Journal of the Neurological Sciences 417 (2020) 117055

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Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Review Article

Approach to patient with diplopia T

a,b,⁎
Edward Margolin
a
University of Toronto, Faculty of Medicine, Department of Ophthalmology and Vision Sciences, Toronto, Ontario, Canada
b
University of Toronto, Department of Medicine (Division of Neurology), Toronto, Ontario, Canada

A B S T R A C T

This article presents an overview of the most important points a neurologist must remember when dealing with a patient complaining of diplopia. Patients with
monocular diplopia and those with full ocular motility and comitant misalignment should be referred to an ophthalmologist and do not require further testing.
Patients with recent onset of binocular diplopia who have associated “brainstem” symptoms should have an urgent brain MRI. All patients with 3rd cranial nerve
palsy require urgent brain CTA to rule out compressive aneurysmal lesion. Management of patients over 50 years of age with microvascular risk factors with new
onset of 6th nerve palsy is controversial: some image these patients at presentation while others choose a short period of observation as most of these patients would
have a microvascular etiology for the 6th nerve palsy which should improve spontaneous in 2–3 months. All others with 6th nerve palsy require brain MRI with
contrast. Patients with 4th palsy with hyperdeviation that worsens in downgaze should have an MRI with contrast and all others referred to an ophthalmologist. If
there is more than one cranial nerve palsy, urgent neuroimaging should be performed with attention to cavernous sinus and superior orbital fissure. Ocular
myasthenia should be suspected in patients with eye misalignment that does not fit a pattern for any cranial nerve palsy. Orbital pathology (most commonly thyroid
eye disease) can result in restriction of ocular motility and has specific clinical signs associated with it.

1. Introduction
Diplopia is a common presenting complaint in an ambulatory set-
ting and in an emergency department, with one recent study reporting
805,000 ambulatory and 50,000 emergency room visits in the United
States yearly with the chief complaint of diplopia [1]. While most pa-
tients with diplopia will have benign underlying causes, the same study
found that potentially life-threatening etiologies were present in 16% of
patients [1]. Often it is a neurologist who is consulted to evaluate a
patient with diplopia, however, many neurologists lack a systematic
approach in evaluating a diplopic patient. This article presents a clear
algorithm that practicing neurologists can use every time they en-
counter this clinical complaint. This approach is summarized in Fig. 1
and detailed below.
Terminology-wise, the word “ductions” should be used when de-
scribing extraocular motility in a patient with diplopia (such as ab-
duction, adduction, supra- and inferoductions). It is also useful to
quantify the motility deficit in percentages using 100% motility from
the midline to the desired end-point as a guideline. Whenever the word
“gaze” is used, it implies involvement of supranuclear pathways that
originate in the frontal eye fields, where voluntary control of eye
movements is located, traveling from there through the thalamus to the
gaze centers in the midbrain for vertical gaze and in the pons for hor-
izontal gaze and finally reaching the nuclei of the 3rd, 4th and 6th
oculomotor nerves in the midbrain and the pons. Patients with supra-
nuclear disoders of eye movements typically do not experience diplopia
thus instead of stating “there was an upgaze deficit”, a statement de-
scribing ductions (“there was 50% supraduction in the right eye”)
should be used.
2. Approach
A summary of important questions that should be asked on history is
presented in Table 1. One study reported that by performing accurate
history and examination, the etiology of diplopia was elucidated in 70%
of patients and only 5% required urgent management [2]. As a rule,
neurologists tend to over-order tests and investigations for patients with
diplopia and one of the purposes of this review is to help clinicians to
identify cases where no further testing is needed.
When evaluating a diplopic patient, first and foremost one has to
determine whether diplopia is monocular or binocular. Skipping this
step will invariably lead to unnecessary investigations. Diplopia is
monocular if it does not resolve with closing one eye (thus is present
with monocular viewing) and it almost invariably indicates an optical
issue thus a non-urgent ophthalmology referral is the correct disposi-
tion for these patients. Monocular diplopia is usually secondary to
cataracts, uncorrected astigmatism, keratoconus (thinning of the cen-
tral cornea resulting in steepening of the remaining corneal surface and

⁎
University of Toronto, Dept of Ophthalmology and Visual Sciences, Dept of Medicine, Division of Neurology, Chief of Service, Neuro-Ophthalmology, 801
Eglinton Ave West, Suite 301, Toronto, ON M5N 1E3, Canada.
E-mail address: Edward.margolin@uhn.ca.

https://doi.org/10.1016/j.jns.2020.117055
Received 27 April 2020; Received in revised form 19 July 2020; Accepted 21 July 2020
Available online 05 August 2020
0022-510X/ © 2020 Elsevier B.V. All rights reserved.
E. Margolin Journal of the Neurological Sciences 417 (2020) 117055

Fig. 1.

Table 1 rarely monocular diplopia can be secondary to the structural disorders

Important questions to be asked on history. of the cerebral cortex and most of the time the patient reports seeing
1. Does double vision resolves when either eye? multiple rather than two images [3]. It is termed cerebral polyopia and
2. Is the onset recent? Is diplopia constant or intermittent? usually arises from the lesions in the occipital lobe and will often pre-
3. Are there are any associated neurological (“brainstem) symptoms? sent with associated hemianopic visual field defect. It can also accom-
4. Is it horizontal, vertical or oblique? pany migranous headaches and is present with monocular viewing in
5. Is there a history of childhood strabismus?
each eye [3].
6. Fatiguability and variability in symptomatology?
7. Associated symptoms (ptosis, abnormal lid movement) The next most important step is to determine that there are no ac-
8. Are there symptoms of increased intracranial pressure? companying “brainstem” symptoms, as diplopia can be the main com-
9. Does double vision resolves when either eye? plaint in patients with strokes involving diencephalon or brainstem
10. Is the onset recent? Is diplopia constant or intermittent?
which involve either the nuclei or fascicles of the IIIrd, IVth or VIth
11. Are there are any associated neurological (“brainstem) symptoms?
12. Is it horizontal, vertical or oblique? cranial nerve, medial longitudinal fasciculus or vertibulo-ocular path-
13. Is there a history of childhood strabismus? ways. In any patient complaining of sudden onset of diplopia that is
14. Fatiguability and variability in symptomatology? accompanied by vertigo, crossed sensory or motor symptoms, im-
15. Associated symptoms (ptosis, abnormal lid movement) balance, ataxia, dizziness, sense of impending doom and other “brain-
16. Are there symptoms of increased intracranial pressure?
stem” symptoms, an emergent brain MRI with diffusion-weighted and
17. Are there symptoms of giant cell arterities (in patients over 50 years of age)?
susceptibility-weighted sequences should be performed in order to de-
tect acute ischemic and hemorrhagic strokes. Areas of brainstem
irregular astigmatism), other corneal irregularity, or is functional (non- ischemia might be very subtle and communication with a neuro-radi-
organic) in nature. In patients with optical causes of monocular di- ologist is crucial in order to alert them to clinician's area of suspected
plopia, diplopia will disappear when they are looking through a pin- localization. In addition to ischemia of the brainstem, demyelinating
hole. If monocular diplopia does not disappear when looking through a lesions can cause similar symptoms but should be distinguishable on
pinhole and a patient otherwise has a normal exam, one would have to imaging from acute strokes.
assume that their complaints are functional in nature. Exceedingly After one has ascertained that diplopia is not accompanied by any

2
E. Margolin
Table 2
Differential diagnosis of vertical diplopia.
1. 3rd nerve palsy
2. 4th nerve palsy
3. Orbital process (thyroid eye disease, Brown's syndrome)
4. Myasthenia gravis
5. Skew deviation
brainstem symptoms, knowledge of whether the diplopia is purely
horizontal or purely vertical can help in shortening the differential di-
agnosis: abduction and, rarely, adduction deficits are usually re-
sponsible for producing purely horizontal diplopia and there are only 5
main entities that can produce vertical diplopia which are summarized
in Table 2.
All patients with diplopia should be asked about the presence of
symptoms of myasthenia (whether their symptoms worsen with fatigue
and vary throughout the day, if there is presence of neck weakness,
dyspnea or dysphagia). Symptoms of increased intracranial pressure
should also be specifically reviewed and all patients over the age of 50
should be asked about the symptoms of giant cell arteritis (GCA) as
intermittent diplopia can be a presenting sign of GCA in up to 20% of
cases [4].
Next a detailed examination of extra-ocular motility should be
performed. The examiner should slowly move a small target, such as
their finger, in front the patient's face and try to identify the deficits in
ocular motility. It is best to observe each eye separately as it will allow
for recognition of small deficits. If deficits in a particular “gaze” are
noticed, it is important to re-check motility of each eye separately in
order to differentiate between the true “gaze” disturbance which im-
plies a supranuclear problem, and duction deficits which imply deficits
anywhere from the brainstem nucleus of a cranial nerve to the neuro-
muscular junction. After extraocular motility data has been collected,
an examiner needs to figure out whether one cranial nerve palsy can
explain motility deficits. This can be easy if motility deficits are obvious
and challenging if they are subtle.
While checking extraocular motility, it is very important to pay
attention to any associated signs such as abnormalities in lid position
and motility and presence of ptosis and proptosis. Presence of lid lag
(upper eyelid lagging behind the limbus on inferoduction) or lid re-
traction (upper eyelid is located above the limbus with the sclera visible
between the lid and the corneal limbus) are very specific signs for the
presence of thyroid eye disease. Presence of proptosis suggests an or-
bital or retro-orbital process such as thyroid eye disease or retrobulbar
mass. Fatigable ptosis is seen in myasthenia and movement of the lid in
the opposite direction from the movement of the globe (i.e. upper lid
goes up when the eye is moving down) is seen in aberrant regeneration
of the third cranial nerve.
Next, an alternate-cover testing to assess eye misalignment should
be performed by quickly moving the occluder from one eye to another
and observing the movement of the uncovered eye. The main goal of
this test is to determine whether the deviation is comitant (remains the
same in all positions of gaze) or does it increase in specific direction.
For instance, an esodeviation which increases when looking to the right
and decreases when looking to the left indicates weakness of the right
lateral rectus muscle. The technique for performing alternate cover
testing can be learned by viewing the on-line tutorials such as this one:
https://www.youtube.com/watch?v=Wf8DGL7WE8U.
Identifying comitant horizontal eye misalignment will avoid many
unnecessary investigations, spare the patient anxiety and produce
savings for the health care system. In comitant misalignments, the eye
deviation will remains unchanged in all positions of gaze. In the pre-
sence of cranial nerve palsy the deviation will invariably be worse in
the direction of action of de-innervated extraocular muscle. Patients
with comitant misalignments should be referred to an ophthalmologist
as they most likely have decompensated strabismus and not a
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Journal of the Neurological Sciences 417 (2020) 117055
Table 3
Differential diagnosis for patient with 6th nerve palsy.
1. Microischemic.
2. Nuclear (presents with gaze palsy, almost always along with 7th nerve
dysfunction): demyelinating, ischemic, neoplastic.
3. Fascicular (often with contralateral hemiparesis)-same etiologies as nuclear.
4. Cisternal portion/petrous portion (often with involvement of 8th, 7th or 5th
nerves): neoplastic, inflammatory, compression by dolichoectatic vessels.
5. Cavernous sinus portion (often along with 3rd, 4th, V1 and V2): inflammatory
(sarcoid, IgG4 disease, idiopathic), infectious, neoplastic (direct extenstion from
skull base structures or metastatic), vascular (carotid-cavernous fistulas, internal
carotid aneurysms).
6. Superior orbital fissure (same etiologies as cavernous portion)-often associated
with proptosis and decreased vision.
7. Disorders of neuromuscular junction.
8. Non-localizing (secondary to high or low intracranial pressure).
9. Traumatic.
neurological deficit, thus no further testing is needed in these patients.
Decompensated strabismus is common and can present with inter-
mittent diplopia and could have fairly sudden onset.
One special circumstance is the so-called divergence insufficiency,
when a patient has comitant esotropia at distance but not ocular mis-
alignment at near. This is a distinct cohort as it has been postulated that
a divergence center might exist somewhere in the brainstem and might
be lesioned in these patients. A large well-conducted study has con-
cluded that patients with divergence insufficiency and no associated
neurological symptoms do not require further investigations, however,
neuro-imaging should be considered if there are other neurological
signs of symptoms [5].
What to do if:
A. Isolated abduction deficit is discovered in one eye?
Table 3 summarizes a differential diagnosis for a patient with an
isolated abduction deficit. An abduction deficit in one eye can be sec-
ondary to a restrictive process (such as thyroid orbitopathy causing
enlargement of medial rectus muscle and a corresponding abduction
deficit), paralytic process (such as any pathological process involving
6th cranial nerve), or be non-localizing when it is secondary to in-
creased intra-cranial pressure (which in most cases is accompanied by
papilledema thus a fundus exam is important in everyone with an ab-
duction deficit).
A restrictive process causing an abduction deficit is most commonly
due to thyroid eye disease causing enlargement of the extraocular
muscles or be secondary to trauma causing impingement of one of the
extraocular muscles. In patients with the 6th nerve palsy the most likely
etiology is microischemia of the nerve if the patient is older than
50 years of age [6]. In a younger adult, processes such as brainstem
demyelination and compression of the 6th nerve by a neoplasm are
more likely. In a child with the 6th nerve palsy, urgent neuro-imaging is
essential to rule out a compressive lesion as up to 50% of 6th nerve
palsies in children are secondary to tumors [7]. Management of patients
over 50 years of age with known vasculopathic risk factors and an
isolated 6th cranial nerve palsy is somewhat controversial. One recent
study reported 10% incidence of non-microischemic nerve palsies in
this group of patients, however, on detailed analysis of their data, there
were only two patients with 6th nerve palsy who had a causative lesion
identified on an MRI: one patient with petroclival meningioma and one
with cavernous sinus lymphoma thus the difference in the outcome if
neuro-imaging was delayed for 2–3 months is debatable [8]. In another
study that evaluated the role of neuro-imaging in patients over the age
of 50 with acute ocular mononeuropathies, out of 52 patients with
isolated 6th nerve palsy only 1 had a causative lesion identified on MRI
(isolated pontine hemorrhage that spontaneously resolved) [9]. The
authors concluded that it might not be medically necessary to perform
neuro-imaging on all patients with isolated ocular motor palsies [9].
E. Margolin
There are several downsides in obtaining an urgent MRI which include
its availability, cost, inconvenience to the patient and potential com-
plications from exposure to contrast agent. Thus, in patients who are
over 50 years of age with microvascular risk factors who present with
an isolated 6th nerve palsy and no history of malignancy, waiting for
2–3 months for spontaneous resolution of symptoms before proceeding
with neuro-imaging is likely reasonable. If no improvement is seen after
2–3 months, brain MRI with contrast should be performed. All patients
under 50 years of age with an isolated 6th nerve palsy should have non-
urgent head MRI performed focused on the brainstem as well as fol-
lowing the course of the 6th nerve through the petrous bone, along the
clivus and into the cavernous sinus and then through superior orbital
fissure into the orbit. Balanced steady-state gradient echo sequence
allows for clear recognition of the cranial nerves' course at the skull
base and can help in localizing small lesions affecting the 6th nerve.
Several associated signs are useful in localization when assessing
patients with the 6th nerve palsy. If there is a lesion in the pons af-
fecting 6th nerve nucleus or proximal fascicle, there will almost in-
variably be varying degree of facial nerve weakness presence on the
same side, as the fascicles of the 7th nerve travel around the 6th nerve
nucleus in the pons. Presence of ipsilateral Horner's syndrome along
with the 6th nerve palsy localizes the lesion to the cavernous sinus
where the sympathetic fibers briefly join the 6th cranial nerve. Presence
of decreased vision in association with 6th nerve palsy should prompt
one to consider a lesion in the superior orbital fissure where the 6th
nerve travels close to the optic nerve. If 6th nerve palsy is not im-
proving after three months yet the neuro-imaging is interpreted as
normal, it is imperative for neuro-imaging to be repeated with contrast
and balanced steady-state gradient echo sequences and re-interpreted
as subtle skull base lesions can be easily missed if the interpreting
radiologist is not experienced in evaluating this area. Finally, one must
remember that neuro-muscular junction disorders can mimic any cra-
nial nerve palsy, however, isolated unilateral abduction deficits are not
common in patients with myasthenia.
B. Motility deficits map out to unilateral 3rd nerve palsy?
Patient with the 3rd nerve palsy would typically have varying de-
gree of ptosis and anisocoria with the eye in the down and out position.
If the eye appears orthophoric (not turning in or out), diagnosis of 3rd
nerve palsy should be questioned as any weakness of the medial rectus
muscle would result in the eye being in abducted position due to un-
opposed action of the lateral rectus. Presence of partial 6th nerve palsy
in addition to the 3rd nerve palsy should be considered in these pa-
tients.
Table 4 presents a list of entities on a differential diagnosis for a
patient with the 3rd nerve palsy. If motility deficits map out to the 3rd
cranial nerve (there is any degree of ptosis plus deficits of supra-, infra-,
Table 4
Differential Diagnosis for patient with 3rd nerve palsy.
1. Aneurysmal compression (most commonly arising from junction of P Com and
Internal Carotid arteries).
2. Microischemic
3. Nuclear (often with bilateral ptosis)
4. Fascicular (associated gait abnormalities, contralateral hemiplegia, ataxia,
tremor).
5. Cisternal lesions (infiltration by malignancies, compression by dolychoectatic
vessel, compression by neoplasms arising from surrounding structures, intrinsic
schwannoma).
6. Cavernous sinus lesions: inflammatory (sarcoid, IgG-4, idiopathic inflammatory);
neoplastic (benign, malignant, from direct extension vs metastasis), vascular
(carotid-cavernous fistula, internal carotid aneurysm), infectious (bacterial,
fungal).
7. Superior orbital fissure (same etiologies as above plus involvement of V1/V2 and
optic nerve.
8. Neuro-muscular junction disorder
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Journal of the Neurological Sciences 417 (2020) 117055
abduction or adduction with or without a larger pupil on the affected
side), urgent vascular neuro-imaging is needed for all patients to rule
out an aneurysmal cause of the 3rd palsy [10–12]. While aneurysmal
compression causes only about 6–11% of all 3rd nerve palsies, the
consequences of missing an aneurysm can be catastrophic as a ruptured
aneurysm causes 50% mortality before the patient reaches the hospital
and severe neurological impairment in 50% of survivors [13,14]. CT/
CTA of the head is readily available in most centers and should be
performed on any patient with any motility deficits, ptosis and aniso-
coria indicating involvement of the 3rd nerve. This includes patients
without anisocoria as subtle/early anisocoria can be difficult to ap-
preciate and the risks of missing an aneurysm causing 3rd nerve palsy is
greater than the risks of the CTA. CTA can identify virtually all an-
eurysmal 3rd nerve palsies but the most important variable is the ex-
pertise of the interpreting neuro-radiologist thus if in doubt re-evalua-
tion of the imaging should be performed [15]. As CTA is
contraindicated in pregnancy and patients who have decreased renal
function and can not receive intravenous contrast and in patients who
have a history of allergic reaction to the contrast. MRA should be
performed in these circumstances as it is also an excellent test to detect
practically all aneurysms that can cause a 3rd nerve palsy. Most third
nerve palsies are microischemic in nature and these will resolve in
about 2–3 months thus patients who are over 50 years of age with
vasculopathic risk factors who had a negative CT/A can be observed for
spontaneous resolution [10–12], However, it is very reasonable to ob-
tain an MRI with contrast and balanced steady-state gradient echo se-
quences protocol at the time of presentation evaluating the entire path
of the third cranial nerve including its cisternal portion to rule out non-
aneurysmal lesions along the course of the 3rd nerve. Lesions affecting
the nucleus of the third nerve in the midbrain can present with bilatetal
complete ptosis because there is only one subnucleus innervating both
levator palpebrae superioris muscles with paired subnuclei innervating
all the other muscles [10]. Lesions affecting third nerve fascicles in the
midbrain can produce multiple associated neurological deficits: con-
tralateral hemiplegia if the cortico-spinal tract is affected, ataxia if the
superior cerebellar peduncle is involved, or tremor if the red nucleus is
damaged by the lesion. In its subarachnoid/cisternal portion, the 3rd
nerve can be affected by infections, inflammatory entities or be com-
pressed by an aneurysm, surrounding dolichoectatic vessel or neo-
plasms which can be extrinsic and rarely intrinsic to the nerve (such as
3rd nerve schwannoma). After a relatively short course in the sub-
arachnoid space, 3rd nerve enters the cavernous sinus where it can be
affected by any pathological procress affecting this area (carotid ca-
vernous fistulas, internal carotid artery aneurysms, inflammatory enti-
ties, infections, and neoplasms). From the cavernous sinus the 3rd nerve
travels to the superior orbital fissure sometimes dividing into superior
(innervating levator palepebrae and superior recti muscles) and inferior
division (innervating medial, inferior and lateral rectus muscle as well
as inferior oblique). In the superior orbital fissure the 3rd nerve runs in
close proximity to the optic nerve thus patients with oculomotor dys-
function and decreased central vision should be suspected of having a
lesion in the superior orbital fissure. One peculiar motility abnormality
in patients who had a traumatic or compressive etiology of 3rd nerve
palsy is aberrant regeneration of its axons which when re-growing in-
nervate another muscle than the one they were originally destined for.
Most commonly it involves the fibers innervating the levator palpebrae
muscle being mis-directed to innervate inferior rectus muscle thus
causing elevation of the upper lid on inferoduction. All patients with
aberrant regeneration require head MRI with contrast to rule out a
compressive lesion affecting the 3rd cranial nerve.
C. If there is vertical movement of the eye on cover-uncover testing?
Patients with vertical diplopia can broadly speaking have only one
of the following processes responsible for their symptoms: 3rd nerve
palsy, 4th nerve palsy, orbital process (such as thyroid orbitopathy),
E. Margolin
skew deviation of myasthenia gravis (Table 2). Figuring out whether
the motility deficits map out to the third nerve can be challenging if the
deficits are partial and presence of ptosis and potentially an anisocoria
can be helpful signs in making the diagnosis. As it is one of the most
important “not to miss” entity when evaluating a diplopic patient, if its
involvement is suspected, urgent head CTA should be performed.
4th nerve palsies are very common but diagnosing it requires a
clinician to perform an alternate cover testing and to be able to judge
whether the hypertropia worsens or improves when looking to the right
or the left and on head being tilted to the right or the left side. If hy-
pertropia worsens in contralateral gaze and ipsilateral head tilt, it
confirms with the so-called 3-step test and the diagnosis of 4th nerve
palsy can be made. While not difficult if deviation is larger, it can be
quite challenging if the ocular misalignment is small and generally re-
quires one to spend at least some time with a knowledgeable observer
who can demonstrate how to perform the 3-step test. Once the diag-
nosis of 4th nerve palsy is established, the next step is to check whether
hypertropia is worse on up- or downgaze. If it worsens on upgaze, it is
almost always congenital decompensated in nature and does not re-
quire further investigations. If it is worse on downgaze, it is acquired
and requires and MRI of the brain with contrast to rule out ominous
etiologies (which are generally speaking very uncommon in patients
with an isolated fourth nerve palsy) [16].
In order to diagnose thyroid eye disease, the position of the lid has
to be observed when performing extraocular motility testing: the
findings of lid lag (upper lid lags behind the limbus) when slowly
looking down and of lid retraction (lid is above the limbus causing
creating sclera to be visible between the limbus and the lid) in primary
position of gaze are pathognomonic for thyroid eye disease. Both can be
discovered only when testing extraocular motility slowly in each eye.
Proptosis is another very common finding in thyroid eye disease. CT of
the orbits is the best baseline test to evaluate the size of the extraocular
muscles (enlarged in thyroid eye disease) and orbital apex (to rule out
optic nerve compression by the enlarged muscles at its most vulnerable
location).
Skew deviation broadly speaking is a vertical eye deviation sec-
ondary to a lesion somewhere along the vestibular-ocular pathway
which is responsible for keeping the eye position in the same plane
during head rotation. It usually does not conform to three-step test and
can be either comitant or incomitant. [17,18]. It is often accompanied
by other neurological signs, most often nystagmus, gaze paresis, ataxia,
saccadic pursuit and internuclear ophthalmoplegia [17,18]. While the
amount of vertical deviation can vary in patients with skew deviation, it
is usually small and one recent study found that it was the patients who
had small eye misalignment (3 prism diopters or less) that complained
of diplopia [17]. Sometimes it can be difficult to differentiate between
the skew deviation and 4th nerve palsy and the principal difference is
that the higher eye is incyclotorted in skew deviation while it is ex-
clyclotorted in 4th nerve palsy [17,18]. Distinction between in- and
exclyclotorsion can be made on fundus photographs observing the po-
sition of optic nerve relative to the macula. It can also be measured
using Maddox rod. It has been reported that because the utricular
system is not as active in supine position, hyperdeviation will decrease
when supine in skew deviation, however, one recent study disputed this
finding [18,19]. If the skew deviation is suspected, MRI focused on
brainstem should be obtained.
When ocular myasthenia is suspected, one could perform the fol-
lowing tests: measuring the strength of the orbicularis oculi muscle (try
pulling the eyelids open while the patient is attempting to squeeze them
shut), rest test (taking a photograph of lid position at baseline and then
after the patient has sat with both eyes closed for 10–15 min), and ice
test (applying a plastic bag with ice on both eyelids and re-measuring
ptosis and eye deviation 5 min later) [20]. Tensilon test (injection of
endrophonium chloride which prevents re-absorption of acetyl choline
from the synapses thus increasing its availability) was utilized in the
past to see whether it improves ocular motility deficits and ptosis but
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Journal of the Neurological Sciences 417 (2020) 117055
Table 5
Treatment options for diplopia.
1. Occlusion (“pirate patch”, tape over one lens in spectacles, colored contact lens).
2. Prisms in spectacles (works for small deviations).
3. Surgery (best for comitant and stable deviations, goal restore single vision in
primary position).
4. Monovision (works for small deviations, one eye is used for distance viewing and
the other for near, with the help of contact lens in one eye).
5. Botulinum toxin injection in antagonist muscle.
endrophonium chroride is unfortunately not available at this time in
North America. Ultimately, measuring the titers of acetylcholine re-
ceptor antibodies is the most sensitive test for myasthenia gravis. It is
positive in about 70% of patients with ocular myasthenia [21]. Single
fiber electromyelogram is highly sensitive (sensitivity of ~90–95%) in
the hands of an experienced operator, but can be difficult to obtain and
requires an experienced neuro-muscular neurologist [22].
3. Treatment of diplopia
Treatment options for patients with diplopia are limited (Table 5).
They include occlusion of either eye if the deviation is large and/or
expected to be transient in nature (such as microischemic 3rd or 6th
nerve palsies). Placing prisms in the spectacles can be an effective way
to eliminate diplopia, but would only work if the deviation is not very
large as the greater the amount of prismatic correction is placed in the
spectacles, the greater is the visual blur induced by the prism. Surgery
to correct strabismus is another modality that can be employed and is
most successful in the presence of comitant deviation. It is offered to
patients whose deviation has been stable for at least six months and
whose disease process is not expected to be dynamic (such as myas-
thenia gravis or thyroid orbitopathy in its initial stages). Most patients
with neurological basis for strabismus will have incomitant deviation
and thus need to be counseled that the goal of strabismus surgery is
restoration of binocular vision in primary position of gaze but not in all
directions. Monovision which uses refraction aids such as contact lenses
to dissociate two eyes so that one eye is used for distance viewing and
another one for near, can be tried as well but typically works for fairly
small deviations only [23]. Sometimes injection of botulinum toxin into
the muscle antagonistic to the paretic one can be performed (i.e. it can
be injected into the medial rectus muscle of a patient with the 6th nerve
palsy). It is difficult to titrate the dose of Botulinum toxin though and
the patient should be counseled on that. The expected duration of ac-
tion of botulinum toxin injected into the extraocular muscle is several
months and varies based on the injected dose.
4. Special situations
A. Patients with history of malignancy
When evaluating a patient who has had a history of malignancy, any
ocular misalignment should be promptly investigated as it can be the
first manifestation of metastatic disease to the brain or extraocular
muscle/orbit.
B. Patients older than 50 with recent onset of intermittent diplopia or 6th/
3rd cranial nerve palsies
Patients over 50 years of age with the new onset of intermittent or
constant diplopia should have inflammatory markers checked as about
20% of patients with giant cell arteritis experience diplopia (likely
secondary to involvement by vasculitis of either vessles supplying the
extraocular muscles or vasa nervosum) [4,24].
E. Margolin
C. Patient is complaining of diplopia but exam is normal. What to do?
If the ocular misalignment is small, it can be difficult to uncover and
measure during the alternate-cover testing and very hard to observe
during extraocular motility testing. Maddox rod can be used in order to
measure small deviations: a red-colored lens with vertical striations is
placed in front of one eye which dissociates the eyes from one another
and makes it much easier to measure the deviation. It requires patient
cooperation and a knowledgeable observer. Engaging an orthoptist (an
allied health professional specializing in measuring ocular misalign-
ments) can be sought if the patient is symptomatic yet no obvious
motility abnormality is present and no ocular misalignment on alter-
nate-cover testing is seen.
D. Patient complains of intermittent diplopia and exam is normal
Careful alignment testing by alternate-cover testing in all positions
of gaze should be performed in these patients. Ocular motility should be
carefully checked and associated abnormalities of eyelid position (lid
lag and/or retraction) and presence of fatigable ptosis and proptosis
should be looked for. Ocular myasthenia should be considered and
acetylcholine receptor antibody titers checked. In patients over the age
of 50 GCA should be considered and inflammatory markers ordered.
Fundus examination should be performed in order to rule out the pre-
sence of papilledema which can cause intermittent diplopia.
5. Summary
Patients with diplopia are very common in neurological practice.
Patients with monocular diplopia as well as those with comitant ocular
misalignments and full ocular motility should not have further testing
but instead referred for an ophthalmological consultation. MRI of the
brain with contrast and DWI and SWI should be ordered for all patients
with recent onset of diplopia and any associated brainstem symptoms.
All patients with 3rd nerve palsy should have an urgent CTA to rule out
aneurysmal compression. MRI brain with contrast and steady-state
imaging sequences should be promptly ordered for patients with 6th
nerve palsy who are younger than 50 years of age or do not have mi-
croischemic risk factors as well as for all patients with more than one
cranial nerve palsy. Myasthenia gravis should be suspected in all pa-
tients with diplopia whose deviation does not fit the pattern for an
isolated cranial nerve palsy and who exhibit variability and fatigability
of of eye misalignment. Patients over the age of 50 with new onset of
diplopia should be screened for giant cell arteritis. Careful history-
taking and some basic examination skills described in this article should
allow a neurologist to make an accurate diagnosis in most cases.
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