Establishing binocularity and direction of diplopia
Patients with a variety of neurological, ophthalmological, and psychiatric disorders complain of diplopia. The first step in diagnosing diplopia is to determine whether the problem occurs only when both eyes are viewing the target (binocular) or if it persists when one eye is closed (monocular). Binocular diplopia is usually secondary to nervous system dysfunction and therefore will be the focus of this chapter. Monocular diplopia is usually secondary to intraocular pathology and should prompt appropriate referral to an ophthalmologist. In some cases, monocular diplopia is due to psychogenic disease – only rarely is it due to CNS disease such as head trauma.1 All patients with monocular diplopia also have binocular diplopia – monocular diplopia that disappears when both eyes are opened is almost always secondary to psychogenic disease. If it is not clear from the history whether diplopia is monocular or binocular, ask the patient to close or cover each eye in sequence. If the diplopia disappears when one eye is covered, it is binocular.
After establishing that diplopia is binocular, the next step is to determine whether it is horizontal, vertical, mixed (diagonal or oblique), or fluctuating. Ask the patient whether the images are stacked on top of each other, are side by side, or are diagonal to each other. For horizontal diplopia, it may be helpful to ask whether the images are worse when viewing objects near (e.g. reading a book) or far away (e.g. watching television): horizontal diplopia worse with near viewing suggests an adduction deficit, while horizontal diplopia worse with distant viewing suggests an abduction deficit. For patients with vertical diplopia, ask about difficulty with reading or descending stairs, both of which suggest difficulty with depressing or intorting the eyes. It is also important to ask about fluctuating symptoms. Double vision that changes from the horizontal to the vertical plane, gets worse as the day progresses, or disappears and reappears later is consistent with neuromuscular junction dysfunction, specifically myasthenia gravis.
Inspecting ocular misalignment
Inspecting the eyes before starting the formal examination often provides valuable information about ocular misalignment. In some cases, eye deviation is obvious at rest. For example, an oculomotor nerve lesion puts the eye in a “down-and-out” position due to the unopposed actions of the superior oblique and lateral rectus muscles, while a severe abducens nerve lesion leads to medial deviation of the eye in the orbit. Shining a flashlight onto both eyes from a distance may uncover subtle diplopia: if the eyes are misaligned, light will reflect from different spots on the two corneas. Examine patients who complain of diplopia for a head tilt indicating a torsional deficit, which is especially common in patients with fourth-nerve palsies and brainstem abnormalities. Finally, look for abnormalities in the pupils and eyelids: a large or blown pupil or ptosis both point to dysfunction of the ipsilateral third nerve.
Localizing the dysfunctional eye movement
In order to localize the cause of binocular diplopia to a particular site in the nervous system, the dysfunctional eye movement must be identified. Figure 6.1 shows the two-step testing schematic for localizing horizontal diplopia, while Figure 6.2 shows the three-step testing schematic for vertical eye movements. In most cases of dysfunction of a single eye movement, these rules are effective. This testing scheme may be less useful when multiple eye movements are abnormal or when the patient has a prenuclear defect such as a skew deviation.
• Step 1: Find the direction of maximal image separation. Ask the patient to follow your finger to the left, right, up, and down, observing for weakness of eye movements in each direction and
Figure 6.1 Testing schematic for horizontal diplopia. LLR = left lateral rectus, LMR = left medial rectus, RLR = right lateral rectus, RMR = right medial rectus. See text for further details.
inquiring specifically about worsening of double vision in each direction of gaze.
• Step 2: Determine which eye is seeing the false image. After the patient identifies the direction of maximal diplopia, point out to them that there is one image on the outside (e.g. to the right when looking to the right) and one image on the inside (e.g. to the left when looking to the right). Once they verify that there is an inner and an outer image, instruct them to cover one eye and ask which image disappears. The outer image will disappear when the abnormal eye is covered. To state this differently, the eye that sees the false image will always see it as the outer one. Steps 1 and 2 will localize the dysfunctional eye movement for patients with horizontal diplopia.
• Step 3 (for vertical diplopia): Steps 1 and 2 will localize the source of vertical diplopia to an oblique muscle or to a rectus muscle in one eye. The oblique muscles are the primary elevators and depressors of the eye in the adducted position, while the rectus muscles are the primary elevators and depressors of the eye in the abducted position. If vertical image separation is greater in adduction, the oblique muscle is dysfunctional. If it is greater in abduction, the rectus muscle is dysfunctional.
Localizations of horizontal diplopia
Abducens nerve palsy
The abducens nucleus, found in the pons, gives rise to both the abducens nerve, which innervates the ipsilateral lateral rectus, and to fibers that ascend in the medial longitudinal fasciculus (MLF) and synapse with the contralateral oculomotor nucleus, thereby yoking horizontal eye movements. Because lesions of the abducens nucleus affect fibers of both the
Figure 6.2 Testing schematic for vertical diplopia. LIO = left inferior oblique, LIR = left lateral rectus, LSO = left superior oblique, LSR = left superior rectus, RIO = right inferior oblique, RIR = right inferior rectus, RSO = right superior oblique, RSR = right superior rectus. See text for further details.
abducens nerve and the MLF, lesions at this site lead to gaze palsy towards the side of the lesion rather than simply restricting lateral movement of the ipsilateral eye. Nuclear lesions usually also affect the facial nerve fascicles as they sweep around the abducens nucleus, leading to ipsilateral gaze palsy and ipsilateral facial paresis.
The abducens nerve fascicles project ventrally through the pons and cross the corticospinal tract, leading to ipsilateral abducens nerve palsy and contralateral hemiparesis. The most common causes of abducens fascicle lesions are demyelination and ischemia.
Prepontine segment lesions
The abducens nerve emerges from the brainstem in the prepontine cistern, and enters the cavernous sinus via Dorello’s canal. The most important cause of abducens nerve palsy in the prepontine cistern is increased intracranial pressure, which often affects both abducens nerves simultaneously. In some cases, decreased intracranial pressure, as may occur after a lumbar puncture or as a consequence of spontaneous intracranial hypotension, may stretch the abducens nerve as it enters Dorello’s canal. Gradenigo syndrome is characterized by ipsilateral facial pain and eye abduction weakness caused by simultaneous involvement of the fifth and sixth nerves at the tip of the petrous bone, usually by spread of infection from the inner ear.
Cavernous sinus and orbit lesions
Within the cavernous sinus, the abducens nerve may be involved in isolation, although the other cranial nerves that travel through the cavernous sinus are usually also involved (see below). The abducens nerve emerges from the cavernous sinus, enters the orbit via the superior orbital fissure, and innervates the lateral rectus muscle. Important causes of abducens nerve lesions within the orbit include trauma, infection, and neoplasm.
Figure 6.3 Illustration of right internuclear ophthalmoplegia. A lesion of the right medial longitudinal fasciculus prevents adduction of the right eye. Abduction of the left eye is preserved.
Partial oculomotor (cranial nerve III) palsy
A more detailed discussion of the anatomy and pathology of the third nerve is provided below. Because it innervates four extraocular muscles, isolated eye adduction weakness is not a common presentation of an oculomotor nerve lesion. Isolated adduction weakness is more commonly secondary to lesions of the MLF or neuromuscular junction.
Internuclear ophthalmoplegia (INO) is caused by a lesion of the MLF, the pathway that connects the abducens nucleus to the contralateral oculomotor nucleus (Figure 6.3). On examination, patients with INO cannot adduct the ipsilateral eye and have nystagmoid movements in the contralateral eye. Internuclear ophthalmoplegia often occurs in combination with other ocular motor abnormalities including vertical nystagmus and skew deviation. Common causes of INO include multiple sclerosis, in which case it tends to be bilateral, and stroke, in which case the INO is more often unilateral. When bilateral, the term wall-eyed bilateral INO (WEBINO) is often used, as neither eye is capable of adducting. The one-and-a-half syndrome is caused by a pontomesencephalic lesion of one abducens nucleus and both MLF pathways. The patient with one-and-a-half syndrome is unable to abduct the eye ipsilateral to the lesion or to adduct either eye.
Localizations of vertical diplopia
Trochlear nerve palsy
Trochlear nerve lesions produce vertical or oblique (diagonal) diplopia. One clue to the presence of trochlear nerve palsy is that the patient will tilt their head to the side opposite to the lesion in order to reduce the diplopia.
Nuclear, fascicular, and cisternal segment lesions
The trochlear nucleus is found in the midbrain, contralateral to the superior oblique muscle that it innervates. Ischemic or demyelinating lesions may affect the nerve or its fascicles within the brainstem. The fibers of the trochlear nerve decussate in the anterior medullary velum and emerge posteriorly from the midbrain. Along this segment, the trochlear nerve is most often affected by trauma. The trochlear nerve then runs anteriorly along the lateral aspect of the brainstem and enters the cavernous sinus.
Cavernous sinus and orbit lesions
Lesions within the cavernous sinus are likely to affect the trochlear nerve in conjunction with the other cranial nerves that pass through it. The trochlear nerve emerges through the superior orbital fissure to innervate the superior oblique muscle, a muscle that depresses and intorts the eye.
Skew deviation is vertical ocular misalignment produced by disruption of prenuclear vestibular inputs to the ocular motor nuclei. Discussing the neuroanatomy and physiology of skew deviation is beyond the scope of the text, and I will direct the interested reader to the review by Brodsky et al.2 Briefly, skew deviation should be considered as the cause of vertical diplopia under the following circumstances:
• when vertical diplopia is comitant (of the same magnitude) with both left and right gaze
• when examination suggests dysfunction isolated to the inferior rectus, superior rectus, or inferior oblique
• when internuclear ophthalmoplegia is present
• in patients with known brainstem disease
Lesions in a variety of locations within the brainstem, cerebellum, and sometimes the peripheral vestibular system may lead to skew deviation. Approximately one-third of patients with brainstem infarction will have skew deviation, which is often explained incorrectly as a “partial third-nerve palsy.”3 Other causes include hemorrhage, trauma, neoplasm, and demyelination.
Partial third-nerve palsy
Damage to the third-nerve fibers that supply either the superior rectus or inferior oblique muscles without involvement of other muscles innervated by the third nerve may produce vertical diplopia. The selective involvement of these specific muscles, however, is uncommon.
Localizations that produce diplopia in more than one direction
Oculomotor nerve palsy
The oculomotor nucleus actually consists of a cluster of subnuclei in the dorsal midbrain. The medial rectus, inferior rectus, and inferior oblique subnuclei are all ipsilateral to the muscles that they innervate. The superior rectus subnuclei are contralateral to the muscles that they innervate, while the levator palpebrae are innervated by a shared midline subnucleus. Thus, a lesion of one side of the oculomotor nuclear complex will affect the:
• ipsilateral medial rectus
• ipsilateral inferior rectus
• ipsilateral inferior oblique
• contralateral superior rectus
• bilateral levator palpebrae
Figure 6.4 Important lesions affecting the oculomotor nerve in the midbrain. Claude’s syndrome is characterized by an ipsilateral third-nerve palsy and contralateral limb ataxia. Weber’s syndrome is characterized by an ipsilateral third-nerve palsy and contralateral hemiparesis.
Pupilloconstrictor fibers are found in the Edinger–Westphal nucleus, as discussed in Chapter 7.
The oculomotor nerve arises from its nucleus in the midbrain and runs anteriorly in the brainstem as the oculomotor nerve fascicles. It contains fibers to the ipsilateral:
• medial rectus
• inferior rectus
• inferior oblique
• superior rectus
• levator palpebrae
• pupilloconstrictor muscles
Fascicles of the third nerve run anteriorly in the midbrain, adjacent to several important structures (Figure 6.4). A third-nerve lesion that involves the adjacent red nucleus produces Claude’s syndrome, characterized by oculomotor dysfunction and contralateral limb ataxia. More anteriorly within the midbrain, a lesion of the third nerve and cerebral peduncle produces Weber’s syndrome, characterized by oculomotor dysfunction and contralateral hemiparesis.
Cisternal segment lesions
The third nerve emerges from the ventral midbrain in the interpeduncular cistern. It passes between the posterior cerebral and superior cerebellar arteries before penetrating the cavernous sinus. A mass lesion in the interpeduncular cistern affects the dorsally located pupilloconstrictor fibers first, leading to a dilated, unreactive pupil, while sparing extraocular motor and lid levator fibers.4 Complete palsy of the third nerve will develop if this mass lesion, most commonly an aneurysm of the posterior communicating artery or herniating uncus, is left untreated. Pupil-involving third-nerve palsies are discussed in further detail in Chapter 7.
Cavernous sinus lesions
The third nerve enters the cavernous sinus, where it is usually affected in combination with the other ocular motor nerves and the first two divisions of the trigeminal nerve. In the anterior cavernous sinus, the nerve divides into superior (which innervates the superior rectus and levator palpebrae) and inferior (which innervates the medial rectus, inferior rectus, inferior oblique, and pupilloconstrictors) divisions. Either division may be affected in isolation.
Pupil-sparing third-nerve lesions
The typical clinical history of the pupil-sparing third-nerve lesion is that of an older patient with diabetes or other risk factors for vascular disease who develops the acute onset of retro-orbital pain and weakness of the extraocular muscles and the levator palpebrae. It is often called a “diabetic third” or an “ischemic third.” The precise localization of the pupil-sparing third-nerve lesion is unclear, and may lie within the midbrain fascicles or in the nerve proper after its emergence from the brainstem.
Wernicke’s encephalopathy is the clinical triad of ataxia, ophthalmoplegia, and confusion in patients with thiamine deficiency, usually secondary to chronic alcohol use. Only a small minority presents with the complete triad, with confusion being the most consistent element.5 Eye movement in any direction may be affected, although the sixth nerve is involved most frequently.6 Treat patients with Wernicke’s encephalopathy with a 5-day course of thiamine (100 mg IV). Timely vitamin supplementation usually reverses the ocular motor deficits within hours to days.
Cavernous sinus lesions
Deficits of multiple extraocular movements should always prompt consideration of cavernous sinus lesions, as the oculomotor, trochlear, and abducens nerves lie in close proximity within the cavernous sinus. Other clues to a cavernous sinus lesion include ipsilateral facial and retro-orbital pain due to involvement of the first two divisions of the trigeminal nerve and visual field defects due to involvement of the adjacent optic chiasm (Chapter 5). The most important cause of cavernous sinus syndrome is septic cavernous sinus thrombosis, a life-threatening emergency that must be treated quickly. Patients usually have a preceding history of a sinus infection and may be immunocompromised. The clinical syndrome develops over hours to days and includes fever, proptosis, ptosis, chemosis, and external ophthalmoplegia. Untreated cavernous sinus thrombosis leads to blindness and clot propagation, which may be fatal. Diagnosis of septic cavernous sinus thrombosis is confirmed with a CT scan or magnetic resonance venography (MRV). Treat patients with a combination of vancomycin, metronidazole, and ceftriaxone. Controversy surrounds anticoagulation with heparin as an adjunct to antibiotics. It may prevent thrombus extension and promote recanalization at the risk of increasing the chance for hemorrhage and allowing the infection (which is theoretically walled off by the clot) to spread. Limited data suggest that anticoagulation may reduce the risk for long-term complications.7 Noninfectious cavernous sinus thrombosis, intracavernous carotid artery aneurysmal rupture, and neoplasms are the other important causes of cavernous sinus syndrome.
Tolosa–Hunt syndrome is characterized by the acute to subacute development of painful ophthalmoplegia.8 The first symptom is usually retro-orbital pain, which is followed several days later by ophthalmoplegia secondary to dysfunction of any of the ocular motor nerves. Ipsilateral facial pain, tingling, and numbness are secondary to involvement of the first and second divisions of the trigeminal nerve. Visual loss may occur as a result of optic nerve compression. As the symptoms suggest, Tolosa–Hunt syndrome is caused by a mass lesion within the cavernous sinus or the orbit. Most commonly, this is an idiopathic granulomatous process, but the syndrome may also be caused by other pathologies including neoplasm, sarcoidosis, or tuberculosis. All patients require MRI of the orbit and cavernous sinus in an attempt to find a cause. Tolosa–Hunt syndrome is usually steroid responsive within 72 hours, but the response may be incomplete and the symptoms may recur after steroid withdrawal. One of the challenges of Tolosa–Hunt syndrome is that both the idiopathic granulomatous form and the more dangerous processes that produce it are steroid sensitive. Patients with ongoing or recurrent symptoms should be re-imaged every 3 months to assure that any responsible mass is not growing. Biopsy and resection of neoplastic or granulomatous masses must be considered with extreme caution.
Orbital lesions, usually secondary to trauma, neoplasm, or infection, may affect any of the extraocular muscles, either alone or in combination. These are usually evaluated and treated by ophthalmologists and therefore will not be discussed further.
Miller Fisher syndrome and brainstem encephalitis
The clinical triad of Miller Fisher syndrome (MFS) is ataxia, ophthalmoplegia, and areflexia. It is often considered a variant of Guillain–Barré syndrome (Chapter 12), as it is also a subacutely progressive autoimmune demyelinating disorder that affects the peripheral nervous system. Miller Fisher syndrome also overlaps with Bickerstaff’s brainstem encephalitis, a disorder also characterized by ophthalmoplegia and ataxia, but also by signs of CNS dysfunction including encephalopathy and hyperreflexia. The diagnosis of MFS is confirmed by finding GQ1b antibodies in the serum. MRI is usually normal. There is no consensus as to the best treatment of MFS. It is usually self-limiting, but for patients with severe symptoms, a trial of intravenous immunoglobulin or plasmapheresis (using protocols similar to those used for Guillain–Barré syndrome) may be warranted.
A small number of conditions may affect multiple cranial nerves simultaneously. These are generally associated with meningeal inflammation, and include carcinomatous meningitis, bacterial meningitis, tuberculosis, sarcoidosis, and Lyme disease. MRI with contrast of the brainstem and lumbar puncture are indicated to evaluate patients with cranial polyneuropathy.
Restrictive extraocular muscle disease prevents movement of the eye in the direction of the involved extraocular muscle. For example, restriction of the medial rectus keeps the eye in the adducted position, and therefore resembles an abduction deficit. The most common causes of restrictive ophthalmopathy are Graves’ disease, which usually affects the inferior and medial recti, and connective tissue disorders. Restrictive disorders are diagnosed by the forced duction test, in which an ophthalmologist finds restricted movement of the anesthetized globe when attempting to move the eyeball with a pair of forceps.
Fluctuating diplopia – ocular myasthenia gravis
Myasthenia gravis is a disorder of postsynaptic neuromuscular function discussed further in Chapter 10. Ocular myasthenia gravis is characterized by diplopia and ptosis without other muscular weakness. Patients with ocular myasthenia classically report that their diplopia is fatigable, initially appearing after long sessions of reading or looking at a computer screen, or towards the end of the day. The fluctuating examination in myasthenia gravis is almost diagnostic: diplopia localizes to different muscles at different times. For example, in the morning, the patient may have diplopia that localizes to the left inferior oblique, while in the afternoon the diplopia localizes to the right medial rectus. Fixed, nonfatigable diplopia that persists for days is less characteristic of myasthenia gravis, but does not exclude the diagnosis.
To demonstrate fatigability, ask the patient to look upwards for 1–2 minutes and observe for worsening diplopia or visible ocular deviation. Two provocative tests may help to establish fatigability and therefore a diagnosis of ocular myasthenia gravis:
• The ice test requires a patient with active diplopia or ptosis. Instruct the patient to close the affected eye and place a plastic bag filled with ice over that eyelid for 1–2 minutes. An improvement in diplopia or ptosis immediately after the ice is removed is often clearly visible.
• The edrophonium (tensilon) test also requires a patient with active diplopia or ptosis. Edrophonium is a short-acting acetylcholinesterase inhibitor, which may be given intravenously. Because edrophonium may cause bradycardia, the patient should be placed on cardiac telemetry and atropine should be available at the bedside. First, inject a 2 mg test dose of edrophonium over 1 minute to assure that the patient tolerates it. Next, inject an 8 mg dose of edrophonium over 2 minutes and observe for an improvement in ptosis or diplopia. Should the patient become bradycardic, inject atropine (0.5 mg × 1, up to a total dose of 3 mg) and continue cardiac telemetry for at least 30 minutes (by which point all the edrophonium will be metabolized). It is usually best to perform the edrophonium test with a blinded observer. Truly blinding an observer may be challenging, however, as the side effects of edrophonium including lacrimation and rhinorrhea are often obvious.
Diagnostic testing for myasthenia gravis is discussed further in Chapter 10. It is important to note that only half of patients with ocular myasthenia will have acetylcholine receptor antibodies.
I attempt to treat most ocular myasthenics with the acetylcholinesterase inhibitor pyridostigmine at a dose of 30–60 mg tid–qid. Side effects include gastrointestinal cramping, lacrimation, and rhinorrhea. There is little benefit in increasing the total daily dose of pyridostigmine beyond 240 mg, so if the diplopia persists after more than a week of pyridostigmine treatment, then initiate corticosteroids as outlined in Chapter 10.
Unless there is obvious evidence for myasthenia gravis, almost all patients with diplopia of neurological origin require a brain imaging study, usually MRI with diffusion-weighted imaging and contrast. Thin cuts through the brainstem, cavernous sinus, and orbits should be performed as indicated by the history and physical examination. Vascular imaging is necessary in patients with suspected aneurysms. Lumbar puncture is useful when infectious, inflammatory, or neoplastic disorders are suspected.
Obviously, treating the underlying disorder offers the best chance of reversing diplopia. Many patients start to wear an eye patch (sometimes over the wrong eye) before even seeing a doctor. Patches may be helpful for diplopia of short duration. Most patients with chronic, persistent diplopia require referral to an ophthalmologist for consideration of prisms or, in some cases, corrective surgery.
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