Overview of diplopia

INTRODUCTION — Dysfunction of the extraocular muscles may be the result of an abnormality of the muscle itself or an abnormality of the motor nerve to the muscle. The major symptom associated with this dysfunction is binocular diplopia, which is present with both eyes open and absent when either eye is closed. The evaluation of neuromuscular diplopia is reviewed here.

NEUROANATOMY — Three pairs of extraocular muscles move each eye in three directions: vertically (superior and inferior), horizontally (medial and lateral), and torsionally (intorsion when the eye rotates toward the patient's nose and extorsion when the eye rotates toward the patient's shoulder). The following muscles are responsible for these movements (table 1 and figure 1 and figure 2):

●The superior rectus and inferior oblique muscles are responsible for upward vertical movements. The superior rectus acts in all fields of gaze, and the inferior oblique helps elevate when the eye is turned inward.

●The inferior rectus and superior oblique muscles are responsible for downward vertical movement. The inferior rectus acts in all fields of gaze, and the superior oblique helps elevate on medial gaze.

●The lateral rectus is responsible for abduction.

●The medial rectus is responsible for adduction.

●The superior oblique is responsible for intorsion.

●The inferior oblique is responsible for extorsion.

The superior oblique muscle is innervated by cranial nerve IV, the lateral rectus muscle by cranial nerve VI, and all others by cranial nerve III (table 1).

Details of the neurologic examination with regard to eye movements are discussed separately. (See "The detailed neurologic examination in adults".)

CLINICAL PRESENTATION

Diplopia

Evaluation — Be sure to determine that the diplopia is present only with both eyes open and absent when either eye is closed (binocular diplopia). Binocular diplopia suggests that the underlying problem is due to ocular misalignment; generally, patients will choose to close the eye with the dysfunctional muscle unless that is the eye with much better vision.

Monocular diplopia (persists with one eye closed) suggests local eye disease or refractive error; this is generally a problem that should be referred to an ophthalmologist and is not discussed further here. Triple vision or triplopia is a rare complaint in patients with extraocular paresis, usually as a transient phenomenon in patients with superimposed nystagmus or oscillopsia [1]. Multiple images with one or both eyes is also a common complaint in patients with nuclear sclerotic cataract.

Important questions to ask the patient with binocular diplopia include:

●In which field of gaze is the double vision worst? The worst position of gaze represents the field of action of a paretic muscle (eg, with a right lateral rectus palsy, diplopia is greatest on right lateral gaze). If a muscle is restricted, however, as in thyroid disease, the double vision is worst when trying to stretch the muscle, that is, opposite to its field of action. Thus, a patient with thyroid ophthalmopathy cannot look up because the inferior rectus is tight, not because the superior rectus is weak.

●In which field of gaze are the double images closest together?

●Is the separation of images vertical, horizontal, or oblique?

●Is there any corrective head position that makes the double vision tolerable?

●Is the double vision worse at a distance (typical of a sixth nerve palsy) or is it worse at near (typical of a medial rectus palsy)?

Vertical diplopia — Patients with vertical diplopia complain of seeing two diagonally displaced images, one higher than the other. There are many causes of vertical diplopia (table 2).

Vertical diplopia in primary gaze suggests underactivity of the right or left inferior rectus, superior rectus, inferior oblique, or superior oblique [2]. If vertical separation is worse on right gaze, the right superior or inferior rectus or the left inferior or superior oblique may be underactive; separation that is worse looking to the right and down suggests underactivity of the right inferior rectus or left superior oblique.

Torsional abnormalities due to oblique muscle involvement should be suspected in patients who complain of image separation that worsens or improves with left or right head tilt.

The direction of compensatory head tilt may provide further diagnostic clues. Underaction of the superior or inferior rectus muscles is compensated by chin flexion or extension. Torsional diplopia due to underaction of the oblique muscles may be associated with an angular head tilt.

Hypertropia refers to an upward vertical displacement of one eye in primary gaze. A right hypertropia occurs with paresis of the right eye depressors (right inferior rectus or superior oblique) or left eye elevators (left superior rectus or inferior oblique). If the right hypertropia increases in left gaze, either the right superior oblique or the left superior rectus muscle is underacting. If the vertical deviation increases with right head tilt, the right superior oblique muscle is weak [2].

A skew eye deviation presenting with hypertropia and vertical diplopia can result from an imbalance in the vestibular system. In such patients, the diplopia typically does not match ocular muscle function and the deviation changes when the patient is tested sitting versus lying down. These features can distinguish a skew eye deviation from extraocular paresis. In addition, patients with vestibular pathology typically have other symptoms.

Horizontal diplopia — Horizontal diplopia is usually due to disease processes that affect the medial or lateral rectus muscles or the innervation of these muscles [3]. The images appear side by side; as mentioned above, image separation that is worse at a distance is typical of a sixth nerve palsy, while image separation that is worse at near is typical of a medial rectus palsy. An esotropia refers to a medial deviation of the eye at primary gaze; an exotropia refers to lateral deviation in primary gaze. There are many causes of horizontal diplopia (table 3) [3].

Ocular misalignment without diplopia — Some patients lack diplopia despite obvious ocular misalignment. There may be a number of explanations for this finding:

●Vision may be suppressed in one eye because of an old strabismus. Some patients with strabismus can develop a type of peripheral double vision if they have anomalous retinal correspondence, which is then followed by the original angle of the double vision changing because of neuromuscular disease or a change in the angle of the strabismus with age.

●Patients may have decreased vision in one eye, in which case the double vision will only be for objects large enough to see by the eye with poor vision.

●Some patients have such a wide separation of the images that they are able to ignore one of the images because it is far out of alignment with the true straight-ahead image.

●Some patients have such a minimal separation of the images that they cannot appreciate that they are seeing two images. They complain, instead, of "blurred vision," which is really a combination of two images.

●Some patients will have a misalignment only when the eyes are moving. However, vision is suppressed when the eyes are moving so that they are not aware of a double vision.

Pain — Ask the patient about the presence or absence of any ocular, orbital, or periorbital pain and request that the patient point to the location of the pain. Painful ophthalmoplegia has a specific differential diagnosis that is distinct from painless ophthalmoplegia (table 4).

●Diffuse intracranial pathology is suggested by complaints of a generalized headache or pain in the area of the temple. By contrast, it is most likely that the patient has an isolated lesion of one of the cranial nerves if the pain is localized to the area just above the eyebrow on the side of the weak muscle.

●Intraorbital pathology should be considered in patients with pain localized directly to the eye.

●Sudden onset of head pain described as the worst ever experienced should be a cause for concern and suggests an intracranial aneurysm. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

●Another worrisome type of pain is one that is severe, requires heavy opiate-type medication, and is distributed to the area of the first or second division of the fifth cranial nerve. It is important in such cases to carefully test for sensory loss in the area of the forehead and cheek; such a symptom often indicates that there is a tumor pressing on the fifth cranial nerve as well as the affected nerve to the eye muscle.

●Pain on eye movement suggests a myopathy or an orbital process. Pain on eye movement but without double vision is also typical of optic neuritis.

Onset and clinical course — Ask the duration of the problem. Sometimes old photographs are useful in doubtful cases. Old photographs are particularly helpful in cases of lid ptosis, fourth nerve palsy, and pupillary abnormalities.

Was the onset sudden and has now plateaued, or was it gradual with steady worsening? Did the pain precede the palsy and resolve shortly after the palsy started? This presentation is typical of idiopathic or ischemic etiologies (eg, due to diabetes mellitus or giant cell arteritis).

Does the motility problem change as the day goes on? This is a classic sign of myasthenia gravis (MG), but MG is not necessarily the only cause of this symptom.

Finally, one should ask a broad question about any other symptoms, particularly neurologic symptoms, that occurred with the double vision.

EXAMINATION

Pupil — When the parasympathetic fibers of the third nerve are involved, resulting in pupillary dilation in association with other dysfunction of the third cranial nerve, it is a warning sign of a compressive lesion of the third nerve, typically an aneurysm or, less commonly, a tumor. (See "Approach to the patient with anisocoria".)

Eye movements — Details of the neurologic examination with regard to eye movements are discussed separately. (See "The detailed neurologic examination in adults".)

It is often enough merely to observe the eye movement in the right, left, up, and down gaze (figure 2). In the more profound expressions of ocular motility disturbance, the astute observer can determine which muscle is dysfunctional by making these observations alone. The following are some simple rules:

●If the double vision is worse on looking to one side and better looking to the other, and if the eyes appear crossed, the problem is most likely that the lateral rectus muscle is not working. Usually this is due to a sixth nerve palsy.

●If there is some droopiness of the lid and if any combination of the following things is present (poor inward turning, poor elevation, or poor depression of the eye), then there is probably at least a partial third nerve palsy.

●If the patient likes to tilt his or her head to get better vision and if the double vision is primarily vertical and worst looking to one side and down, there is probably a fourth nerve palsy.

With most patients, one can hold a finger vertically or horizontally and move it into different fields of gaze asking in which field of gaze the image separation is the worst and in which it is the best. While holding the finger in the field of gaze with the worst double vision, cover one eye and ask which image disappears. With a vertical diplopia, when the higher image disappears the covered eye is lower in position than its partner is and vice-versa. With horizontal diplopia, when the image to the right of the other image disappears, the covered eye is pointed to the left of its partner. Crossed diplopia means uncrossed eyes and vice-versa.

A relatively simple office test that can be helpful is use of a red glass over one eye. This device helps the patient identify the two images more clearly and helps the clinician identify from which eye each image is coming. However, the results of this test should be interpreted with caution; some patients seem to be able to fuse the red and white light with effort. Also, some patients give potentially misleading interpretations, saying, for instance, that they see one light on top of the other when they mean that the lights are superimposed.

There are several ways to precisely measure the amount of eye deviation. Prism measurements are commonly used since this number is necessary if the ultimate goal is to correct the deviation with a prism in the glasses, or at least to help the patient with a prism.

Restrictive ophthalmoplegia — If a patient has a tight and fibrous or entrapped muscle, attempted gaze in the direction away from the field of action of the muscle will result in a rise in intraocular pressure. A rise of 7 mmHg is considered diagnostic of restrictive ophthalmopathy. On examination, the patient will appear to have a weakness of the opponent muscle due to failure of relaxation of the restricted muscle. A patient with Graves' disease will frequently have this problem due to fibrosis of the inferior rectus muscle. In such cases, on attempted upward gaze the intraocular pressure will rise in the affected eye.

Other cranial nerves — The second important observation is the possible involvement of any other cranial nerves. Mononeuropathies (dysfunction of only one cranial nerve) are often idiopathic. However, polyneuropathies require a full and extensive neuroradiologic and laboratory workup. Of particular importance are processes that involve the nerves near the third, fourth, and sixth cranial nerves. As examples, the second cranial nerve is concerned with vision, the pupillary light reaction, and visual fields; the fifth cranial nerve is responsible for facial and corneal sensation; abnormalities of the seventh cranial nerve may cause facial droop or weakness of the orbicularis oculi muscle; and pathology of the eighth cranial nerve can be suggested by dizziness or loss of hearing.

Globe — The presence of forward protrusion of the eye, exophthalmos, suggests thyroid ophthalmopathy or Graves' disease. To assess for the presence of exophthalmos, have the patient look down while retracting the upper lids, and look down past the patient's brow to compare the forward location of the two corneas. A small amount of upper lid ptosis, often present in these cases, will mask the appearance of exophthalmos as viewed from straight ahead. In testing for orbital resiliency (that is, how easily can one retroplace the globe digitally), stand to the side of the patient and observe the eye going back when pressing with the finger. This gives a visual and tactile input.

Observe whether the eyeball is congested. Ask the patient to assume the head position that maximizes the double vision and the one that minimizes the double vision. Is there any droopiness of the lid?

DIAGNOSTIC APPROACH — It is difficult to establish a standard guideline for the evaluation of diplopia. Multiple possible etiologies exist, many of which can be serious. Some important caveats are helpful:

●The first rule is to determine if a single nerve is involved. Involvement of other nerves, even the opposite cranial nerve (eg, bilateral sixth nerve palsy), suggests a more serious underlying disorder and requires more extensive evaluation, including neuroimaging. Descriptions of cranial mononeuropathies involving the third, fourth, and sixth cranial nerves, along with their most common causes, are described below. (See 'Third cranial nerve palsy' below and 'Fourth cranial nerve palsy' below and 'Sixth nerve palsy' below.)

●The presence or absence of associated pain is an important distinguishing feature. Painful ophthalmoplegia has a specific differential diagnosis that is distinct from painless ophthalmoplegia (table 4). The presence of severe headache of sudden onset demands an urgent evaluation for cerebral aneurysm. (See 'Pain' above.)

●The second question is whether associated medical comorbidities (diabetes, thyroid disease) are relevant. As examples, diabetes is associated with cranial mononeuropathies affecting the third, fourth, or sixth nerves; chronic alcoholism is a risk factor for Wernicke syndrome.

●The onset and clinical progression of the disorder can be helpful. Signs of improvement over time almost always means the process is benign, fluctuating symptoms may suggest myasthenia, and a sudden onset is consistent with ischemia. (See 'Onset and clinical course' above.)

ETIOLOGIES — Diplopia may arise due to a number of causes, including a neurogenic lesion (supra-, inter-, or infranuclear), a neuromuscular transmission defect, myopathy, or mechanical restriction in the orbit. An exhaustive summary of these etiologies is the subject of other reviews [2,3]. Some helpful clues in patients with vertical or horizontal diplopia and some of the more common acquired causes of diplopia are discussed here.

Third cranial nerve palsy — Third cranial nerve (oculomotor) palsies may cause both vertical and horizontal diplopia. Patients with a complete unilateral third nerve palsy have ptosis, a large unreactive pupil, and paralysis of adduction, elevation, and depression; the eye rests in a position of abduction, slight depression, and intorsion [2]. The asymmetry of pupil size is greater in the light than in the dark.

Absence of pupillary involvement suggests a benign process that can be observed over a couple of weeks. A fixed, dilated pupil requires extensive neurologic evaluation. Partial involvement of the pupil (defined in one report as anisocoria greater than 0.5 but less than 2.0 mm in room light, and in which the affected pupil maintained reactivity to light) may be associated with either serious or benign underlying pathologies; neuroimaging is indicated in these individuals [4].

This topic is discussed separately. (See "Third cranial nerve (oculomotor nerve) palsy in adults" and "Third cranial nerve (oculomotor nerve) palsy in children".)

Fourth cranial nerve palsy — Cranial nerve IV (trochlear) palsy is a common cause of vertical diplopia. Congenital fourth nerve palsy may present at any age as most patients are able to compensate for the double vision. Most acquired fourth nerve palsies are either traumatic or microvascular in etiology.

Fourth cranial nerve palsy is discussed separately. (See "Fourth cranial nerve (trochlear nerve) palsy".)

Sixth nerve palsy — Patients with sixth cranial nerve (abducens) palsies primarily complain of horizontal diplopia worse at distance and often noted while driving. Causes include malignancy, vascular disease, and trauma. Sixth cranial nerve palsy is discussed separately. (See "Sixth cranial nerve (abducens nerve) palsy".)

Internuclear ophthalmoplegia — Internuclear ophthalmoplegia is a specific gaze abnormality characterized by impaired horizontal eye movement with weak adduction of the affected eye and abduction nystagmus of the contralateral eye. This results from a lesion (usually stroke or demyelination) in the medial longitudinal fasciculus in the dorsomedial brainstem tegmentum of either the pons or the midbrain. (See "Internuclear ophthalmoparesis".)

Myasthenia gravis — The extraocular eye muscles are often involved in myasthenia gravis (MG). The clinical manifestations vary from subtle blurring of vision to severe diplopia. MG-induced diplopia can mimic an internuclear ophthalmoplegia. Unilateral or bilateral ptosis is common but variable in severity and may switch from eye to eye. Most patients with MG do not complain of eye pain or headache. Fatigability and variability of clinical findings are characteristic.

Physical examination may reveal impaired eye movements that do not conform to the anatomy of one nerve or muscle. The pupils are always spared in MG, helping in the differentiation from other disorders such as botulism. Ocular MG is discussed separately. (See "Ocular myasthenia gravis".)

Thyroid ophthalmopathy — Thyroid ophthalmopathy is a common cause of horizontal or vertical diplopia. Restriction of extraocular movement preferentially affects the inferior rectus, medial rectus, and superior rectus, in that order [2]. Because the process causes muscle tightness or restriction, the diplopia is worse in the direction opposite that of the involved muscle action [3]. Thus, hypertropia (upward vertical deviation) and esotropia (medial deviation) are common in patients with thyroid ophthalmopathy, but exotropia (lateral deviation) is uncommon because the lateral rectus muscle is usually not involved.

Limitation in elevation of one or both eyes with vertical misalignment is the most common defect of ocular motility in these individuals. The other characteristic signs of thyroid ophthalmopathy include proptosis and periorbital edema. (See "Clinical features and diagnosis of thyroid eye disease".)

Ophthalmoplegic migraine — Ophthalmoplegic migraine is rare and most often seen in children and young adults. It is a diagnosis that should be made only after other disorders have been ruled out. It may affect the third (most common), fourth, or sixth cranial nerves. Extraocular muscle paralysis can occur with the first attack of headache or, rarely, precede it. Permanent damage to the third nerve has been reported [5]. Other causes of painful ophthalmoplegia (eg, aneurysm) should be excluded with neuroimaging studies.

Ophthalmoplegic migraine is now considered a cranial neuralgia because magnetic resonance imaging (MRI) gadolinium enhancement of the cisternal segment of the affected cranial nerve has been demonstrated in patients with a typical clinical presentation, suggesting that the condition may be a recurrent demyelinating neuropathy. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine subtypes'.)

Wernicke syndrome — Wernicke syndrome is caused by thiamine deficiency and is typically associated with alcohol abuse. Patients with Wernicke encephalopathy may complain of vertical or horizontal diplopia due to a supranuclear or nuclear lesion [2]. Encephalopathy and gait ataxia are common but not invariable accompaniments; ptosis and pain are uncommon. (See "Wernicke encephalopathy".)

Orbital myositis — Orbital myositis is an idiopathic inflammation of an extraocular muscle. The diagnosis should be considered in patients who have seemingly isolated extraocular muscle dysfunction, especially in the distribution of cranial nerve III.

Patients present with acute or subacute orbital pain and horizontal diplopia; absence of pain suggests an alternate diagnosis [6,7]. On physical examination there may be conjunctival chemosis and injection, ptosis, and proptosis. The process can be unilateral or bilateral. Neuroimaging reveals a focal or diffuse inflammatory lesion. The disorder usually resolves with corticosteroids [8], particularly in severe cases, although in the author's experience corticosteroids tend to prolong the course of what might otherwise be a self-limited illness.

Tolosa-Hunt syndrome — The Tolosa-Hunt syndrome (THS) is a rare syndrome, which is characterized by painful ophthalmoplegia involving one or more of the third, fourth, and/or sixth cranial nerves. THS is caused by an idiopathic granulomatous inflammation of the cavernous sinus. This syndrome responds to corticosteroid therapy.

While considered a benign condition, permanent neurologic deficits can occur, and relapses are common, often requiring prolonged immunosuppressive therapy. THS must also be carefully differentiated from more commonly occurring malignancies and infections involving the cavernous sinus, a task made difficult by the lack of a specific diagnostic test abnormality. (See "Tolosa-Hunt syndrome".)

Others — A number of other pathologies can lead to diplopia and/or ophthalmoplegia [9].

●Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) can affect the extraocular muscle function as a presenting manifestation. This is often referred to as the Fisher or Miller Fisher variant. Typically, deep tendon reflexes are also absent. Ocular muscle involvement is often, but not always, bilateral and symmetrical. Affected patients are often ataxic as well. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'GQ1b syndromes'.)

●Tick bite paralysis and botulism are neuromuscular junction pathologies that can lead to extraocular muscle weakness. (See "Botulism" and "Tick paralysis".)

●Structural lesions (metastases, infections) affecting the skull base cavernous sinus can lead to a cranial polyneuropathy with diplopia as the primary manifestation.

●Giant cell arteritis can present with diplopia, usually with other suggestive clinical features. (See "Clinical manifestations of giant cell arteritis" and "Clinical manifestations of giant cell arteritis", section on 'Ophthalmic syndromes'.)

SUMMARY AND RECOMMENDATIONS

●Binocular diplopia (double vision with both eyes open and absent when either eye is closed) often results from dysfunction of one or more of the extraocular muscles. By contrast, monocular diplopia, which persists when one eye is closed, suggests local eye disease or a refractive problem. (See 'Clinical presentation' above.)

●Three pairs of extraocular muscles move each eye in three directions: vertically (superior and inferior), horizontally (medial and lateral), and torsionally (intorsion when the eye rotates toward the patient's nose and extorsion when the eye rotates toward the patient's shoulder) (table 1 and figure 1 and figure 2). (See 'Neuroanatomy' above.)

●The presence or absence of pain is an important distinguishing feature in considering a differential diagnosis (table 4). (See 'Clinical presentation' above.)

●The examination should focus on establishing which particular extraocular muscle or muscles may be weak. The presence of pupillary or other cranial nerve abnormality and other ocular findings are also important. (See 'Examination' above.)

●When the pattern of muscle weakness suggests that the problem is isolated to a single cranial nerve, the differential diagnosis is specific to the individual nerve:

•For third nerve palsies, the presence or absence of pupillary involvement and other associated signs is critical to localization and diagnosis (table 5). (See "Third cranial nerve (oculomotor nerve) palsy in adults" and "Third cranial nerve (oculomotor nerve) palsy in children".)

•Most fourth cranial nerve palsies are idiopathic or traumatic in etiology. (See 'Fourth cranial nerve palsy' above.)

•Sixth nerve palsies cause isolated weakness of abduction and may result from poorly controlled diabetes, among other causes (table 6). Bilateral sixth nerve palsies may be seen in elevated intracranial pressure. (See 'Sixth nerve palsy' above.)

●Internuclear ophthalmoplegia is a specific gaze abnormality characterized by impaired horizontal eye movement with weak adduction of the affected eye and abduction nystagmus of the contralateral eye. This results from a lesion (usually stroke or demyelination) in the medial longitudinal fasciculus in the dorsomedial brainstem tegmentum of either the pons or the midbrain. (See "Internuclear ophthalmoparesis".)

●The extraocular eye muscles are often involved in myasthenia gravis (MG). Multiple extraocular muscles in both eyes are typically involved and ptosis is also often present. Fatigability and variability of clinical findings are characteristic clues to this diagnosis. (See "Ocular myasthenia gravis".)

●Thyroid ophthalmopathy leads to muscle tightness and restriction of movement. Proptosis is usually also present. (See "Clinical features and diagnosis of thyroid eye disease".)

●Other causes of binocular diplopia affecting multiple, bilateral extraocular muscles include orbital myositis, Tolosa-Hunt syndrome (THS), Miller Fisher variant of acute inflammatory demyelinating polyneuropathy, and structural and/or inflammatory lesions involving the skull base cavernous sinus, or basilar meninges. (See 'Etiologies' above.)