1991b;65(2):218229.
Onofrj M, Iacono D, Luciano AL, et al. Clinically evidenced unilateral dissociation
of 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 for
the 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 rectus
nuclear palsy. Am J Med 2005;118(8):836837.
Saeki N, Yamaura A, Sunami K. Bilateral ptosis with pupil sparing because of a discrete
midbrain lesion: magnetic resonance imaging evidence of topographic arrangement
within the oculomotor nerve. J Neuroophthamol 2000;20(2):130134.
Sharpe JA, Rosenberg MA, Hoyt WF, Daroff RB. Paralytic pontine exotropia: a sign of
acute unilateral pontine gaze palsy and internuclear ophthalmoplegia. Neurology
1974;24(11):10761081.

SUGGESTED ADDITONAL RESOURCE

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

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167