Evaluation and Management
For the most part, patients with monocular diplopia do not warrant a neurologic evaluation since a careful ophthalmic evaluation will reveal the cause (see Table 1). Monocular diplopia generally results from an optical aberration and improves with pinhole viewing. A careful refraction including retinoscopy may reveal previously unidentified or irregular astigmatism from corneal or lenticular causes. Corneal topography and hard-contact- lens refraction can detect an irregular corneal surface or contour. Intermittent monocular diplopia often results from tear film insufficiency measured by early tear-film breakup time or Schirmer test. Generally, macular pathology can be noted on biomicroscopic examination and can cause distortion of the Amsler grid or abnormal optical coherence tomography (OCT) findings. Some patients may note monocular diplopia after ocular surgery. For instance, polycoria can lead to a second image after iridectomy. Diplopia secondary to irregular astigmatism and higher-order ocular aberrations (identified on wavefront analysis) can occur after refractive surgery. A dislocated intraocular lens can cause double vision from the lens edge within the visual axis or from a change in refractive error (ie, anisometropia).
The evaluation of binocular diplopia begins with examining the saccades and pursuit of the eyes individually (ductions) and together (versions). Ophthalmoplegia secondary to a neuropathy, myopathy, or neuromuscular junction disorder reveals slowed saccades. In some patients with binocular diplopia, the extraocular motility may appear full but saccadic velocity is slow. In contrast, restrictive ophthalmoplegia generally demonstrates normal saccadic velocity. A restrictive process can be verified with forced ductions if a substantial ductional deficit is present.
Ocular alignment should be evaluated in primary gaze, upgaze, downgaze, and horizontal gaze positions, including distance and near. C over-uncover testing distinguishes phorias from tropias, whereas alternating cross-cover and Maddox rod testing (Figure 1) reveals the full deviation of tropia plus latent phoria. Maddox rod, red glass, or Hess screen testing is extremely useful for measuring small ocular deviations and to quickly assess comitance. In addition to a thorough ophthalmologic examination, specific attention should be directed to eyelid position, orbicularis oculi strength, facial sensation, and exophthalmometry.
The main treatment objective in patients with binocular diplopia is to create the largest and most central area of single binocular vision. In some cases, achieving single vision with both eyes open in all fields of gaze may not occur. Occasionally, patients may choose to adopt a head tilt (eg, fourth nerve palsy), head turn (eg, sixth nerve palsy), or chin-up position (eg, thyroid eye disease) to utilize both eyes and eliminate diplopia. These patients may develop neck strain or headache from the anomalous head position.
Occlusion of the vision in one eye remains the easiest and most conservative treatment of binocular diplopia. Patients younger than 9 should alternate occlusion because of the risk of amblyopia. Therapies include using a pirate patch, frosting an eyeglass lens, or placing Scotch Satin tape (3M Co, St Paul, Minnesota) on one eyeglass lens. The advantages of Scotch Satin tape are the low cost, reasonable appearance, and ability to patch only portions of the lens where diplopia occurs. More costly options involve wearing a contact lens with an opaque center, Bangerter occlusion foils that adhere to the glasses, or hyperopic overcorrection to induce monocular blur.
Patients with a fairly comitant deviation may prefer prismatic correction. Significant incomitance (third nerve palsy) gives the patient a very small, single binocular field of vision, even with prisms, and therefore monocular occlusion remains the better option. Fresnel prisms range from 1 to 40 prism diopters (Δ). Ground-in prisms are significantly more expensive and are limited to 10 to 12 Δ per lens because of cosmetic appearance and the weight of the lens.
Patients with long-standing, stable strabismus for more than 6 to 12 months could consider strabismus surgery. Patients with significant ophthalmoplegia and incomitance generally do not fare well with surgery.
Isolated Cranial Nerve Palsy
The most common cause of a neurologically isolated, acute, ocular motor cranial neuropathy (third, fourth, or sixth nerve palsy) is microvascular ischemia. This presumptive diagnosis depends upon the presence of patient characteristics including older age, vasculopathic risk factors (hypertension, diabetes mellitus, or hyperlipidemia), and spontaneous recovery. A patient younger than 50 with an isolated mononeuropathy should undergo neuroimaging, preferably magnetic resonance imaging (MRI) of the brain and orbits with fat suppression and gadolinium administration. Intracranial lesions may mimic a vasculopathic oculomotor cranial nerve palsy in patients older than 50, but it is unclear whether early neuroimaging is truly indicated in this group of patients. In fact, many retrospective case series suggest delaying neuroimaging until an isolated palsy (in patients older than 50) remains unresolved for 3 to 4 months.
Third (Oculomotor) Cranial Nerve Palsy
The third cranial nerve innervates four EOMs (superior, inferior, and medial recti, and inferior oblique), one eyelid muscle (levator palpebrae superioris), and two intraocular muscles (pupillary sphincter and ciliary muscle). A complete third nerve palsy indicates total dysfunction of the EOMs and levator. Partial third nerve palsy reveals variable degrees of dysfunction of the EOMs and levator. The pupil is described separately as spared or involved. Pupil sparing signifies a normal pupil equal in size and reactivity to its partner, whereas pupillary involvement indicates a larger pupil, poorly responsive to light and accommodation. Some patients may have relative pupil sparing where the affected pupil is larger (0.5 to 2.0 mm) but remains briskly reactive.
The pupillary fibers travel along the superficial and superior aspect of the oculomotor nerve, exposed to compression by external lesions. One should consider a posterior communicating artery aneurysm in an adult with a new-onset third nerve palsy and pupillary involvement (including relative pupil involvement). An emergent MRI or CT of the brain is reasonable before proceeding to conventional catheter angiography to rule out a compressive or infiltrative abnormality (Figure 2). In conjunction with this, MR angiography (MRA) or CT angiography (CTA) of the intracranial vessels should be performed. These noninvasive techniques identify aneurysms as small as 3 to 5 mm. If these tests return negative and clinical suspicion remains high, then conventional catheter angiography should be ordered.
A complete, pupil-sparing third nerve palsy in a patient older than 50 with vasculopathic risk factors does not necessitate neuroimaging. However, incomplete recovery after 3 months, development of aberrant regeneration, or additional cranial nerve involvement should prompt neuroimaging directed at the cavernous sinus and skull base. In cases where there is partial extraocular motor dysfunction with normal pupils, it is reasonable to either closely observe for the first week watching for pupillary involvement or to obtain a brain MRI and MRA of the intracranial vessels from the outset. A patient with an isolated, dilated and nonreactive pupil with normal extraocular movements and eyelid position does not have a third nerve palsy.
Fourth Cranial (Trochlear) Nerve Palsy
A fourth nerve palsy results in poor superior oblique function. Patients note vertical, oblique, or torsional diplopia worse in downgaze, and they often adopt a contralateral head tilt to counteract the diplopia. The extraocular motility may appear full, but cover or Maddox rod testing shows an ipsilateral hypertropia that increases in contralateral gaze and ipsilateral head tilt (Figure 3). Double Maddox rod testing and funduscopy show excyclotorsion of the ipsilateral eye (Figure 4a).
A common cause of acquired fourth nerve palsy is head trauma, which should be identified by history. In cases of decompensated congenital fourth nerve palsy, patients may note intermittent diplopia, especially with fatigue. Old photographs often demonstrate a long-standing head tilt. Additionally, the ability to vertically fuse more than 3 or 4 Δ may be present. However, because long-standing acquired deviations also have increased fusional amplitudes, their presence or absence is helpful only in acute cases. With decompensated fourth nerve palsy, due to the long- standing nature, the hypertropia may become more comitant with time. In these cases the ocular motility examination often reveals ipsilateral inferior oblique overaction.
An isolated fourth nerve palsy does not typically result from demyelinating disease (because of its short course through the brainstem), mass lesion, or aneurysm. Neuroimaging is often unrevealing but can be initiated if the palsy does not remit. Other mimickers of fourth nerve palsy include skew deviation, myasthenia gravis, and thyroid eye disease.
Sixth Cranial (Abducens) Nerve Palsy
Poor lateral rectus function characterizes sixth nerve palsy. Patients complain of horizontal diplopia worse in the distance, and examination reveals an esotropia that increases with ipsilateral horizontal gaze. In some cases, cover testing may also reveal a small, less than 5 Δ of hypertropia (likely a hyperphoria that manifests itself when fusion is interrupted).
In cases of microvascular ischemia, observation is reasonable for an isolated palsy in an older patient. Progression or lack of improvement after several weeks merits MRI of the brain with gadolinium along the course of the sixth nerve, with specific attention to the brainstem, clivus, cavernous sinus, and orbit. With normal neuroimaging, the clinician may consider lumbar puncture with opening pressure, especially if optic nerve edema is also present. Raised intracranial pressure can cause sixth nerve palsy presumably from mechanical stretching of the nerve; thus, many cases may actually have bilateral, but asymmetric, sixth nerve palsy.
Patients with Duane retraction syndrome (Type I) have a substantial abduction deficit yet a comparatively small primary position esotropia. The affected eye retracts with adduction. In general, patients with Duane syndrome do not complain of diplopia. In patients with spasm of the near reflex, there is variable esotropia and abduction. Careful observation of the pupil will show constriction with attempted abduction. Other mimickers of sixth nerve palsy include myasthenia gravis and thyroid eye disease.
Because any eye muscle or motility pattern can occur in myasthenia gravis (MG), it should remain on the differential diagnosis of any patient with binocular diplopia. The pupillary examination should be normal and there should be no sensory symptoms (ie, pain or numbness). Examination of the eyelids may demonstrate ptosis or orbicularis weakness, although cases without eyelid involvement occur. Variability of diplopia by history or of measurements between examinations is suggestive of MG.
Pseudo-Third Nerve Palsy in Myasthenia Gravis
This patient can abduct the right eye normally. She cannot adduct, elevate or depress the right eye fully. Although she has right upper lid ptosis requiring the examiner to hold the lid open, the ptosis does not occur until midway through the examination. Close inspection of the pupils shows that they are equal in size.
Video copyright 2006, Simmons Lessell, MD. Used by permission.
Intravenous injection of edrophonium 5 to 10 mg may resolve ptosis, diplopia, or motility deficits. The ice test, sleep test, or neostigmine test can also be considered. Acetylcholine receptor binding and modulating antibodies are highly specific, but false negative results occur more frequently if MG is restricted to the ocular form (25% to 50%). Patients who are seronegative for acetylcholine receptor antibodies may harbor muscle- specific receptor tyrosine kinase (MuSK) antibodies. MuSK antibodies are more prevalent in patients who have bulbar (dysphagia, dysarthria) symptoms. Repetitive stimulation electromyography (EMG) shows a decrement of the action potential in patients with MG. This test is fraught with false negative results in ocular MG. Single-fiber EMG of the orbicularis oculi is highly sensitive and specific for both the ocular and generalized forms of MG. If a diagnosis of MG is established, a chest CT should be performed to rule out a thymoma, which occurs in 10% of patients with MG.
Thyroid Eye Disease
Thyroid eye disease (TED) is a common cause of diplopia in adults. Symptoms, often worse in the morning, may start with complaints of irritation and blurry vision followed by slowly progressive binocular diplopia. The inferior rectus is the EOM most commonly affected, and patients may complain of vertical double vision unless they adopt a chin-up face position. In decreasing order of frequency, the medial, superior, and lateral recti may also be affected. Involvement of the medial rectus causes restriction of abduction and a pseudoabducens nerve palsy. Other findings that may be absent in early disease include eyelid retraction or edema, proptosis, positive forced ductions, and lagophthalmos.
Orbital imaging can show enlargement of the EOMs with sparing of the tendinous insertion via echography, MRI, or CT (Figures 5a, 5b). In early TED, imaging may be normal.
Up to 10% of patients with TED can have normal thyroid function testing (TSH, T3, T4). Other serologic markers for autoimmune thyroid dysfunction to consider include thyroid stimulating immunoglobulin or antibody (20% to 70%), thyroglobulin antibody (9%), and thyroid peroxidase or microsomal antibody (17%).
Patients generally develop worsening ophthalmoplegia for 12 to 18 months from onset, despite systemic therapy for thyroid dysfunction. Some patients prefer monocular occlusion, as Fresnel prisms often require repeated modification. Although effective at improving symptoms, corticosteroids should be reserved for severe and acute worsening. Tapering the dose becomes difficult, because symptoms return quickly and the risk of long-term adverse effects of corticosteroids arises. Cigarette smoking may worsen TED, and this should be discussed with the patient. Myasthenia gravis can, rarely, co-exist with TED and warrants consideration if ptosis develops.
Supranuclear Motility Disorders
Many supranuclear disorders do not cause diplopia, because ophthalmoplegia is symmetric between the eyes. However, the following conditions may result from supranuclear disruption and often cause diplopia.
Divergence Insufficiency and Paralysis
Divergence insufficiency is an ocular motor anomaly characterized by horizontal diplopia in the distance. The esodeviation remains comitant in all fields of gaze at distance and markedly lessens or resolves at near. Ductions are full without evidence of abduction deficit. A cluster of cells in the pons called the nucleus reticularis tegmenti pontis may represent the supranuclear divergence center, but it is unclear if there is a particular abnormality in this region. Divergence insufficiency arises as a benign phenomenon with spontaneous resolution in many cases. Neuroimaging should be considered because bilateral sixth nerve palsies, mass lesions, and demyelinating disease may present with the clinical findings of divergence insufficiency. Base-out prisms eliminate diplopia effectively but may cause diplopia at near unless they are applied on the distance portion of the glasses only. Long-standing, stable misalignment may warrant surgery in patients intolerant of prisms.
Convergence Insufficiency and Paralysis
Convergence insufficiency is a relatively common cause of diplopia at near in children and adults. It can develop after head trauma, but often the cause is unknown. Patients report diplopia, blurred vision, and asthenopia with prolonged near tasks. Examination reveals an exodeviation greater at near than distance and a remote near point of convergence of greater than 6 to 8 cm. Simple eye exercises (“pencil pushups”) are effective in a minority of cases. Orthoptic training using base-out prisms for near viewing, convergence exercises using stereograms, home computer orthoptics, and changing fixation from distance to near targets may improve symptoms. Base-in reading glasses are not helpful in children and adolescents but may be effective in older patients.
Patients with skew deviation complain of vertical and occasionally torsional binocular diplopia. Other neurologic deficits such as ataxia, if present, are suggestive of the diagnosis. Skew deviations generally result from asymmetric input from the otolithic pathways to the vertically acting ocular motor neurons in the midbrain. Both peripheral vestibular and central lesions of the brainstem/cerebellum can cause a skew deviation. The hypertropia is generally present in primary gaze and may be comitant or incomitant. Ocular torsion and head tilt may accompany a skew deviation (ocular tilt reaction [OTR]). Patients with OTR generally have binocular torsion instead of excyclotorsion of one eye seen in fourth nerve palsy (see Figure 4b).
The medial longitudinal fasciculus (MLF) connects the sixth nerve nucleus on one side of the pons to the contralateral medial rectus subnucleus in the midbrain. Interruption of the MLF produces an ipsilateral internuclear ophthalmoplegia (INO). Patients may note horizontal or oblique diplopia, difficulty tracking moving objects, or transient blurred vision with sudden shifts in lateral gaze. Extraocular motility demonstrates slowed or impaired adduction. The contralateral eye may show nystagmus in abduction and ocular dysmetria. A skew deviation or upbeat nystagmus in upgaze may be present, as the MLF also carries vertical eye movement information and input from the cerebellum to the midbrain.
Left Internuclear Ophthalmoplegia
On right gaze, this patient cannot adduct the left eye fully. Note the slowed saccades of the left eye compared to those of the right. The right eye demonstrates abducting nystagmus. The patient can converge the left eye well. There is upbeat nystagmus in upgaze.
Video copyright 2006, Simmons Lessell, MD. Used by permission.
An isolated adduction deficit with a skew deviation should not be confused with a partial, pupil-sparing, third nerve palsy. If the MLF lesion also involves the ipsilateral abducens nucleus or pontine paramedian reticular formation, this leads to a one-and- a-half syndrome. In these patients, the ocular motility demonstrates ipsilateral gaze palsy (“one”) and an ipsilateral INO (“half”), leaving contralateral abduction as the only intact ocular movement. Demyelination often causes INO in younger adults and microvascular infarction typically causes INO in elderly patients. Myasthenia gravis can produce a motility disorder identical to an INO or a one-and- a-half syndrome.
Dragged-Fovea Diplopia Syndrome
Maculopathies such as epiretinal membranes can anatomically pull one fovea out of correspondence with the fellow fovea. This misalignment of foveas leads to central binocular diplopia. Nevertheless, because the majority of the retinas correspond, these patients maintain peripheral fusion. Therefore, patients may note relief of diplopia initially (central fusion) with prism trials. Within minutes, peripheral fusion takes over and the central diplopia returns.
The "lights on-off test" is a very reliable test for this syndrome. The diplopic patient fixates on a single white 20/70 letter situated on a black LCD screen, and the examiner extinguishes all light (removes all peripheral stimuli). If the patient can see singly (fuse centrally), then this is a positive test indicating dragged-fovea diplopia syndrome. If diplopia persists, then this is a negative test (Figure 6).
Most patients have a visible maculopathy, but others may simply note metamorphopsia on Amsler grid testing. These patients typically do not benefit from prism therapy, vitreoretinal surgery, or strabismus surgery. Monocular occlusion appears to be the sole therapy in most instances.
Some patients may note diplopia soon after ocular surgery because a preoperative ocular misalignment failed to cause diplopia (due to poor vision in the preoperative eye). A thorough preoperative evaluation should identify this issue and a pre-emptive discussion can occur. In other cases, aniseikonia from anisometropia leads to disparate-sized images from each eye and the perception of diplopia. Postoperative refraction may reveal an inter-eye difference of approximately 3 to 4 diopters (6% to 8% aniseikonia) while cover testing shows orthophoria. These patients may be good candidates for monovision or contact lenses. Also, all lenses have some degree of prismatic power with eccentric viewing from the optical center proportional to the power of the lens. Anisometropia induces different prismatic effect between eyes leading to diplopia. This is usually vertical diplopia due to small fusional amplitudes and may be correctable with a slab- off prism from the more-minus or less-plus lens.
Other patients suffer from surgical trauma to the EOMs after peribulbar injections or superior rectus bridle sutures. Local anesthetics can cause myotoxicity from diffusion into a muscle or more likely from direct injection. Patients typically complain of vertical diplopia in the early postoperative period and demonstrate a paresis of the involved EOM. The deviation either resolves within the next several days to weeks or evolves into a permanent restrictive strabismus.
Scleral Buckling Surgery
Diplopia can result from scleral buckling surgery. Expansion of hydrogel explant material may cause a restrictive orbitopathy. Temporary strabismus lasting several months is not uncommon even after uncomplicated procedures. However, permanent strabismus may occur from inaccurate reattachment of the EOM, direct injury to the EOM, and scarring of Tenon’s capsule. The encircling element may compress an EOM and functionally alter its action or restrict contraction of the muscle. In some cases, a silicone element can transect and disinsert the EOM. Lastly, scleral buckling can induce a myopic shift in the affected eye leading to anisometropia and aniseikonia.
Binocular diplopia may occur after glaucoma implant surgery. This complication was much more common with the early Baerveldt implants than with the Ahmed or Molteno implants. Recent modifications to the Baerveldt end plate have reduced postoperative diplopia. Implant reservoirs result in a bleb that may involve the extraocular muscles; therefore, repositioning the implant may eliminate diplopia. If diplopia persists, it may require implant removal.
Patients can report monocular or binocular diplopia after refractive surgery. Wavefront technology can measure higher-order optical aberrations, which have been associated with monocular diplopia. Other technical problems include scarring, under- or overcorrected refractive error, or an ablation zone smaller than the scotopic pupil. Binocular diplopia may result from a decentered ablation zone in one eye. In addition, it is important to check for incorporated prism in glasses prior to any refractive surgery procedure, as patients may be unaware of its presence. Some patients with a history of strabismus or amblyopia are at risk of developing postoperative diplopia. Postoperative residual hyperopia may cause breakdown of a previously controlled accommodative esotropia. Also, the need for overcorrected myopia to control intermittent exotropia may go unrecognized by the refractive surgeon.
Monovision correction may render some patients diplopic by two mechanisms. First, patients with well- compensated intermittent strabismus (eg, exophoria, congenital fourth nerve palsy) are able to fuse images to eliminate diplopia. However, with the introduction of monovision, their stereopsis is reduced and breakdown of fusional capacity and diplopia may ensue. Second, patients with a history of amblyopia or congenital strabismus may have a suppression scotoma in their nondominant, misaligned eye. With monovision correction, forcing the nondominant eye to fixate (fixation switch diplopia) does not lead to a suppression scotoma in the dominant eye and the patient develops double vision. Preoperatively, the surgeon should pay attention to ocular history, cover testing, and Worth four-dot testing to assess for potential fixation switch diplopia in the refractive and cataract patient.