Diplopia

Etiology

The etiology of diplopia is either eye misalignment (if diplopia is binocular) or an optical phenomenon (if diplopia is monocular). Eye misalignment can have numerous causes; to understand it, it is important to follow the anatomical algorithm of eye alignment. Specifically, both eyes need to receive equal innervation of all extraocular muscles to be in the primary position when the innervation to antagonist extraocular muscles in each eye is equal. Any lesion that affects the muscles and nerves up to the cranial nerve nuclei and their tracts can cause double vision.

Innervations of extraocular muscles occur via cranial nerves III, IV, and VI. These 3 nerves need to work well on each side to maintain both eyes in the primary position and aligned with each other. All of the nuclei of these cranial nerves originate in the brainstem (III and IV in the midbrain and VI in the pons); their fascicles traverse the brainstem, exiting ventrally for the third and sixth nerves and dorsally for the fourth nerve. The nerves then travel at variable distances in the subarachnoid space, susceptible to different pathologies affecting cerebrospinal fluid (inflammatory conditions, infections, and malignancies). Eventually, all oculomotor nerves emerge from the subarachnoid space and converge in the cavernous sinus, a space filled with venous blood located laterally on each side of the pituitary gland.

After passing through the cavernous sinus, the oculomotor nerves are surrounded by numerous structures (sphenoid sinus, pituitary gland, nasopharynx, intracavernous carotid arteries, etc). Any pathology affecting these neighboring structures can affect the oculomotor nerves—by compression or direct extension—thus causing diplopia. As all 3 oculomotor nerves are located close to each other in the cavernous sinus when a patient presents with more than one oculomotor nerve palsy, the cavernous sinus should be considered the most likely location of the causative lesion.

From the cavernous sinuses, all 3 oculomotor nerves travel close to each other to enter the superior orbital fissure, where they are also located close to the second cranial nerve (optic nerve); thus, lesions in the superior orbital fissure produce decreased 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 also produce diplopia. Eventually, the nerve will join the muscle that it innervates; pathology at the neuromuscular junction can also cause ocular misalignment and, thus, binocular diplopia. Finally, extraocular muscles themselves need to be intact for the eyes to be aligned with each other; thus, myopathies can also produce diplopia. 

A study in South China used a new classification system for assessing diplopia according to extraocular muscle (EOM) dysfunction. In their study, the patients were categorized into 3 groups: single EOM (sEOM), multiple EOMs (mEOMs), and comitant strabismus group.

• sEOM: This is the most common type of EOM. It is usually caused by microangiopathy and trauma with frequent involvement of the lateral rectus. Some patients were considered as having nasopharyngeal carcinoma (NPC)-associated diplopia; for others, sEOM was caused by radiation neuropathy following radiation therapy.
• mEOMs: The predominant etiology in this group is thyroid-associated ophthalmopathy.
• Comitant strabismus group: The most common etiology for this group is acute acquired comitant esotropia.[2]

Monocular diplopia is almost always an ophthalmological problem and stems from the cataractous changes in the crystalline lens, abnormalities in the corneal surface (keratoconus or uncorrected astigmatism), and, exceedingly rarely, lesions affecting the occipital cortex (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, it is assumed to be functional in nature. 

A nonophthalmological cause of diplopia related to COVID-19 infection has been identified. Findings from a study detected marginally insignificant excess abducens nerve affection in the COVID-positive group, and postvaccination diplopia was common in patients who received vector-based or RNA-based vaccines.[3] 

Acute onset diplopia is a rare and challenging presentation for ophthalmological management. Most cases presenting in an ophthalmology clinic are isolated third, fourth, or sixth nerve palsy; other causes include mechanical causes, dysfunction of higher control, decompensation of a pre-existing heterophoria, idiopathic causes, causes of monocular diplopia, and other diagnoses. The etiology is commonly identifiable at the first presentation based on clinical assessment, with a minimal percentage needing urgent radiological evaluation; only a minority of cases are likely to have serious emergent pathological causes.[4]

Diplopia has also been reported as an adverse complication of some neurosurgical procedures, dental procedures, endoscopic paranasal sinus surgery, and several ophthalmic procedures.[5] There are also studies on the occurrence of diplopia after surgical repair from blowout fractures[6], orbital floor fracture[7][8], or dehiscence of scleral belt loop tunnels.[9]

Another review identified the common cause of binocular diplopia according to etiologic distribution and clinical features such as microvascular, strokes, neoplastic, myasthenia gravis, and traumatic and decompensated phoria. The study also revealed that the majority of the patients with binocular diplopia were managed by neurologists, followed by ophthalmologists, emergency physicians, and neurosurgeons.[10]

Epidemiology

Diplopia is a common complaint in the ambulatory setting and the emergency department (ED), with one study reporting almost 80,5000 ambulatory visits and 50,000 ED visits in the United States yearly, with the chief complaint of diplopia.[11] Diplopia, particularly when acute in onset, is very unsettling to the patient. Although there can be life-threatening causes of diplopia, one study found that only 16% of patients with diplopia had potentially life-threatening etiologies.[4] 

Another study recently discussed diplopia as an important and debilitating symptom of malignancies due to different pathogenetic mechanisms. The authors also found that the cause of diplopia was due to orbital or brain metastasis or local invasion. Findings showed that diplopia manifested among patients with cancer together with paralytic strabismus and restrictive strabismus. Among the paralytic cases, sixth nerve palsy was found to be the most common. The authors also found that the cause of diplopia was due to orbital or brain metastasis or local invasion. They concluded that metastasis is the most common cause of diplopia in patients with cancer, and that screening for metastasis is vital upon the onset of diplopia for a better life expectancy.[12] 

Pathophysiology

Binocular diplopia occurs because the image falls outside of the fovea in 1 eye, thus triggering the perception of 2 separate images. If eye misalignment is horizontal, diplopia is horizontal; if the eye misalignment is vertical, diplopia will be vertical. 

Maculopathies can alter point-to-point foveal correspondence, causing diplopia. The effect that maculopathies have on the interaction of central sensory fusion compared with peripheral fusion is not similar to the common understanding of treatment for diplopia.[13]

Common cases of diplopia in adults are outpatient and can be classified based on their type of strabismus, which share typical age ranges and features. Although diplopia in adults is typically idiopathic, diplopia can be an indication of a serious pathological cause.[14] 

In an epidemiological study, orbital pulley disorders were diagnosed on the basis of MRI. Elderly patients with binocular diplopia usually exhibited vertical deviation compared with other types of strabismus like exotropia, esotropia, vertical strabismus, and combined strabismus. Findings showed the causes of disease in each group:

• Exotropia group: Convergence insufficiency exotropia, basic exotropia
• Esotropia group: Orbital pulley disorder, sixth cranial nerve palsy
• Vertical strabismus group: Fourth cranial nerve palsy, orbital pulley disorder
• Combined strabismus group: Orbital pulley disorder, fourth cranial nerve palsy.[15]

Another study focused on horizontal strabismus complicated by the disorder of the inferior oblique muscle or superior oblique muscle. This type of strabismus can cause compensatory head posture, vertical diplopia, torsional diplopia, and abnormal binocular fusion.[16]

Diplopia has also been evaluated among children, and most of them had nonemergent conditions. For those pediatric patients with life-threatening conditions, diplopia was characterized to have an acute onset associated with neurologic signs and visual symptoms.[17] 

History and Physical

A thorough history and clinical examination for diplopia must identify the following:

• Type (monocular/binocular)
• Onset
• Progression
• Associated symptoms
• Relieving factors [18]

When evaluating a patient with diplopia, the first determination is whether diplopia is monocular or binocular. Skipping this step will lead to unnecessary investigations and anxiety for the patient. 

The next step is to search for accompanying brainstem symptoms. Although isolated brainstem strokes are uncommon, diplopia can be the main complaint in patients with strokes involving the diencephalon or brainstem, which involve either the nuclei or fascicles of cranial nerves III, IV, or V, medial longitudinal fasciculus, or vestibulo-ocular pathways producing the skew deviation.[19]

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 ED for an MRI of the brain with attention to the brainstem. The MRI should include diffusion-weighted and susceptibility-weighted images to detect subtle ischemic or hemorrhagic lesions. 

All patients with diplopia should be asked about the fatiguability and variability of their symptoms and 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. In a study, the clinical characteristics of acquired diplopia in adults were double vision, followed by blurred vision, monocular diplopia, and eye strain. Past ocular histories were significant for early childhood strabismus and amblyopia. Hypertension and cranial nerve paresis were also associated with symptomatic strabismus, followed by benign, age-related divergence insufficiency esotropia.[20] 

Next, a careful examination should be performed, first testing ocular motility to identify obvious deficits and determine whether they map out to the dysfunction of the third or sixth 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 3-step test where the hypertropia increases in contralateral gaze and ipsilateral head tilt. A positive 3-step test indicates fourth nerve paresis.[19]

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 (preferably in percentages [eg, "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. A dilated fundus examination looking for the presence of optic nerve head edema and any signs of venous stasis retinopathy should also be performed in all patients with diplopia.

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), all findings must be combined to determine whether they can be due to an isolated palsy of the third, fourth, and sixth 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; to diagnose fourth nerve palsy, the examiner must be familiar with the 3-step test.

If there is more than 1 cranial nerve palsy, urgent neuroimaging (MRI of the brain and orbits with contrast enhancement) is mandatory to look for the lesions in the area of the cavernous sinuses, superior orbital fissure, and extraocular muscles. Ordering an MRI for emergencies can improve the etiological diagnostic performance of binocular diplopia and reduce a patient's exposure to ionizing radiation without increasing the average turnaround time or length of stay in the ED.[21]

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%.[22] 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.[23] 

All patients with third nerve palsy (regardless of whether it is complete or partial, pupillary sparing, or pupillary involving) should undergo an emergency CT angiography (CTA) of the brain in order to rule out an aneurysmal compressive lesion of the third cranial nerve in its subarachnoid compartment.[24] CTA is widely available and is very sensitive for detecting any aneurysms larger than 2 to 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[25]. 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 vasculopathy risk factors, it is reasonable to assume that the etiology of the third nerve palsy is likely micro-ischemic in nature. The patient should be observed for 2 to 3 months, during which time 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, an urgent MRI with contrast utilizing steady-state imaging sequences should be performed to follow the entire course of the third nerve and rule out any pathology affecting it along its course.[24] 

For patients with the fourth 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, posttraumatic, or micro-ischemic in nature and should either be palliated with the prisms in the spectacles or observed for spontaneous improvement.[26] 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 sixth nerve palsy who have vascular risk factors and 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 to 3 months. Patients without microvascular risk factors and all patients under 50 years of age with sixth nerve palsy should have an MRI with contrast and steady-state imaging acquisition performed to rule out demyelinating or compressive etiology anywhere along the course of the nerve.[19]

In the ED, the following strategies are discussed based on previous studies:

• Unenhanced plain CT of the head or orbits is not helpful in the workup of diplopia.
• MRI is preferred for ocular motor nerve palsies.
• Patients with isolated fourth and sixth nerve palsies without other neurological signs on examination should be referred to a neurologist or ophthalmologist for further evaluation due to limited resources in the ED.
• All patients presenting with an acute isolated third nerve palsy should be imaged with CT and CT angiography of the brain to eliminate compressive aneurysms.
• Contrast-enhanced CT imaging of the brain and orbits would be useful in suspected orbital apex syndrome, retro-orbital mass, thyroid eye disease, or ocular trauma.
• CT and CT venogram can be helpful in suspected cavernous sinus thrombosis.
• In any patient over the age of 60 years presenting with a recent (1-month) history of diplopia, inflammatory markers should be collected to rule out giant cell arteritis.[21]

Treatment / Management

Diplopia is typically an ophthalmologic complaint, predominantly found among elderly patients, that can have both ocular and neurological etiologies. Treatment and management are based on the specific cause of diplopia. For monocular diplopia, refraction and biomicroscopic examination of the ocular media are required. The etiology of ocular misalignment for binocular diplopia must be identified, and life-threatening conditions such as posterior communicating artery aneurysms must have immediate intervention.[4](B2)

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.[27]
• Monovision (placing a contact lens in one eye 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.[28] 

Case reports presented diplopia outcomes following stereotactic radiosurgery for petroclival or cavernous sinus meningiomas. The reports mentioned that skull base meningiomas (SBM) often present with diplopia due to compression of the abducens cranial nerve (cranial nerve VI). The study revealed that diplopia, related to a basal meningioma, may improve following gamma knife surgery (GKS). An earlier time course to radiosurgery after diplopia onset was associated with better outcomes.[29] (B3)

Recent advances in diagnosing diplopia include the observation that vertical diplopia from skew deviation is going to improve with supine positioning more than that caused by trochlear nerve palsies. Advances in the field of ocular myasthenia include the observation of decreased conversion to the generalized form with either steroids or thymectomy.[30] (B3)

Another study evaluated the therapeutic effect of temporal slant recession of the inferior rectus muscle (TSRIRM) for the treatment of small vertical deviations in patients with vertical diplopia. TSRIRM provided an effective and reliable treatment for small-angle vertical strabismus. Since this procedure has easy surgical access, it has a useful implementation in an outpatient neuro-ophthalmology setting.[31]

Differential Diagnosis

There is a long list of differential diagnoses for patients with binocular diplopia, and the best way to formulate them is through an anatomical approach. The following are some factors for consideration:

• Any lesions affecting the brainstem can affect the nuclei or the fascicles of the third, fourth, and sixth cranial nerves, involving the vestibulo-ocular pathways or medial longitudinal fascicule.

• Any lesions affecting the horizontal or vertical gaze centers (located in the pons and midbrain, respectively) rarely cause diplopia.

• Posterior reversible encephalopathy syndrome (PRES) presents with acutely altered mentation, drowsiness or sometimes stupor, visual impairment such as visual hallucinations, cortical blindness, hemianopia, quadrantanopia, and diplopia, seizures (focal or general tonic-clonic), sudden or constant, nonlocalized headaches.[32] 

• 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.

• Superior oblique myokymia (SOM) is described as monocular, high-frequency, low-amplitude, torsional, and involuntary contractions of the superior oblique muscle, resulting in oscillopsia and diplopia.[33]

• Uveomeningitis and myelodysplastic syndrome present with new onset uveitis, ataxia, diplopia, and fluctuating consciousness level without any significant findings from brain imaging or blood chemistries.[34]

• Pathology affecting the cerebrospinal fluid (CSF) (malignant cells circulating in it, inflammatory processes disturbing normal CSF composition, increased protein, etc) can also produce oculomotor palsies. Increased intracranial pressures can cause sixth nerve palsies.

• Guillain-Barré syndrome can cause diplopia when it preferentially affects the oculomotor nerves (third, fourth, and sixth) in the  Miller-Fisher variant, where the levels of GQ1b antibodies are often elevated. Among adults, neurological examination shows ophthalmoplegia, ataxia, and areflexia.[35] In children, diplopia along with ptosis, diplopia, and overall weakness may have serious underlying causes such as Guillain-Barré syndrome as well as myasthenia, botulism, and poisoning, which require a systematic and timely evaluation and proper management.[36]

• Thiamine deficiency (Wernicke encephalopathy) can produce diplopia as well; thus, intravenous thiamine should be administered in all patients with diplopia who are confused or 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, immunoglobulin G4 (IgG4) disease or granulomatosis with polyangiitis; vascular lesions from the expanding aneurysms of the intracavernous 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. 

• Lyme neuroborreliosis should be considered in the differential diagnosis of diplopia and oculomotor palsy. A case was presented with a history of radicular neck pain, binocular diplopia, and a left partial oculomotor palsy. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis and confirmed intrathecal synthesis of IgG and IgM antibodies against Borrelia burgdorferi.[37] 

• An extrarenal rhabdoid tumor in the right carotid space was manifested in a patient with diplopia during an ophthalmological examination, which is confirmed by the Lancaster test.[38] Metastatic lung squamous cell carcinoma should be considered since a study reported an unusual presentation of binocular diplopia and headache.[39] Osteomas usually involve paranasal sinus walls, and there was a case reported on the demonstrative radiological features of an unusual case of giant osteoma presenting with proptosis and diplopia.[40]

• Many lesions affecting superior orbital fissures can cause diplopia by affecting one or several cranial nerves that travel through it. These may include, but are not limited to, inflammation, infection, and bleeding from trauma. 

• Systemic lymphohistiocytic infiltration is a rare, peculiar condition associated with autoimmune disease, drug interaction, viral or mycobacterial infection, or malignancy. A case was presented on a patient with a history of moderate COVID-19 infection with binocular diplopia, acute loss of vision in the left eye, and orbital mass. A CT-guided biopsy of the right lung showed negative for malignancy but had features of lymphohistiocytic pleuritis.[41] 

• Orbital disease (such as thyroid eye disease, tumors, or vascular lesions of the orbit) can also cause diplopia. Recent studies mentioned that thyroid eye disease is characterized as progressive proptosis or diplopia, and the use of teprotumumab, compared with intravenous methylprednisolone, is associated with a higher reduction in diplopia.[42]

• Gradenigo syndrome consists of the clinical triad: abducens nerve palsy, retro-orbital pain (trigeminal ganglionitis), and chronic otorrhea (otitis media). This syndrome results from apical petrositis due to suppurative otitis media.[43]

• Convergence insufficiency is a binocular vision disorder described as maintaining fusion while looking at a near target due to the eyes’ tendency to point outwards. Associated symptoms include asthenopia (eye strain), diplopia, headaches, blurred vision, movement of print while reading, and difficulty with reading comprehension.[44]

• Keratoendotheliitis fugax hereditaria is a rare inflammatory genetic condition manifested as recurrent episodes of debilitating unilateral corneal and conjunctival hyperemia, corneal edema, visual impairment, corneal opacification, and photophobia that last for 2 to 5 days. Associated symptoms include lacrimation, pain, colored halos, diplopia, a mild anterior chamber reaction, guttata-like changes (pseudoguttata), and a ‘gritty’ feeling.[45] 

• Finally, disorders of neuromuscular junctions and myopathies affecting extraocular muscles can also produce diplopia. This includes seronegative ocular myasthenia gravis in older patients with transient dizziness and diplopia.[46] 

Prognosis

The prognosis of diplopia is very variable and depends entirely on the underlying condition that is causing it. Benign cases may be chronic and will need surgical correction. Diplopia may be corrected in cases where the underlying condition is treated, as in most cases of myasthenia gravis and Guillain-Barré variants. Lesions in the brainstem (small strokes) may improve over time.

Complications

The main complication of diplopia is patient discomfort. Many patients may also be unable to drive as a result of their diplopia. Individual etiologies that can cause diplopia have their own complications associated with them.