IgG4-related disease: neurologic manifestations
Nov. 29, 2022
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Diplopia, or double vision, is the sensation of seeing 2 copies of a viewed object. It arises because of disturbed optical elements within the eye (“monocular diplopia”) or ocular misalignment (“binocular diplopia”).
Diplopia is believed to constitute from 0.1% to 0.4% of emergency department visits (23; 07; De Lott et al 2012). Most cases are caused by ocular misalignment but in 1 study, monocular diplopia accounted for 10% of diagnoses (13). Among causes of ocular misalignment, ocular motor cranial nerve palsies are preponderant, with skew deviation, internuclear ophthalmoplegia, myasthenia gravis, orbitopathy, and decompensated esophoria accounting for the remainder (07; 13).
Evaluation of diplopia is challenging, which may explain why some reports have documented inappropriate management. For example, 1 study disclosed that 60% of emergency department visits for diplopia resulted in the ordering of noncontrast brain computed tomographic scans, which are not useful in diagnosis (De Lott et al 2012). Another study found that over one quarter of patients referred to neuroophthalmologists with prior brain imaging had undergone the wrong studies (22). A study of the performance of consulting neurologists in the evaluation of diplopia in 100 consecutive patients examined in the emergency department of a single academic medical center found that an incorrect diagnosis was made in one third of encounters and that many unindicated and incorrect studies were ordered (13).
Monocular diplopia. Monocular diplopia is usually caused by an uncorrected refractive error or a deformity in the cornea or lens. Less common causes are corneal surface irregularities or opacities, iris holes, and dislocated native or implanted lenses.
Such optical defects may occur in one eye or both. If the diplopia is present in 1 eye only, occluding that eye will eliminate the perception of the second image whereas occluding the other eye will not eliminate the second image. If optical defects are present in both eyes, occluding either eye will not eliminate the second image.
Patients with monocular diplopia typically report that the secondary image appears “ghost-like,” that is, indistinct and overlapping the primary image (32). The clue that this illusion originates from an optical aberration of the eyes is that the ghost image always disappears when the patient views the object through a pinhole (25; 29; 06).
A rare and underdiagnosed cause of monocular diplopia is defective cerebral visual processing, usually produced by a stroke or tumor in the occipital or paraoccipital regions (19). This phenomenon is actually called “cerebral polyopia” (rather than “cerebral diplopia”) because the patient perceives more than 2 images with each eye. Occluding either eye will not eliminate this perceptual disorder. Another important feature that distinguishes this phenomenon from an optical aberration is that each eye sees exactly the same pattern of multiple images. Cerebral polyopia is usually a temporary or intermittent sensation and is almost always accompanied by persistent homonymous visual field loss. In fact, the patient usually reports that the secondary images appear faintly in a partially defective homonymous hemifield defect. Visual perseveration (“palinopsia”), distortion of viewed objects (“illusory spread”), and visual hallucinations are common accompaniments (32).
Binocular diplopia. Ocular misalignment causes diplopia because the fixating eye views the object of regard with the fovea, whereas the nonfixating (deviating) eye views it with a parafoveal retinal element. One image will, therefore, appear displaced to the viewer. If the fixating eye has good visual acuity, it will provide a distinct image of the viewed object. Even if the nonfixating eye has good visual acuity, it will provide an indistinct image of the viewed object because the parafoveal retina has relatively poor image resolution (03). The patient will report seeing one distinct image and one indistinct image displaced in a direction determined by the nature of the misalignment.
Patients with ocular misalignment might not report diplopia for the following reasons:
(1) Poor vision in 1 or both eyes;
(2) Visual field defect; the secondary image falls into the defective field
(3) Minor ocular misalignment; the secondary image is so minimally displaced that patients report “blurred vision” rather than “double vision”;
(4) Major ocular misalignment; the secondary image is displaced so far from the fixated image that patients do not notice it;
(5) Impaired cognition; patients do not appreciate diplopia (15);
(6) Impaired consciousness or language; patients cannot communicate the sensation of diplopia;
(7) Suppression of the secondary image, an automatic brain process that occurs if ocular misalignment is present within the first decade of life, when the brain is still highly plastic.
Suppression of the secondary image, a phenomenon of early childhood, often leads to the development of reduced visual acuity in the suppressing eye, a phenomenon called “amblyopia”. Amblyopia is associated with atrophy of cell bodies in the lateral geniculate nucleus and in the portion of visual cortex that receives information from the fovea of the amblyopic eye (32). Suppression and amblyopia become less common with each passing year during the first decade of life. Indeed, amblyopia rarely develops after 6 years of age. Therefore, when providing an ocular occluder to eliminate diplopia in patients older than 6 years, there is no need to instruct them to switch the occluder from one eye to another to prevent amblyopia. Moving the patch from one eye to the other eye is justified only to protect the skin from constant pressure.
The first maneuver in evaluating diplopia is to determine whether it is monocular or binocular. If the diplopia persists when either eye is covered, the diagnosis is monocular diplopia. You should confirm the diagnosis of monocular diplopia by noting that the pinhole occlude eliminates the secondary image perceived by the affected eye. The pinhole does this by bypassing refractive or media abnormalities (29). However, the results of the pinhole test are not reliable children and the elderly or mentally impaired patients, who often have difficulty placing the pinhole onto the optical axis.
Cerebral polyopia will not be corrected by the pinhole test. You should suspect that diagnosis when there is accompanying homonymous visual field loss, palinopsia, or binocular visual hallucinations (see above) (32).
If occluding either eye causes the diplopia to disappear, assume that the underlying problem is ocular misalignment. The challenge is to determine whether the causative lesion lies within the central nervous system, ocular motor cranial nerves, myoneural junction, or extraocular muscles. Clues come from history, assessing the pattern of eye movement and alignment abnormalities, and detecting accompanying neuro-ophthalmic abnormalities (28; 10; 21; 17; 31).
History. Three questions may provide useful information:
(1) Are the 2 images separated horizontally, vertically, or torsionally with respect to one another? These questions are aimed at eliciting whether the malfunction affects principally the horizontally-acting, vertically-acting, or torsionally-acting extraocular muscles. In some cases, the image separation may exist in more than 1 plane, in which case the image separation will appear to be diagonal. Torsional displacement of 1 image, which patients rarely report without prompting, suggests superior oblique muscle malfunction (01; 20).
(2) Does image separation vary as gaze shifts in different directions? A useful rule is that the greatest image separation will occur in the field of action of the malfunctioning cranial nerve or extraocular muscle (20).
(3) Did image separation evolve over time? A widening image separation suggests worsening malfunction; a narrowing separation suggests lessening malfunction.
Eye movements and alignment. The range of eye movements in horizontal and vertical planes must be assessed first because it may provide a clue to the cause of the misalignment. For example, reduced abduction in 1 eye could result from a damaged sixth nerve or lateral rectus muscle, or from a scarred (contracted) medical rectus muscle that impedes abduction. However, even apparently full eye movements can conceal a subtle ductional impairment that would become evident only when eye alignment is tested.
Range of eye movements. The range of binocular eye movements (“versions”) is conventionally tested by pursuit of a moving target. A better target choice is a flashlight, which is easier to follow because it is more defined. A full amplitude of horizontal gaze is indicated by the fact that the white canthal region in each eye disappears behind the lid tissue (“burying the sclera”). The normal amplitude of vertical gaze is more difficult to define because of the wide normal range. A rough guide is that two thirds of the cornea should disappear under the lower lid in down gaze, and one half of the cornea should disappear under the upper lid in up gaze. Some allowance must be made for a natural reduction in the normal amplitude of up gaze in the elderly (03).
If versions show reduced amplitude, you should test the range of eye movement of each eye individually (“ductions”) by covering the other eye. The testing of ductions is necessary because when the eyes are misaligned, the nonfixating eye will often fail to execute a full movement unless the fixating eye is covered (26; 30).
Although eliciting pursuit eye movements is the principal maneuver in assessing the range of eye movements, it is useful to add the assessment of saccades because they may be slow, delayed, or hypometric abnormalities that contribute to diagnosis.
Eye alignment. Subjective and objective tests are used to determine the pattern of ocular alignment. In some cases, these 2 approaches complement one another. In other cases, only one approach can be applied.
Subjective tests of ocular alignment. The subjective tests are based on providing a different viewing experience for each eye. With communication from the patient about where the images are in space, the examiner can identify the pattern and degree of misalignment.
Maddox rod tests. The Single Maddox rod test is a practical yet sensitive and quantitative method of assessing ocular misalignment. It consists of an occluder made up of stacked transparent cylinders. When the Maddox rod is placed in front of an eye, the patient viewing a stationary bright fixation light will see that light as a bright red line oriented perpendicularly to the plane of the cylinders. This is how to do this test and interpret its results:
(1) After positioning the patient so that the eyes are in straight-ahead gaze (“primary position”), place the Maddox rod in front of the right eye and instruct the patient to view a bright light directly ahead at a distance of about 20 feet (6 meters). The left eye should see the white spot of light while the right eye sees a red line whose orientation is perpendicular to the plane of the cylinders. To assess horizontal alignment, position the Maddox rod so that its cylinders are stacked horizontally. The patient should report that the right eye sees a vertical red line and that the left eye sees a spot of white light. If the patient does not report seeing a single clear red line with the right eye, make sure that the Maddox rod is positioned properly in front of that eye, that the fixation light is bright, and that the room lights are dimmed. If those parameters are met and the patient reports seeing more than 1 red line or not seeing any red line, abort the test because it will give unreliable results.
(2) If the patient reports seeing 1 clear red line displaced to the right or left of the light, there is a horizontal misalignment. If the patient reports seeing 1 clear red line to the left of the fixation light, you would diagnose an exodeviation. You should then place base-in prisms of increasing magnitude in front of the right eye until the patient reports that the red line intersects the light. If the patient reports seeing 1 clear red line to the right of the light before you have placed any prism in front of the eye, you would diagnose an esodeviation. Place base-out prisms over the right eye until the patient reports that the red line intersects the fixation light. The magnitude of the prism necessary to produce an intersection of light and line is the quantitative measure of misalignment (in prism-diopters) in that gaze position.
(3) Repeat this maneuver in eccentric gaze positions.
(4) To test vertical misalignment, repeat these steps with the Maddox rod cylinders stacked vertically. If the patient reports seeing the red line below the light, the patient has a right hypertropia. Place the correcting prisms base down over the right eye. If the patient reports seeing the red line above the light, the patient has a left hypertropia. Place the correcting prisms base up over the right eye.
In patients with vertical diplopia, use the Double Maddox rod test to assess torsional ocular misalignment. This is how to do this test and interpret its results:
(1) Place a spectacle trial frame before the patient’s eyes and drop 1 Maddox rod into the slot in front of each eye.
Position the rods so that the cylinders are stacked vertically. A patient who reports vertical diplopia should see 2 horizontal red lines. If they appear parallel, the patient’s eyes are torsionally aligned. If 1 line appears in an oblique plane, the eyes are torsionally misaligned.
(2) Instruct the patient to turn the knob on the trial frame that adjusts the axis of the Maddox rod placed in front of the right eye until the 2 lines appear parallel.
(3) Note the angulation (in degrees away from 90 degrees) of the cylinders in the Maddox rod placed in front of the right eye. Record that interval (in degrees) as the amount of torsional misalignment. If the dial has been turned counterclockwise, the patient has an excyclodeviation; if it has been turned clockwise, the patient has an incyclodeviation. Acquired fourth cranial nerve palsy always produces excyclodeviation.
The Maddox Rod Tests cannot be performed on patients with impaired cognition or language because they will not be able to communicate what they are seeing. Nor can these tests be applied in many young children, who typically suppress the image seen by the nonfixating eye (see suppression, above). But in cooperative adults who have diplopia associated with ocular misalignment, these subjective tests have the following three advantages over objective tests:
(1) They can detect minor degrees of ocular alignment.
(2) They can quantify ocular misalignment even when the patient has paralyzed or scarred eye muscles.
(3) They can separately measure ocular misalignment in horizontal, vertical, and torsional planes.
Objective tests of ocular alignment. The cover-uncover test and the cross-cover test are the most widely used objective tests of eye alignment. Unlike the subjective tests, they require no communication from the patient but they do require fixational eye movements.
Cover-uncover test. This test is designed to measure manifest misalignments of the eyes, or “tropias”. This is how to perform this test and interpret its results:
(1) Instruct the patient to fixate a target placed at a distance of 20 feet (6 meters). Use a discrete fixation target such as a large alphabet letter rather than a light.
(2) Block the vision of the right eye with an occlude and observe the left eye for a fixational movement. If there is no movement, place the occluder over the left eye and observe the right eye for a fixational movement. In order to be sure that the patient knows to make a fixational movement with the nonfixating eye, you must remind her to “make the viewed target clear.”
If covering either eye evokes no fixational movement, the eyes are manifestly aligned. If there is a reproducible fixational movement of the uncovered eye, the patient has a manifest ocular misalignment, called a “tropia.” If the cover test evokes an inward fixational movement, the patient has an exotropia. If it evokes an outward fixational movement, the patient has an esotropia. If it evokes a downward eye movement, the patient has a hypertropia. If the right eye moves downward, the patient has a right hypertropia; if the left eye moves downward, the patient has a left hypertropia.
(3) The tropia may be quantified by placing prisms of increasing strength over the deviating eye until no further fixational movement occurs (“neutralization”). The strength of the prism needed to eliminate a fixational eye movement in the uncovered eye is the measure of the tropia in that gaze position.
(4) Repeat this maneuver with the eyes placed in eccentric positions of gaze and in right and left head tilt positions. Finally, measure alignment with the eyes viewing a target at reading distance.
Cross-cover (or alternate cover) test.
If the cover-uncover test does not reveal a manifest ocular misalignment, use the cross-cover test to detect a latent ocular misalignment, called a "phoria." This is how to perform this test and interpret its results:
(1) Move the occluder back and forth to cover one eye at a time. If you observe fixational movements in the uncovered eye, yet you saw none when performing the cover-uncover test, the patient has a latent misalignment, called a “phoria.”
(2) Perform this test with prisms to quantify the misalignment in all positions of gaze.
(3) Repeat these maneuvers with the eyes in all relevant positions of eccentric gaze, in head tilt, and viewing a near target straight ahead.
The 2 cover tests have some important drawbacks. They cannot be applied in patients who do not understand how to fixate a target (20). Nor can they be applied when fixational eye movements are precluded by extraocular muscle restriction or paresis. They are not effective in very small ocular misalignments because small fixational eye movements are hard to observe. But unlike the Maddox Rod tests, the cover tests do not require communication from the patient about the position of the images. In that sense, they provide objective information.
Corneal reflex test. When patients are unable to cooperate with the Maddox rod or cover tests, ocular misalignment can be crudely assessed with the Hirschberg corneal reflex test. This is how to do it and interpret its results:
(1) Instruct the patient to fixate a bright light shined in both eyes from a distance of 6 m or 20 feet. Note the position of the corneal light reflection in both eyes. If the eyes are aligned, the reflection will appear slightly nasal to the center of the 2 pupils.
(2) If the reflection is displaced temporally, the patient has an esotropia. If it is displaced nasally, the patient has an exotropia. If it is downwardly displaced in 1 eye, the patient has a hypertropia of that eye.
The corneal reflex test is not very sensitive to small ocular misalignments. It takes 7 degrees of ocular misalignment to see a 1 mm shift of the corneal reflection (03).
Determining the pattern of ocular misalignment. The information gathered from the Maddox rod and cover tests is used to determine the pattern of misalignment. If the degree of misalignment is equal in all positions of gaze, the diplopia is considered “comitant”. If the degree of misalignment varies from one gaze position to another, the diplopia is considered “incomitant”.
Child comitant misalignments. Comitant ocular misalignments often arise shortly after birth or in early childhood. They are usually caused by a disturbance of convergence or divergence. An idiopathic form of esotropia is often noted at birth (“infantile esotropia”). Esotropia diagnosed within the first years of life may be caused by excessive accommodation or by poor sight in 1 eye or both. Early acquired exotropia is typically idiopathic, but may also be caused by poor sight in 1 eye or both (33). In these childhood conditions, the patient does not report diplopia because suppression of the image from the deviating eye occurs rapidly (09). Should a child with esotropia also report diplopia, consider an underlying meningitis, encephalitis, increased intracranial pressure, or brain stem tumor (06).
Adulthood comitant misalignments. A common cause of adulthood comitant misalignment is poor convergence, called “convergence insufficiency.” The eyes are aligned for distance viewing but exotropic for reading. It may be a nonspecific sign of brain dysfunction, a specific sign of a midbrain lesion, or merely a manifestation of poor effort on the part of the patient (20). In “convergence excess,” the eyes are esotropic at all viewing distances. Like convergence insufficiency, convergence excess be a nonspecific sign of brain dysfunction, a specific sign of a midbrain lesion, or a manifestation of anxiety or malingering (32; 20). When inappropriate accommodation and miosis accompany excessive convergence, consider a diagnosis of “spasm of the near reflex,” a condition usually triggered by anxiety or malingering (32; 20).
Comitant misalignment may also evolve from a longstanding incomitant misalignment (see Incomitant misalignment, below). For example, a unilateral sixth cranial nerve palsy will initially produce an incomitant misalignment in which the image separation varies with gaze position and is greatest in the field of gaze of the paretic muscle. If the sixth cranial nerve palsy does not recover within months, the patient may gradually slip into a comitant esotropia (06; 20).
Incomitant misalignment typically results from malfunction or restriction of action of one or more extraocular muscles, a disorder of the neuromuscular junction, a disorder of one or more ocular motor cranial nerves, or 2 disorders of the brainstem known as skew deviation and internuclear ophthalmoplegia. The pattern of incomitant ocular misalignment, together with associated neurologic features, allows proper diagnosis.
Extraocular muscle disorders. Ocular misalignment may be caused by impaired muscle contraction, scarring, or entrapment. In acute or subacute inflammation or trauma of these muscles, they fail to contract and the eye will not move in the direction of normal muscle action. In extraocular muscle dystrophies, the muscle becomes atrophic and fails to contract. In chronic inflammation or blunt trauma to the orbit, the muscles may become scarred (contracted) or entrapped by an orbital wall fracture, preventing the eye from moving in the opposite direction. For example, an inferior rectus muscle trapped within an orbital floor fracture may impede supraduction of the involved eye.
Graves disease. In this most common autoimmune cause of extraocular muscle dysfunction, there is infiltration of the extraocular muscles and orbital fat by lymphocytes, plasma cells, and edema, resulting in impaired eye movements. After a period of months to years, the inflammation is replaced by scarring, which shortens the extraocular muscles. Eye movements directed away from the shortened extraocular muscle are restricted. The inferior and medial rectus muscles are most commonly involved, impeding supraduction and abduction, respectively (24; 04). The pattern of misalignment in Graves disease can mimic that of any ocular motor cranial nerve palsy. Tearing, conjunctival hyperemia and swelling, lid swelling and retraction, lid lag, and proptosis help to establish the diagnosis (04). Periocular pain is usually not a prominent feature.
Idiopathic orbital inflammation. In this acute or subacute autoimmune condition, there is infiltration of the extraocular muscles by inflammatory cells, resulting in restricted movements of the eyes. Moderate to severe periocular pain is prominent (04). The pattern of diplopia and ocular misalignment will depend on which muscles are affected. As in Graves disease, the conjunctiva may be hyperemic and swollen, and the lids may be edematous, but lid retraction and lag are typically absent (04).
Blunt trauma to the orbit. In this condition, extraocular muscles are often contused and rendered unable to contract effectively. Moreover, a blow-out fracture of the orbital floor (or, much less often, its medial wall) may result in entrapment and restricted movement of extraocular muscles, particularly the inferior rectus (30). A history of preceding trauma, together with clinical and imaging evidence of orbital and ocular adnexal soft tissue and bony injury, will help to establish the diagnosis.
Neoplastic infiltration of the extraocular muscles. Lymphoma, metastatic carcinoma, or other neoplasms may invade the extraocular muscles (11). The pattern of diplopia, ductional deficits, and misalignment will depend on which muscles are affected. Periocular pain, proptosis, lid swelling, and conjunctival hyperemia may be present (11). Orbital imaging may offer clues that allow distinction from inflammatory conditions, but sometimes diagnostic evidence must be gathered from additional laboratory and imaging studies or extraocular muscle biopsy.
Superior oblique tendon sheath (Brown) syndrome. This condition arises when the superior oblique tendon is prevented from moving freely through the trochlear pulley. It may occur as a congenital dysplasia or as an acquired tenosynovitis = (12). The patient reports vertical diplopia when gaze is directed toward the affected trochlea. In acquired tenosynovitis, this eye movement often evokes periocular pain (30). In primary gaze, the eyes are generally aligned, but supraduction-in-adduction of the affected eye will be impaired. The affected eye will be displaced downward relative to the fellow eye when gaze is directed toward the affected trochlea. Diagnosis is confirmed on the basis of positive forced duction testing, in which the anesthetized eye is grasped and moved by a forceps or suction device placed over the cornea (30; 12).
Genetic extraocular myopathies. Often subsumed under the heading of “chronic progressive ophthalmoplegia”, these conditions result from mitochondrial or nonmitochondrial genetic dysfunction of extraocular muscles. These conditions generally produce symmetric impairment of eye movements in the 2 eyes so that patients rarely report diplopia when viewing a distant target (27). But convergence is often impaired, so that diplopia occurs at reading distance. On ductional testing, eye movements are reduced symmetrically in all directions of gaze. The oculocephalic (Doll’s eye) maneuver and instillation of cold or warm water into the ear canals (caloric testing) fail to improve the ductional movements. These disorders are generally easy to recognize, as the features have been present from an early age. Bilateral ptosis often accompanies or precedes the ductional deficits (27). Patients may also have weakness of the orbicularis oculi and facial muscles and evidence of a more widespread myopathy. Severe or longstanding myasthenia gravis and inflammatory polycranial neuropathies (Guillain-Barré syndrome, CIDP, see below) must be excluded as alternative causes.
Neuromuscular junction disorders. The prototypical neuromuscular junction disorder to cause diplopia is myasthenia gravis. Botulism, which prominently affects the autonomic nervous system, is a rare cause. Eaton-Lambert syndrome is almost never a consideration.
Myasthenia gravis. Any pattern of diplopia and misalignment may occur in myasthenia gravis, often resembling an ocular motor cranial nerve disorder or internuclear ophthalmoplegia (see below) (16). Because the muscles are fatigable in myasthenia gravis, the diplopia is often variable in degree and typically lessens or disappears after sleeping or resting the eyes. Fatigable ptosis is present in over 50% of cases, and orbicularis oculi weakness is usually found with forced eyelid closure. The iris sphincter muscle, being of autonomic origin, is always spared. Other associated neurologic findings include bulbar, limb, and trunk weakness (16).
Botulism. In this condition, diplopia occurs in about 50% of patients but never without autonomic manifestations, including dry eyes, mydriasis, impaired pupil constriction to light, and impaired accommodation that causes impaired reading vision in those aged under 50 years (14). The diplopia is typically horizontal, and the ductional deficits are mild. Dry mouth, constipation, dysphagia, and nausea and vomiting often overshadow the ophthalmic manifestations.
Lambert-Eaton myasthenic syndrome. In this condition, diplopia and ductional deficits are rare and mild. They occur late in the course of the illness and are minor compared to limb weakness (14).
Ocular motor cranial nerve palsies. Palsies of the third, fourth, and sixth cranial nerves may occur in isolation or in combination. The diagnosis may be challenging, particularly when the deficits are mild.
Third cranial nerve palsy. The third cranial nerve innervates the superior rectus; inferior, medial, and inferior rectus muscles; the inferior oblique muscle; levator palpebrae superioris; and iris sphincter muscle. At the superior orbital fissure, the nerve divides into a superior branch, which innervates the superior rectus and levator palpebrae superioris muscles, and an inferior branch, which innervates the remaining muscles.
Complete third nerve palsy causes profound ptosis, a fixed dilated pupil, and absent adduction, supraduction, and infraduction. Incomplete third cranial nerve palsy causes lesser deficits and may entirely spare 1 or more components. Alignment testing shows a hypertropia and or exotropia, depending on gaze position.
Third nerve palsies may be congenital. Acquired causes include head trauma, inflammation, and neoplasm. Aneurysm and ischemia are extraordinarily rare causes. In adults, extraaxial ischemia is the leading cause but aneurysm is the chief concern (02; 01; 31).
Fourth cranial nerve palsy. The fourth cranial nerve innervates the superior oblique muscle. Patients report vertical diplopia and sometimes the perception of 1 tilted image. The diplopia is worse in gaze contralateral to the lesion and with head tilt ipsilateral to the lesion. To eliminate diplopia, patients often adopt a head tilt contralateral to the side of the lesion. There are often no visible ocular ductional deficits. If a ductional deficit is evident, it will be when the ipsilateral eye looks down and in. The eye ipsilateral to the lesioned nerve may appear deviated upwards (hypertropic) as injury to this nerve results in impaired infraduction. Alignment testing will show an ipsilateral hypertropia that becomes greater in gaze contralateral to the lesion and with the head tilted toward the ipsilateral shoulder. Double Maddox rod testing typically shows an excyclodeviation of up to 10 degrees (06). In bilateral fourth cranial nerve palsies, the patient may have a right hypertropia on left gaze and a left hypertropia on right gaze. In such cases, the excyclotropia usually exceeds 10 degrees (06). In children, head trauma is the leading cause. In adults, the leading causes are ischemia, head injury and neurosurgical trauma, and decompensation of a lax superior oblique tendon. Decompensation of a lax superior oblique tendon is distinctive in that the hypertropia is typically greatest in upgaze (18). Neoplasm and inflammation are less common causes and aneurysm is almost never a consideration (see MedLink Neurology article Isolated fourth nerve palsy).
Sixth cranial nerve palsy. The sixth cranial nerve supplies the lateral rectus muscle. Patient report a horizontal diplopia that is generally worse when viewing at distance and often entirely absent when viewing at reading distance. The images will appear farther apart in gaze ipsilateral to the lesion. Accordingly, the patients will often adopt a face turn to the side of the lesion in order to avoid diplopia. The eye ipsilateral to the lesion may appear deviated inward (esotropic) due to weakness of abduction. There is usually an ipsilateral abduction deficit but it may be minimal. Alignment testing will usually show an esotropia in straight ahead gaze that becomes greater in ipsilateral gaze and less in contralateral gaze. In children, leading causes are congenital sixth nerve nuclear dysplasia (Duane syndrome) and head trauma. Other important causes are increased intracranial pressure (“false-localizing palsy”), inflammation, and neoplasm. In adults, the leading causes are extra-axial ischemia and head trauma, but increased intracranial pressure, neoplasm, and inflammation must be considered (21).
Combined ocular motor nerve palsies. When 2 or more ocular motor nerve palsies are present at the same time, ischemia is not a major consideration. Inflammatory, aneurysmal, and neoplastic disorders in the region of the superior orbital fissure, cavernous sinus, or cranial base meninges are more likely causes (01). With cavernous sinus lesions, involvement of the first 2 sensory divisions of the trigeminal nerve is common, resulting in facial numbness or paresthesias. Because the third cranial nerve splits into superior and inferior divisions in the cavernous sinus, lesions here may spare the inferior division (pupil, adduction, supraduction, infraduction) (01).
Less common causes of multiple ocular motor palsies are acute and chronic inflammatory polycranial neuropathies (Guillain-Barre syndrome) and chronic inflammatory demyelinating polyradiculoneuropathy. The ductional deficits may be partial and either symmetric or asymmetric between the 2 eyes. Ptosis and mydriasis are variably present (20). In the Fisher variant of Guillain-Barre syndrome, ataxia and deep tendon areflexia are usually present as well. In Guillain-Barre syndrome, distal greater than proximal weakness and areflexia are the important distinguishing features. In chronic inflammatory demyelinating polyradiculoneuropathy, as in the Fisher variant of Guillain-Barre syndrome, ocular ductional deficits are often incomplete, asymmetric, sometimes accompanied by ptosis and rarely by pupillary dysfunction (20). The finding of extremity deep tendon areflexia is a critical clue to these diagnoses.
Brainstem disorders. Brainstem disorders may produce dysfunction of ocular motor cranial nerves. They may also cause 2 disorders – skew deviation and internuclear ophthalmoplegia – that mimic ocular motor nerve palsies and are often misdiagnosed as such.
Skew deviation. This condition arises from interruption of the connections between the vestibular pathways and the ocular motor brainstem nuclei. Lesions can lie in the brainstem or, less commonly, in the vestibular nerve or vestibular end organs (34). Patients complain of vertical diplopia. They will usually display full ocular ductions and an incomitant or comitant. The vertical misalignment that can range from 1 to 30 prism-diopters but is most often less than 3 prism-diopters (05; 34). Associated features include saccadic pursuit, nystagmus, and ataxia (05; 34). Skew deviation is often misdiagnosed because the vertical misalignment is small and patients may, therefore, report blurred rather than double vision. Common causes include thalamic or midbrain stroke, inflammation (including multiple sclerosis), vascular malformation, and neoplasm.
Internuclear ophthalmoplegia. Internuclear ophthalmoplegia results from lesions in the medial longitudinal fasciculus, the pathway that connects the sixth cranial nerve nucleus to the contralateral third cranial nerve nucleus. This pathway permits yolking of the lateral rectus and medial rectus muscles in conjugate horizontal eye movements. Patient report blurred vision or horizontal diplopia on lateral gaze away from the side of the lesion. Ductional testing reveals impaired or slow adduction of the ipsilateral eye and often a jerk nystagmus of the abducting contralateral eye. Like skew deviation, internuclear ophthalmoplegia is often misdiagnosed, but for different reasons. It is usually called a “partial third nerve palsy”, yet the eyes are often aligned in straight ahead gaze, and there are no deficits in supraduction or infraduction, no ptosis, and no anisocoria. As with skew deviation, common causes are stroke, inflammation (including multiple sclerosis), vascular malformation, and neoplasm. In fact, skew deviation and internuclear ophthalmoplegia often occur together (20).
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
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