Diplopia

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Author: Kinda Najem Editor: Edward Margolin Updated: 2/20/2023 8:40:04 PM

Introduction
Diplopia refers to seeing two images and is due either to ocular misalignment in which
case it disappears when either eye is occluded or to an optical problem in which case it
is termed monocular diplopia and does not disappear with monocular viewing.

Patients with ocular misalignment can harbor serious pathology and should be
evaluated in a systematic and thorough manner in order to uncover all potentially
serious cases. This article will present an outline of the approach to diplopic patients.

Etiology
The etiology of diplopia is either eye misalignment if diplopia is binocular or an optical
phenomenon if it is monocular. Eye misalignment can occur due to a variety of causes,
and in order to understand it, one has to follow the anatomical algorithm of what needs
to happen in order for the eyes to be aligned together. Both eyes have to receive equal
innervation of all of their extraocular muscles in order to be in the so-called primary
position when the innervation to antagonist extraocular muscles in each eye is equal.
Innervation to extraocular muscles is provided by the 3rd, 4th, and 6th cranial nerves;
thus, all three have to be working well on each side in order to maintain both eyes in
the primary position and aligned with each other. The nuclei of all three of these cranial
nerves originate in the brainstem (3rd and 4th in the midbrain and 6th in the pons).
Their fascicles then traverse the brainstem exiting it ventrally in the case of the 3rd and
6th nerve and dorsally in the case of the 4th nerve. The nerves then travel variable
distances in the subarachnoid space, where they are susceptible to a variety of
pathologies affecting cerebrospinal fluid (inflammatory conditions, infections, and
malignancies). Eventually, all oculomotor nerves (3rd, 4th, and 6th) emerge from the
subarachnoid space and converge in the space filled with venous blood located
laterally to each side of the pituitary gland, which is termed cavernous sinus. The
cavernous sinus is surrounded by a lot of structures, and pathologies affecting these
neighboring structures (sphenoid sinus, pituitary gland, nasopharynx, intracavernous
carotid arteries, etc.) can affect any of the oculomotor nerves and thus cause diplopia.
As all three oculomotor nerves are located in close proximity to each other in the
cavernous sinus, when encountering a patient with more than one oculomotor nerve
palsies, one should think of cavernous sinus as the most likely location of the causative
lesion. From the cavernous sinuses, all three oculomotor nerves travel in close
proximity to each other to enter the superior orbital fissure, where they are also located
close to the 2nd cranial nerve (optic nerve); thus, lesions in the superior orbital fissure
produce decrease vision and often forward displacement of the globe (proptosis) in
addition to multiple oculomotor nerve palsies. From the superior orbital fissure, each
nerve travels to the extraocular muscle it innervates through the orbit; thus, orbital
pathology can produce diplopia as well. Eventually, the nerve will join the muscle that it
innervates, and pathology at the neuromuscular junction can also cause ocular
misalignment and thus binocular diplopia. Finally, extraocular muscles themselves
need to be intact in order for the eyes to be aligned with each other; thus, myopathies
can also produce diplopia.

Monocular diplopia is almost always an ophthalmological problem and stems most

commonly from the cataractous changes in the crystalline lens, abnormalities in the
corneal surface (keratoconus or uncorrected astigmatism), and exceedingly rarely
lesions affecting occipital cortex can produce monocular diplopia as well (termed
"cortical polyopia") in which case they are almost always accompanied by
homonymous visual field defects. Finally, when no organic etiology for monocular
diplopia can be found, and diplopia does not disappear when looking through a pinhole,
one has to assume that it is functional in nature.

Epidemiology
Diplopia is a common complaint in both the ambulatory setting as well as in the
emergency department, with one study reporting almost 805000 ambulatory and 50000
emergency department visits in the United States yearly with the chief complaint of
diplopia[1]. Diplopia, particularly when acute in onset, is very unsettling to the patient
and will prompt most to visit an emergency department. While we are always
concerned about the potential sinister and even life-threatening causes of diplopia, only
16% of patients with diplopia were found to have potentially life-threatening etiologies in
one study.[2]
Pathophysiology
Binocular diplopia occurs because the image falls outside of the fovea in one eye, thus
triggering the perception of two separate images. If eye misalignment is horizontal,
diplopia is horizontal, and if the eye misalignment is vertical, it will be vertical.

History and Physical

When evaluating a diplopic patient, one has first to determine whether diplopia is
monocular or binocular. While this has already been mentioned above, it is of
paramount importance as skipping this step will lead to unnecessary investigations and
anxiety for the patient.

The next most important step is to search for accompanying “brainstem” symptoms.
While isolated brainstem strokes are uncommon, diplopia can be the main complaint in
patients with strokes involving diencephalon or brainstem, which involve either the
nuclei or fascicles of the IIIrd, IVth, or VIth cranial nerves, medial longitudinal
fasciculus, or vertibulo-ocular pathways producing the so-called skew deviation[3].

Any patient with an acute onset of binocular diplopia who has any accompanying
symptoms that can be caused by brainstem dysfunction (vertigo, dizziness, dysarthria,
crossed motor or sensory symptoms, ataxia, imbalance, etc.) should be immediately
referred to an emergency department for in order have an urgent MRI of the brain with
attention to the brainstem performed. MRI should include diffusion-weighted as well as
susceptibility-weighted images in order to detect subtle ischemic and/or hemorrhagic
lesions.

All diplopic patients should be asked about the fatiguability and variability of their
symptoms as well as the presence of symptoms of increased intracranial pressure, and
all patients over the age of 50 should be asked about the symptoms of giant cell
arteritis.

Next, a careful examination should be performed, first testing ocular motility in order to
try to identify obvious deficits and determine whether they map out to the dysfunction of
the 3rd or 6th cranial nerves. Motility testing should be performed by slowly moving a
target in all directions of gaze and should be checked in each eye separately. After
motility testing, ocular alignment should be checked by performing alternate cover
testing. If a vertical deviation is uncovered, testing of misalignment in ipsi- and
contralateral gaze as well as ipsi- and contralateral head tilt positions should be
performed to determine if the deviation fits the pattern of the so-called 3-step test
where the hypertropia increases in contralateral gaze and ipsilateral head tilt. A positive
3-step test indicates 4th nerve paresis[3].

If ocular motility is full and eye misalignment remains the same in all positions of gaze,
it is termed comitant and is almost always secondary to decompensated congenital
strabismus. It does not require further investigations or testing other than a referral for
ophthalmological evaluation. After ocular motility and alignment have been examined
and recorded (we prefer recording ocular motility in percentages, i.e., "there was only
70% of expected supraduction"), pupillary examination, the position of the lids, and
movement of the lid during the motility testing, presence of proptosis, and orbicularis
strength should all be examined and recorded. Dilated fundus examination looking for
the presence of optic nerve head edema and any signs of venous stasis retinopathy
should be performed in all diplopic patients as well.

Evaluation
After performing careful testing of extraocular motility in each eye separately followed
by ocular alignment testing (which should be performed by doing alternate cover
testing and abnormalities recorded in each cardinal position of gaze utilizing
measurements in prism diopters), an examiner has to combine all findings to figure out
whether they can be due to an isolated palsy of the 3rd, 4th or 6th cranial nerves. The
management of each one of these entities is different and is discussed below.
Identifying complete third nerve palsy and sixth nerve palsy is relatively straightforward,
but diagnosing partial third nerve paresis can be tricky. The examiner has to be very
familiar with the 3-step text described above in order to diagnose 4th nerve palsy.

If there is more than one cranial nerve palsy, urgent neuroimaging (MRI of the brain
and orbits with contrast enhancement) is mandatory, looking for the lesions in the area
of the cavernous sinuses, superior orbital fissure, and extraocular muscles. If
fatiguability, variability, decreased orbicularis strength or any other symptoms of ocular
or generalized myasthenia gravis are present, acetylcholine receptor antibody testing
should be performed, although its sensitivity is only about 50 to 70%[4]. If the diagnosis
is strongly suspected despite the negative acetylcholine receptor antibody titers, a
single fiber electromyogram of the orbicularis muscle should be performed as in the
hands of an experienced operator it has a sensitivity of about 95% in diagnosing
abnormalities specific to ocular myasthenia[5].

All patients with the third nerve palsy (regardless of whether it is complete or partial,
pupillary sparing or pupillary involving) should undergo an emergency CT angiography
of the brain in order to rule out an aneurysmal compressive lesion of the third cranial
nerve in its subarachnoid compartment[6]. CTA is widely available and is very sensitive
for detecting any aneurysms larger than 2-3 mm in diameter (it is generally agreed
upon that an aneurysm has to be at least 4 mm in diameter in order to produce
compression of the third nerve). The main limitation of the CT angiogram in detecting
all relevant third nerve palsies is the experience and knowledge of the interpreting
radiologist[7]. If there is pupillary involvement and the CTA has been interpreted as
normal, a clinician should personally communicate their clinical findings to the
radiologist and ensure that they have carefully reviewed the junction between the
internal carotid and posterior communicating arteries as this is the most common
location of an intracranial aneurysm that can produce third nerve palsy. If the CTA is
normal and the patient is over the age of 50 with vasculopathic risk factors, it is
reasonable to assume that the etiology of the third nerve palsy is likely microischemic
in nature and observe them for 2-3 months when the resolution or significant
improvement of the nerve palsy is expected. If the patient is under the age of 50 or
does not have any microvascular ischemic risk factors and the CTA is negative, urgent
MRI with contrast utilizing steady-state imaging sequences should be performed in
order to follow the entire course of the third nerve and rule out any pathology affecting it
along its course[6].

For patients with the 4th nerve palsy, if the hyper deviation in the affected eye is
greater in upgaze than in downgaze, it can be safely assumed that it is likely either
decompensated congenital, post-traumatic, or microischemic in nature and should
either be palliated with the prisms in the spectacles or observed for spontaneous
improvement[8]. If the deviation is worse in downgaze, an MRI of the brain with
contrast and steady-state imaging should be performed, evaluating the course of the
fourth cranial nerve.

Patients with acute onset of 6th nerve palsy who have vascular risk factors who are
older than 50 years of age should be observed if it can be assured that cranial nerve
palsy is isolated and imaged only if their motility deficit does not improve after 2-3
months. Patients without microvascular risk factors and all patients under 50 years of
age with the 6th nerve palsy should have an MRI with contrast and steady-state
imaging acquisition performed in order to rule out demyelinating or compressive
etiology anywhere along the course of the nerve.[3]

Treatment / Management
Treatment options for patients with diplopia are limited. Patients with monocular
diplopia should be evaluated for possible cataract surgery, and their refractive errors
should be corrected. Patients with binocular diplopia who are symptomatic should
ideally first try to palliate the diplopia with prisms in their spectacles. Prisms are
generally effective only for patients with small (~up to 10-12 prism diopters)
misalignments. For patients with larger misalignments, occlusion of either eye with a
patch or a tape applied to one lens in the spectacles can be an effective way to
eliminate diplopia. Patients with stable misalignments should be assessed by a
strabismologist for potential surgical correction of the eye misalignment. Injection of
Botulinum toxin into the antagonist of the paretic muscle has also been suggested but
can be difficult as it is hard to predict the reaction of each patient to a specific dose of
Botulinum toxin, and its effect will eventually wear off[9]. Monovision (placing a contact
lens in one eye in order to make this eye hyperopic or myopic and thus disrupting
binocular viewing) has also been tried for patients with diplopia who have small
misalignments and could be an effective treatment option for some[10].

Differential Diagnosis
The differential diagnosis for patients with binocular diplopia is vast. The anatomical
approach in formulating the differential diagnosis will again be used.

Any lesions affecting the brainstem can affect the nuclei or the fascicles of the 3rd, 4th,
and 6th cranial nerves, involve the vestibulo-ocular pathways or medial longitudinal
fascicule.

Any lesions affecting the horizontal or vertical gaze centers (located in the pons and
midbrain, respectively) can rarely cause diplopia.
Lesions of the medial longitudinal fasciculus, which connects the sixth cranial nerve to
the medial rectus subnucleus on the other side, can also produce diplopia. These
lesions tend to be demyelinating in patients under the age of 50 and ischemic in those
older than 50.

Pathology affecting the CSF (malignant cell circulating in it, inflammatory processes
disturbing normal CSF composition, increased protein, etc.) can also produce
oculomotor palsies.

Guillain-Barre syndrome can cause diplopia when it preferentially affects the

oculomotor nerves (3rd, 4th, and 6th) in the so-called Miller-Fisher variant where the
levels of GQ1b antibodies are often elevated.

Thiamine deficiency (Wernicke encephalopathy) can produce diplopia as well; thus,

intravenous thiamine should be administered in all diplopic patients who are confused,
have nystagmus, or ataxia.

A variety of lesions can affect the cavernous sinus, often producing multiple cranial
nerve palsies. These include inflammatory lesions from idiopathic cavernous sinus
syndrome, sarcoidosis, IgG4 disease or granulomatosis with polyangiitis; vascular
lesions from the expanding aneurysms of the intra-cavernous carotid artery, carotid-
cavernous fistulas; mass lesions due to expanding pituitary apoplexy, neoplastic or
inflammatory lesions in the sphenoid sinus; infections lesions due to cavernous sinus
thrombosis, or direct spread of infection from the face; spread of malignancy from the
nasopharynx or sphenoid sinus, as well as distant metastasis.

A multitude of lesions affecting superior orbital fissures can cause diplopia by affecting
one or several cranial nerves that travel through it.

Orbital disease (such as thyroid eye disease, any tumors or vascular lesions of the
orbit) can also cause diplopia.

Finally, disorders of neuromuscular junctions and myopathies affecting extraocular

muscles can also produce diplopia.

Prognosis
The prognosis of diplopia is very variable and depends entirely on the underlying
condition that is causing it.

Complications
The main complication from diplopia itself is the discomfort experienced by the patient
and the inability to drive for many patients. Of course, individual etiologies that can
cause diplopia have their own complications associated with them.

Deterrence and Patient Education

Patients should be educated about the nature of diplopia and that treating binocular
diplopia can be challenging. They should be explained what the thinking process of the
examiner is and how they will approach the diagnostic and treatment process based on
their clinical findings.

Enhancing Healthcare Team Outcomes

Patients with diplopia may initially present to the emergency department physician,
primary care provider, and nurse practitioner. However, because there are many
causes of diplopia and the workup is beyond the scope of the primary provider, these
patients should be referred to an ophthalmologist and preferably to a neuro-
ophthalmologist for definitive diagnosis and treatment planning. The prognosis
depends on the cause. Emergency department and ophthalmology nurses are involved
in the initial evaluation and coordination of evaluation. This interprofessional team can
coordinate care to improve outcomes. [Level 5]