Diagnostic Approach to Diplopia Review Article

Home , Cover test, Cyclotropia, Diplopia, Enophthalmos, Esophoria, Fourth nerve palsy

August 2014 gists alike. Theusing a evaluation detailed of andexamination targeted diplopia, history, of an ocularmotility, and, alignment when and appropriate,imaging neuro- of theessential brain skill and forgists. all orbits, This practicing article is will neurolo- take an a broad view of findings are morevexing to subtle neurologists and ophthalmolo- and can be This article offers a pragmatic roadmap to the practicing Recent advances in the diagnosis of diplopia include the observation With proper skills, the neurologist can elucidate the localization of diplopia, Marc Dinkin, MD ABSTRACT Continuum (Minneap Minn) 2014;20(4):942–965. testing, are primary components of the efferent neurologic examination. Further testing designed to detect myasthenia (eg, lid(eg, testing measuring proptosis, and testing for fatigable resistance upgaze) to andRecent retropulsion) may orbital Findings: be disease necessary. that vertical diplopiapositioning from than that caused skew by trochlear deviation nervemyasthenia palsies. include is Advances the in observation the more of field ofwith decreased likely treatment ocular with conversion either to to steroids or the thymectomy, although improve generalized thesebe conclusions form need confirmed with by to prospective, randomized supine trials. Rarely, pureassociated ocular with myasthenia may the be muscle-specific tyrosine kinaseSummary: (MuSK) antibody. even in cases of complex ocularcan misalignment, address and the generate underlying disease, a and, in management many plan cases, that ameliorate or cure the diplopia. causes of diplopia organizedsymptom by neuroanatomic of localization. Diplopia seriouslocalization may and be vision the diagnosis first or aremovement therefore life-threatening and essential. neurologic alignment Thesupranuclear systems circuitry, in disease, brainstem responsible nuclei, the cranial and for nervesneuromuscular ocular III, vertical junctions its IV, and and and target VI, correct muscles. andor Disruption horizontal their at respective within any plane point the within includemovements vestibular this may system afferents complex therefore that produce governfor diplopia, eye the leading patient movement to with in ashould diplopia. broad response be With differential able to a diagnosis to head carefulthus observe history generating the a and patterns shorter examination, of localization-specificocular the motility diplopia list including smooth neurologist pursuit of that and saccadic possible function, followed, reveal if etiologies. necessary, by thetesting Examination designed site of to of uncover misalignments dysfunction, of the eyes, including cover and Maddox rod Purpose ofneurologist Review: on how totaking approach and the examination techniques patient are with reviewed, double followed by vision. a Strategies broad of overview history of the an underlying injury, often the physical INTRODUCTION Double vision, ormon diplopia, visual is concern afirst that com- warning may of belife-threatening vision-threatening the neurologic or disease. While someaccompanied cases by obvious of ocularity diplopia motil- deficits that are allow easy diagnosis of Diagnostic Approach to Diplopia Review Article . Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is www.ContinuumJournal.com 2014, American Academy versions ofURLs are this provided in article;version. the print Video the legendson begin page 963. Supplemental Digital Content. Videos mayclicking be on accessed linksthe by provided HTML, in PDF, and iPad Supplemental digital content: Videos accompanying thisticle ar- are cited in the text as Unlabeled Use of Products/Investigational Use Disclosure: Dr Dinkin reports no disclosure. * of Neurology. affidavit preparation from several law firms andserved has on an advisoryfor board Acorda Therapeutics. Address correspondence to Dr Marc Dinkin, WeillOphthalmology, Cornell 1305 York Avenue, Floor 11, NewNY York, 1002, [email protected] Relationship Disclosure: Dr Dinkin has received personal compensation for medical record review and 942

Downloaded from https://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3bhnalqTQiPuGRXx5KyPdFZxo9C56RINY1tvxttd6QzCr6PRM+bdgGw== on 06/18/2020 Downloaded from https://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3bhnalqTQiPuGRXx5KyPdFZxo9C56RINY1tvxttd6QzCr6PRM+bdgGw== on 06/18/2020 KEY POINT diplopia, offering the reader a framework movements and stabilize them within the h Diplopia may be the for the focused attainment of patient orbits during head movements. Figure 8-1 presenting symptom of historyaswellasacomprehensivereview summarizes the pathways responsible potentially blinding or of the efferent neuro-ophthalmic exami- for horizontal eye movements, including life-threatening disease. nation and how it may be used to yoked versions (conjugate movements The ability to localize, distinguish the various categories of dis- of the eyes) and vergence (convergence work up, and appropriately ease that may present with double vision. and divergence) movements, as well as manage double vision is the horizontal vestibular ocular re- essential to the practicing ANATOMIC FRAMEWORK sponse. Figure 8-2 addresses the same neurologist. This section provides a brief review of the systems in the vertical plane.1,2 In both neuroanatomic pathways that govern eye figures, the boxed elements indicate

FIGURE 8-1 Control of horizontal eye movements. Voluntary lateral gaze is governed by the parapontine reticular formation (PPRF), under cortical control by the contralateral frontal eye field. The PPRF excites the adjacent abducens nucleus (VIn) which contains two major populations of neurons. The first are the cell bodies of the abducens nerve that stimulates the ipsilateral lateral rectus (LR). The second population of neurons are interneurons whose axons decussate and ascend within the medial longitudinal fasciculus (MLF) to synapse with the neurons of the medial rectus subnucleus (MR [white text]) of the oculomotor nucleus (IIIn). These neurons then form the branch of the third nerve to the medial rectus, resulting in yoked adduction of the contralateral eye together with abduction of the ipsilateral eye. The convergence nucleus (CN) activates as part of the accommodative reaction, resulting in bilateral MR (white text) activation. The horizontal vestibular ocular reaction is governed by the horizontal semicircular canal (HSCC). With left head turn, endolymphatic fluid deforms hair cells in the cupula of the HSCC, leading to activation of the vestibular nerve (VIII) and the ipsilateral medial vestibular nucleus (MVN). The contralateral VIn is stimulated in turn, leading to contralateral gaze, as described above. Pathologic conditions are shown in boxes: a lesion of the PPRF or VIn would cause an ipsilateral gaze palsy. Note that an internuclear ophthalmoplegia results from a lesion of the MLF. The VIn fires, resulting in abduction of the ipsilateral eye, but the message to adduct never reaches the contralateral medial rectus muscle (MR [black text]). One-and-a-half syndrome results from a lesion encompassing the VIn and the MLF on one side. Thus, there is an ipsilateral gaze palsy and a contralateral internuclear ophthalmoplegia. Aq = aqueduct; R = red nucleus; CI = convergence insufficiency; NMJ = neuromuscular junction.

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KEY POINTS h Yoked horizontal eye movements are controlled by a series of nuclei and tracts, including the parapontine reticular formation, abducens nucleus, medial longitudinal fasciculus, and the medial rectus subnucleus of cranial nerve III. The ability to distinguish central causes of horizontal diplopia from cranial neuropathies or orbital disease depends on an understanding of the relevant neuroanatomy. h Vertical eye movements are governed by the rostral interstitial nucleus of the medial longitudinal fasciculus FIGURE 8-2 Control of vertical eye movements. Vertical saccades are governed by the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), while the and interstitial nucleus interstitial nucleus of Cajal (INC) is involved in smooth pursuit and maintenance of Cajal, both located in of the eyes in eccentric vertical gaze. The medial riMLF stimulates the ipsilateral inferior rectus the mesencephalon. subnucleus of IIIn (IR [white text]) resulting in ipsilateral depression and IVth nucleus (IVn), whose fibers decussate and cause contralateral depression. There are also fibers from the INC These nuclei control the that decussate to the opposite riMLF, so that its activation would result in activation of all four oculomotor nuclei muscles of depression. Upgaze appears to be governed by the lateral riMLF, which stimulates responsible for vertical the inferior oblique (IO [white text]) and superior rectus (SR [white text]) subnuclei of IIIn, resulting in ipsilateral and contralateral (the SR fibers decussate) elevation, respectively. The gaze and the trochlear relative height of the two eyes is governed by afferents from the utricle that sense body or head nucleus. tilt. Ipsilateral head tilt results in utricular activation, carried by the vestibular branch of the eighth nerve (VIII) to the medial vestibular nucleus (MVN), which in turn activates compensatory h A careful history of a contralateral depression (red dotted lines) and ipsilateral elevation (not shown). Injury to this patient’s double vision pathway mimics activation of the contralateral pathway, resulting in a pathologic vertical strabismus known as a skew deviation. Damage within the medulla prior to decussation would may elucidate the therefore result in ipsilateral depression, while injury to the midbrain portion above its etiology before the decussation would result in hypertropia on the side of the lesion. examination is started. Aq = aqueduct; R = red nucleus; SR (black text) = superior rectus muscle; NMJ = neuromuscular Queries regarding the junction; SO = superior oblique muscle; IR (black text) = inferior rectus muscle; IO (black text) = presence of diplopia inferior oblique muscle. with either eye closed, in the distance and near, and in various points in the pathway where disruption Question 1: Does the Double fields of gaze, may be may result in diplopia. Vision Go Away When Closing used to confirm and Either Eye? localize a neurologic HISTORY If the diplopia persists with either eye cause of diplopia. Taking a careful history can often open by itself, it is monocular, resulting localize the site of anatomic dysfunction from aberrant refraction, so that identi- causing diplopia and, in some cases, cal light rays land on different parts of even delineate the underlying disease the retina. The patient typically de- process, before even examining the scribes a second ‘‘ghost image.’’ Astig- patient or obtaining any neuroimaging. matism,3 corneal pathology, dry eyes,

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. complex cataracts, poorly centered for convergence, but may also reflect intraocular lenses, and severe structural a convergence insufficiency, which retinal pathology4 should be consid- manifests as a limitation of conver- ered. If the issue is refractive, the gence in the presence of full medial diplopia will usually resolve with appli- rectus function. cation of a pinhole or proper correc- tion of astigmatism. Diplopia caused by Question 4: In Which Direction ocular misalignment (binocular) re- Is the Double Vision Worse? solves with closure of either eye. Worsening of vertical diplopia in downgaze implicates either a trochlear Question 2: Are the Two Images palsy or inferior rectus weakness, while Separated Vertically, Horizontally, a worsening in upgaze will occur in Obliquely, or Torsionally? complete third nerve palsies since there Once the diplopia is confirmed as is weakness of both the superior rectus binocular, the orientation of the two and inferior oblique. A worsening in images should be elucidated. Pure upgaze also occurs in inferior oblique horizontal diplopia suggests medial rec- overaction, since the affected eye will tus or lateral rectus dysfunction (which elevate more than normal in upgaze. A can result from cranial neuropathies, worsening of horizontal diplopia in orbital pathology, or myasthenia), or an lateral gaze in one direction implicates internuclear ophthalmoplegia (INO). either the ipsilateral lateral rectus or Pure vertical diplopia suggests either a contralateral medial rectus. The answer trochlear nerve palsy or skew deviation, to question 3 can distinguish the two. the latter of which reflects an imbalance in the vestibular-ocular signal governing Question 5: Is There a History ocular torsion and vertical alignment in of Congenital Strabismus or response to body or head tilt. Oblique Abnormal Head Position? diplopia may result from oculomotor The term strabismus refers to any palsies (since muscles governing both ocular misalignment of the eyes, but horizontal and vertical motility can be may specifically be used to refer to a affected), diffuse orbital disease, or congenital misalignment which typi- ocular myasthenia. Trochlear nerve cally reflects a deficiency in higher- palsies may also result in torsional order neuromuscular control of eye diplopia, caused by extorsion of the position, and may also reflect cranial affected eye. neuropathies or muscle defects. Chronic head turns or tilts are a Question 3: Is the Diplopia common compensatory response. Worse at Distance or at Near? Surprisingly, many patients will not Worsening of horizontal diplopia at include a remote history of strabismus distance, such as when driving, is in their past medical history until consistent with lateral rectus or specifically asked, and most will not abducens nerve dysfunction, since consider an abnormal head position abduction is necessary for divergence. important. Since adult-onset diplopia Worsening of horizontal diplopia at may result from a decompensation of near, typically manifesting as trouble a childhood strabismus, the examiner reading or seeing a smartphone, is should always inquire about prior consistent with medial rectus dysfunc- strabismus, a ‘‘lazy eye,’’ eye patching tion, as may be found in an oculomo- as a child, childhood eye surgery, and tor palsy, since adduction is required any abnormal head positions.

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KEY POINTS h The diplopia examination Question 6: Are Associated may be noted to occur in opposition begins with testing of Pain, Headache, or Neurologic to head or body tilting when aided by ductions (the Symptoms Present? the presence of prominent conjuncti- movement of each eye Headache may accompany aneurysmal val vessels. Convergence and diver- individually), versions third nerve palsies but also occurs in gence may be tested by the slow (both eyes moving in the 62% of ‘‘microvascular’’ cranial neu- movement of the fixation target in same direction), and ropathies,5 which refer to infarctions toward the nose and outward again. vergences (the eyes of the cranial nerves presumably due moving in opposite to insufficiency of the vasa nervorum, Forced Ductions horizontal direction). typically in patients with vascular risk In cases of orbital disease, diplopia Forced duction testing frequently results from restriction of can be performed by an factors such as hypertension or diabe- an extraocular muscle due to infiltra- ophthalmologist and tes mellitus. In patients aged 55 or may reveal a restriction over, the presence of a concurrent tion, fibrosis, or bony entrapment suggestive of orbital headache, scalp tenderness, or jaw following trauma. In such cases, a disease. claudication should raise the question worsening in a certain direction suggests restriction of the antagonist h A tropia is a of temporal arteritis. Finally, pain with misalignment of the eye movement suggests orbital dis- muscle. For example, a vertical diplo- eyes that manifests even ease, such as idiopathic orbital inflam- pia that worsens in upgaze in a patient with both eyes open. A mation, or an orbital apex lesion. with thyroid eye disease is likely to phoria is a misalignment reflect inferior rectus restriction rather that is only present EXAMINATION than superior rectus weakness. Oph- when binocular vision is Motility: Ductions, Versions, thalmologists, after anesthetizing the disrupted, as when and Vergences cornea, may attempt to move the eye covering one eye. A careful assessment of ocular motility passively by gently grabbing hold of is essential to localization and diagno- the conjunctiva with a forceps or even sis of diplopia. Examining each eye two Q-tips. If the eye still will not individually (ductions) may reveal sub- move in the direction of weakness, a tle limitations of movement in one eye restrictive etiology is likely. that could be missed if visualized alongside a fellow eye with greater Misalignment: Tropias and limitations. This is followed by an Phorias examination of both eyes together, In some cases, diplopia occurs in versions. See Supplemental Digital patients with full or near-full motility Content 8-1, links.lww.com/CONT/ of both eyes but whose eyes are A124 for a demonstration of testing nevertheless misaligned. This suggests of versions. To test versions, the congenital strabismus but also is typ- patient is asked to fixate on a target ical for skew deviations,6 and even in which is then slowly moved laterally, cases of some ocular motor palsies, testing the lateral rectus of the the limitations in motility may be abducting eye and medial rectus of subtle. When the misalignment is the adducting eye. Once in lateral present with both eyes open, it is called position, the target is moved superi- a heterotropia or tropia, but if it mani- orly and then inferiorly. This will test fests only when stereo fusion is disrupted the superior rectus and inferior rectus, (eg, with unilateral eye closure), it is respectively, in the abducted eye and termed a heterophoria or phoria. Pre- the inferior oblique and superior fixes may be used to qualify the direc- oblique, respectively, in the adducted tion of the misalignment: exotropia eye. The same is then repeated in refers to outward deviation, esotropia contralateral gaze. Torsional motility to inward deviation, hypertropia to

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT elevation of an eye, and hypotropia to a innervation, which states that an equal h Ocular misalignments lower eye. Exophoria, esophoria, force must be supplied to both eyes. (phorias and tropias) hyperphoria, and hypophoria are used In a mild left abducens palsy, for may be observed using to describe the misalignment for phorias. example, a covered left eye will devi- the alternate cover test Several methods are used to determine ate medially and refixate to the target or Maddox rod test. the relative position of the two eyes in when uncovered. When the right eye Testing in the nine variousfieldsofgazeandultimately is covered, however, a good deal of cardinal fields of gaze as localize the cause of the diplopia. leftward force must be applied to pull well as in head tilt can the weak left eye to fixation and that elucidate the pattern of Cover Testing same force applied to the healthy weakness and help When the patient’s visual acuity, ability right eye deviates it medially (second- localize the responsible lesion. to move the eyes, and ability to ary deviation). When it is uncovered, it cooperate are all intact, cover testing too will have to refixate from an may help indicate a tropia or phoria. adducted position. Finally, a prism Cover-uncover test. The cover- rod with multiple strengths may be uncover test differentiates a tropia placed over one eye and steadily from a phoria. First, one eye is occluded increased until the refixation move- while the patient is fixating on a target. mentscease,thusestimatingthe If the fellow eye shifts to pick up prism required to ameliorate the dip- fixation, it must have been deviated lopia. Typically, patients benefit from a prior to occlusion of the other eye, and strength of 50% to 75% of the mea- one can conclude that a tropia is sured prism, ensuring some contin- present. If, however, the fellow eye ued effort on their part. The examiner does not shift, but instead the occluded may perform the alternate cover test eye moves in the direction of weakness in the nine cardinal fields of gaze to while covered (noted as the eye returns look for changes in the degree of to fixation after the occluder is re- refixation. In the case of vertical de- moved), a phoria is present. In either viations, checking in right and left case, the type of tropia or phoria can be head tilt is also helpful. When the determined by noting the direction of patient is gazing in the direction of an refixation of the deviated eye. An inward eye’s weakness, the movements will be movement of an eye when it is uncov- greater (Supplemental Digital Content ered informs the examiner that the eye 8-2, links.lww.com/CONT/A125). had been outwardly deviated when covered, which is called an exo (tropia Maddox Rod Testing or phoria). An outward movement with A Maddox rod is a red lens with multiple uncovering reflects a prior inward devi- aligned prisms that will convert a white ation or eso. If the uncovered eye moves light into a red line. During testing, the downward, it is consistent with an lens is held over the right eye (by ipsilateral hyper or contralateral hypo. convention), while a light is shined at Alternate cover test. By alternating the patient. The left eye will see the white which eye is covered, the physician light, but the right eye will see a red line, will bring out phorias and tropias, and which can be horizontal (to test vertical can quickly determine the direction of alignment) or vertical (to test horizontal deviation. Even when misalignment is alignment). Thus, akin to covering one the result of unilateral eye weakness, eye, stereo fusion is disrupted, and both eyes will move when uncovered phorias will emerge. A review of horizon- during the alternate cover test. This tal and vertical Maddox rod techniques is results from the Hering law of equal presented in Figure 8-3 and Figure 8-4,

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FIGURE 8-3 Horizontal Maddox rod. A, Patient with a left esotropia. B, The right eye (OD) sees a vertical red line in the middle, but the left eye (OS) sees the white light (yellow in the figure for illustrative clarity) deviated to the left. The result is a white light to the left of the red line with both eyes (OU) open. C, Repeat testing in right and left gazes indicates a worsening in left gaze, consistent with lateral rectus weakness of the left eye.

respectively. Although its limitations, in- needed to correct the hypertropia in cluding the induction of excessive each position, but the author finds that esophoria and inability to see the red eliciting a subjective response from the line in some patients, have been noted patient regarding the distance between since the beginning of the 20th century,7 the red line and white light on the Maddox rod testing remains a practical Maddox rod test (in each direction of and fast means of assessing phorias in gaze and in head tilt) provides a faster most patients. and, in most cases, equally reliable solution. The test is not perfect, as this Parks-Bielschowsky pattern may be mimicked by orbital Three-Step Test disease or ocular myasthenia gravis. As described by Marshall Parks,8 a Double Maddox rod. Bilateral superior oblique palsy can be identi- trochlear palsy may be seen after head fied in three steps: trauma or congenitally occur. It may 1. Determinewhicheyeishypertropic. be elusive, as one palsy dominates in 2. Confirm that the hypertropia primary gaze, but will produce a worsens in contralateral gaze. characteristic pattern of a hypertropia 3. Confirm that the hypertropia in lateral gaze of whichever eye is worsens in ipsilateral head tilt. adducted and a V-pattern esotropia An ophthalmologist might answer (meaning that the esotropia is worse these questions by measuring the prism in downgaze) due to weakness of the

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FIGURE 8-4 Vertical Maddox rod. A, Patient with a left hypertropia. B, The right eye (OD) sees a horizontal red line in the middle, but the left eye (OS) sees the white light (yellow in the figure for illustrative clarity) below it. The patient sees a white light under a red line with both eyes (OU) open, consistent with a left hypertropia. C, The hypertropia is worse in right gaze, downgaze, and left head tilt, all consistent with a fourth nerve palsy.

superior oblique’s tertiary function, ie, while the other is offset by about KEY POINT abduction. Because the superior 10 degrees and a light is shined at the h Using a Maddox rod oblique intorts the eye (rolls it along patient. Using a knob, the patient is over each eye (double the coronal plane so that the top of asked to rotate the second lens until the Maddox rod test), the the eye rotates toward the nose), a red lines ‘‘line up.’’ The resulting devia- practitioner can unilateral fourth nerve palsy will result tion reflects the total relative extorsion estimate the degree of ocular torsion between in extorsion of an eye (the top of the between the two eyes. the two eyes, as is seen eye is rotated toward the ear), but by in cases of fourth nerve Hirschberg Test only 10 degrees or less. In bilateral palsy. trochlear palsies however, intorsion of One may more easily detect a tropia both eyes is affected so that the by comparing the location of the combined extorsion is higher, at a reflection of a penlight on the cornea median of 14.5 degrees.9 The double of both eyes, termed the Hirschberg Maddox rod test allows the neuro- test. This is particularly useful when ophthalmologist to quantify the relative poor vision or cooperation precludes extorsion of the two eyes and detect the cover testing or Maddox rod examina- presence of bilateral trochlear palsies. tion. In the case of an exotropia, for One Maddox lens is placed at 0 degrees example, the reflection will fall medial

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KEY POINTS h The general neurologic to the pupillary axis in at least one eye. In such as a large pituitary adenoma or examination, testing of the Krimsky test, various prisms may be pituitary apoplexy. The recognition of afferent visual function, held in front of an eye until one amblyopia in an eye, which manifests as and the funduscopic normalizes the location of the reflection, decreased acuity in the absence of findings all may help thus estimating the degree of misalign- specific optic nerve field defects, is localize the lesion ment and required prism needed to treat helpful in identifying a decompensation responsible for diplopia. the diplopia. This test has recently been of a congenital phoria that was associat- h Extraneous workups can shown to correlate well with measure- ed with the amblyopia. 10 be avoided by the ments using cover testing. recognition of General Neurologic Examination congenital strabismus Funduscopy A complete neurologic examination is patterns. A tolerance by Funduscopy may provide additional essential to the localization and diag- the patient of strong clues to the etiology of diplopia. nosis of most disorders responsible for prisms (fusional Papilledema in the setting of esotropia diplopia. For example, the recognition amplitude), the suggests intracranial hypertension- of a hemiparesis contralateral to a third presence of chronic related abducens palsies. Retinal pig- nerve palsy suggests injury at the contralateral head tilt in past photographs in mentary deposition in association with level of the third nerve fascicle as it cases of trochlear nerve diffuse ophthalmoplegia and ptosis sug- passes through the cerebral peduncle. palsy, and globe gests the mitochondrial disease Kearns- Areflexia would suggest Guillain-Barre´ in cases of abducens Sayre syndrome. Finally, retinal artery syndrome or the Miller-Fisher variant, palsy (Duane syndrome) occlusion or anterior ischemic optic while an associated delirium or amne- are all suggestive of neuropathy, in association with an sia raises the specter of Wernicke congenital disease. acute ocular motor palsy, reflects tem- encephalopathy. poral arteritis until proven otherwise. Viewing the fundus under high PATTERNS OF DISEASE magnification can help the neuro- Detecting Infantile Strabismus ophthalmologist confirm torsional de- Patients with a strabismus of infantile viations of either eye. Dilation is neces- onset may manage to fuse for years, until sary, as the optic disc and fovea would age, disease, or drug exposures lead to need to be seen simultaneously. A an eventual decompensation and associ- horizontal light beam projected across ated diplopia. Determining when this is the fovea will typically cross the optic the case is crucial in preventing needless disc with approximately one-third of the workups and anxiety. Examples of infan- disc below it.11 Cyclotorsion (turning in tile strabismus syndromes include con- the coronal plane) of the eye in either genital trochlear nerve palsies, Duane direction will cause the beam to inter- syndrome (abducens palsy with globe cept the disc either higher or lower retraction in adduction), Brown syn- than normally predicted.12 drome (congenital fibrosis of the superi- or oblique tendon with depression in Afferent Neuro-ophthalmic adduction), and inferior oblique overac- Examination tion with an associated V-pattern In any patient with diplopia, assessment esotropia. Methods used to detect such of afferent visual function is essential. A cases are summarized in Table 8-1. retrobulbar optic neuropathy accompanying cranial nerve III, IV, or VI dysfunction Ruling Out Orbital Disease suggests an orbital apex syndrome, while Double vision may be the first or only a bitemporal hemianopia suggests a sign of diseases affecting the orbit, in- suprasellar lesion with chiasmal compres- cluding thyroid eye disease, inflammatory sion and spread to the cavernous sinus, disease, trauma, infection, neoplasm, and

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS h TABLE 8-1 Testing for Infantile Strabismus Orbital disease is a frequent mimicker of Examination Description neurogenic diplopia and is most frequently the Fusional amplitude In the case of vertical phorias, chronic result of orbital compensation results in a tolerance for a wide range of vertical deviations such inflammation, thyroid that the patient will fuse the images and eye disease, or orbital not experience diplopia even when more tumors. prism is given than required. This range is h Signs of orbital disease known as the fusional amplitude. Scores include proptosis, of 93 diopters suggest chronicity. conjunctival injection or Worsening of trochlear This finding suggests secondary inferior oblique swelling, resistance to palsy in upgaze overaction that occurs over many years. retropulsion, and a Family album tomography A review of older pictures of the patient positive forced duction (‘‘FAT scan’’) may reveal a head tilt contralateral to the test. hypertropia, offering further reassurance of a congenital trochlear palsy. Forced duction In cases of Brown syndrome, the adducted eye will not elevate with passive attempts because of superior oblique tendon restriction. This distinguishes it from an inferior oblique paresis.

congenital myopathies. Such conditions As previously mentioned, the mo- may be missed by the neurologist who is tility limitation in orbital disease often not as accustomed to thinking about reflects antagonist muscle restriction orbital disease. Red flags include propto- rather than weakness of the agonist sis, periorbital edema, resistance to muscle. MRI of the brain only shows a retropulsion, and lid retraction. An oph- few slices through the orbits and thalmologist may quantify the degree of will often miss orbital disease. Thin proptosis using a Hertel ophthal- cuts through the orbits, with T1 mometer, which uses angled mirrors to fat-saturated images (removing the simultaneously project lateral views of bright T1 signal of intraorbital fat) both eyes with superimposed rulers. increase sensitivity for orbital disease, However, the general neurologist may while orbital CT is especially useful in be able to estimate the severity of cases of trauma and suspected bony proptosis simply by viewing the patient abnormalities. As orbital disease is not from the side and noting the anterior covered elsewhere in this issue of extent of one eye versus the other. , special attention will Resistance to retropulsion refers to a be given here. limitation in the degree of backward Orbital inflammation. Idiopathic movement of the globe when gently orbital inflammation (formerly known pushed on with two fingers during eye as orbital pseudotumor) can affect the closure. Its presence suggests a muscles, soft tissue, and even optic retrobulbar tumor or thyroid eye dis- nerve, potentially resulting in blind- ease, although in one study the physi- ness. In some cases, only one muscle cians’ estimation of the resistance did is affected, producing an orbital myo- not reliably predict the actual force sitis. In addition to diplopia, patients needed to push the eye back.13 typically report pain, especially with

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eye movement, proptosis, and, in vides a review of inflammatory orbital severe cases, vision loss. Sarcoidosis, disease and appropriate testing. rheumatoid arthritis, and some vascu- Treatment of idiopathic orbital in- litides (including granulomatosis with flammation includes corticosteroids, polyangiitis14 and, rarely, giant cell nonsteroidal anti-inflammatory drugs arteritis15) may lead to orbital inflam- (NSAIDS), and, in rare cases, radiation mation (Figure 8-5). Recently, some therapy, but in one 10-year retrospec- cases of idiopathic orbital inflamma- tive study evaluating all treatment tion, particularly with inflammation of modalities, only 63% showed a long- the ocular adnexa (ie, eyelids, lashes, term complete remission.17 extraocular muscles, and lacrimal sys- Thyroid eye disease. A lymphocytic tem), have been linked to IgG4, a inflammatory infiltration of the orbital subclass of IgG that appears linked tissues occurs in approximately 50% of with multiple forms of systemic in- patients with Grave disease and some flammatory disease.16 Table 8-2 pro- with Hashimoto thyroiditis.18 Smoking,

FIGURE 8-5 Examples of orbital inflammation in three patients. A, Orbital myositis of medial rectus (yellow arrow) seen on orbital MRI. The diagnosis was missed on multiple brain MRIs. B, Bilateral orbital inflammation (yellow arrows) was the first sign of disease in this patient with temporal arteritis. Note temporal artery enhancement (blue arrow). C, Massive infiltration of eye muscles on the right, especially lateral rectus (yellow arrow) was seen in this patient with proptosis. Elevated angiotensin-converting enzyme (ACE) level and extension outside of the orbit to the pterygopalatine fossa in the same patient (D, green arrows) suggested sarcoidosis.

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Type Workup Sarcoidosis Chest CT, angiotensin-converting enzyme (ACE) level Thyroid eye disease Thyroid function tests, thyroid antibodies Systemic lupus Antinuclear antibody (ANA) erythematosus Rheumatoid arthritis Rheumatoid factor (RF) Granulomatosis Central antineutrophilic cytoplasmic antibody with polyangiitis (c-ANCA) Giant cell arteritis Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), temporal artery biopsy family history, and female sex are risk chemosis (swelling of the conjunctiva), factors. Clinical findings include prop- and lid edema and erythema (Figure 8-6). tosis, conjunctival injection (redness) The difficult task of distinguishing thyroid over points of eye muscle insertion, eye disease from other inflammatory

FIGURE 8-6 Thyroid eye disease. A, A 65-year-old woman presented with lid erythema and edema, lid retraction, conjunctival injection, chemosis, and proptosis of both eyes. Note the widening of the palpebral fissure of the left eye. B, Coronal noncontrast CT reconstruction of the orbits revealed thickening of multiple extraocular muscles. C, Axial noncontrast CT of the orbits. Note the relative sparing of the medial rectus tendons in both eyes (red arrows). D, Axial postcontrast MRI of a different patient who presented with diplopia and a left optic neuropathy. Note the crowding at the left orbital apex (yellow arrow) consistent with thyroid eye disease.

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KEY POINTS h Signs of thyroid eye diseases of the orbit is made easier by cause ophthalmoparesis through re- disease include lid the recognition of several classic findings, striction and entrapment of orbital retraction, lid lag, described in Table 8-3. muscles or even muscle disinsertion increased intraocular Orbital neoplasm. Orbital neo- from the globe. Hypoglobus and pressure in upgaze, and plasm, whether in the form of a bulky enophthalmos are common. Orbital sparing of the tendons tumor or diffuse infiltration of muscles CT is the preferred imaging study in on orbital CT or MRI. and soft tissues, may present with such cases as it clearly shows bony h The orbit may be diplopia. Proptosis and resistance to fractures and defects. Early surgical affected by a wide retropulsion are common features, but repair of the orbital wall with relaxa- variety of neoplasms superior orbital tumors may result in a tion of involved muscles can help that cause diplopia, downward displacement of the globe in prevent scarring. including benign lesions the orbit, hypoglobus, while metastatic Rarely, obstruction of the ostium of (eg, dermoid cysts, breast cancer may cause enophthalmos, the maxillary sinus can block aeration, cavernous hemangiomas) a recession of the globe within the producing a negative pressure that and malignant lesions (eg, orbit.21 Table 8-4 demonstrates the pulls down on the inferior wall of the non-Hodgkin lymphoma, relative incidence of orbital tumors in orbit. This silent sinus syndrome may adenoid cystic carcinoma, 22 and metastases). one study. While the lack of result in enophthalmos and a down- diffusion-weighted signal on MRI was ward displacement (hypoglobus) of h Double vision may result shown to predict benign disease with a the eye, the latter of which may lead from orbital trauma, 75% concordance rate in one study,23 to a vertical diplopia.24 typically due to muscle entrapment within a biopsy is necessary for a definitive Iatrogenic Diplopia bony fracture. These diagnosis. Figure 8-7 describes the rare lesions may be missed occurrence of a granulocytic sarcoma Trauma to extraocular muscles may on general brain MRI, so in the orbit presenting as diplopia. occur after cataract, retina, orbital, and orbital imaging should Diplopia associated with trauma sinus surgery. Diplopia occurs in be pursued in any cases and defects in the bony orbit. As 0.17% to 0.85% of patients following of suspected demonstrated by Figure 8-8, direct cataract extraction.25 In one large trauma-related diplopia. mechanical orbital trauma may study, approximately 25% of cases

TABLE 8-3 Findings in Thyroid Eye Disease

Finding Description Lid retraction Results from circulating thyroid hormone and, eventually, infiltration and scarring of the levator palpebrae. Lid lag (Von Graefe sign) Up to 8% of patients with thyroid eye disease demonstrate a delay in the lowering of the lid with globe depression.19 Both lid retraction and lag may result in secondary keratopathy. Increased intraocular Greater than 4 mm Hg, presumably a result pressure in upgaze of compression by inflamed inferior rectus; nonspecific and has been reported in controls.20 Tendon sparing Orbital imaging demonstrates enlargement and increased enhancement of the muscles and/or soft tissue of the orbits in both thyroid eye disease and idiopathic orbital inflammation, the primary difference being that the muscle tendons are typically spared in thyroid eye disease.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 8-4 Orbital Tumors and Pseudotumors: Lesion Types in 268 Consecutive Patients Undergoing Biopsies of Suspected Orbital Tumorsa

% of All Orbital Tumor Tumors Secondary orbital tumor 26% Lymphoproliferative lesion (74% of which were lymphoma) 25% Metastatic tumor 10% Epithelial lacrimal gland tumors (67% of which were 10% adenoid cystic carcinoma) Inflammatory condition 8% Vascular lesion 7% Mesenchymal tumor 7% Optic nerve or nerve sheath tumor 3% Peripheral nerve tumor 1% Histiocytic lesion 1% Cystic lesion 1% Miscellaneous G1% a Modified with permission from Shinder R, et al, Head Neck.22 B 2010 Wiley Periodicals, Inc. onlinelibrary.wiley.com/doi/10.1002/hed.21498/abstract.

FIGURE 8-7 Orbital tumor. A 20-year-old painter presented with oblique diplopia and a red and proptotic eye on the right (A). Neuro-ophthalmic examination revealed limitation of adduction, elevation, and depression of the right eye. Thyroid eye disease was suspected, but MRI orbits revealed a mass lesion in the lateral-superior orbit (B). A complete cell blood count showed a leukocytosis with blasts, and biopsy of the lesion (C) confirmed a granulocytic sarcoma. Chemotherapy was initiated for systemic leukemia and, within days, visual symptoms resolved (not shown) and the patient remained in remission.

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KEY POINTS h Ocular myasthenia myasthenia gravis, in which the neuro- presents with isolated muscular blockade of acetylcholine re- fatigable ptosis and/or ceptors has a particular predilection for ophthalmoplegia and is the highly metabolic and fatigable often accompanied by extraocular muscles. An inherently sim- fatigable upgaze, plified folding of the postsynaptic enhanced ptosis, and a endplate in extraocular muscles makes lid twitch. them susceptible to the effects of h Screening for ocular further simplification associated with myasthenia includes the acetylcholine receptor destruction, thus edrophonium test, sleep predisposing them to loss of the safety test, and ice test. The factor that ensures proper neuromus- disease may be cular transmission.27 A recent history confirmed by the of trouble breathing, swallowing, or finding of acetylcholine walking may suggest the disease, receptor antibodies but generalized symptoms may be (although these are only FIGURE 8-8 Muscle entrapment. A absent (ocular myasthenia). The con- 50% sensitive), or a previously healthy 53-year-old decrement on repetitive woman reported vertical diplopia after current finding of fatigable ptosis is a nerve stimulation. The falling down the stairs. Examination showed red flag, but, in unclear cases, several limitation of elevation, depression, and diagnosis is further adduction of the left eye, suggestive of a examination techniques, summarized supported by a finding posttraumatic, partial third nerve palsy. With in Table 8-5, may prove pivotal in of jitter on single fiber an unremarkable MRI of the brain and making the diagnosis. magnetic resonance angiography (MRA) of EMG. the head, the patient was prepared for These examination findings are discharge. As no ptosis or mydriasis was complemented by further testing, which present, a CT of the orbits was obtained and revealed a blowout fracture of the inferior may include acetylcholine receptor anti- orbit and protrusion of the inferior rectus bodies (present in only 50% of ocular through the defect with associated entrapment (red arrow). myasthenia cases), muscle-specific tyrosine kinase (MuSK) antibodies, repetitive stimulation nerve conduction testing, involved muscle restriction or paresis,26 and single fiber EMG. Figure 8-9 de- ostensibly due to trauma to the muscle scribes an examination of a patient with cone (where the origins of the ocular myasthenia gravis. Supplemental extraocular muscles coalesce in the pos- Digital Content 8-3, links.lww.com/ terior orbit) from retro-orbital anesthesia, CONT/A128, demonstrates enhanced which occurs more frequently in the left ptosis in a patient with the disease. eye because of a greater difficulty of left Furthermore, improvement of either eye injections in right-handed surgeons. ptosis or ophthalmoplegia after injection In these cases, most patients had either a of the acetylcholinesterase inhibitor hypotropia (54%) or hypertropia (44%) edrophonium (edrophonium test),35 or of the affected eye. Other mechanisms after 30 minutes of rest and lid closure include an unmasking of a congenital (the sleep test),36 or 2 minutes of phoria with resumption of binocular application of ice (ice test)37 suggests vision (34%), a prismatic effect by the the diagnosis. implanted lens (4%), and concurrent onsetofsystemicdisease(5%). Trends The existence of pure ocular myasthenia Detecting Myasthenia Gravis associated with the MuSK antibody is Essentially any pattern of ophthalmoplegia questionable. A large study of 110 pa- or ocular deviation can be mimicked by tients with MuSK myasthenia described

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Finding Description Fatigable upgaze Maintain upgaze for at least 1 minute before assessing for fatigability. ‘‘Cogan lid twitch28’’ A rapid recovery in the neuromuscular junction while rested in downgaze results in enhanced release on return to primary gaze. Also described in cases of brainstem tumors,29 parasellar tumors, and aneurysms.30 Sensitivity is 50% and positive predictive value is 25%.31 Curtaining Lifting of the weak lid leads to a slow drooping of the fellow lid, presumably related to the Hering law of equal innervation. ‘‘Quiver movements32’’ Attributed to a relative preservation of the twitch (lightning saccades) fiber system responsible for the initiation of saccades, even as the tonic fiber system subserving later stages of the saccade is injured. Pale global singly innervated fibers, which fire at the onset of saccades and appear to govern the initial acceleration phase, possess a more complex postsynaptic folding than other extraocular muscle fibers,33 which helps protect them from the effects of myasthenia. This may explain the presence of these lightning saccades. Orbicularis weakness Suggests ocular myasthenia gravis rather than cranial neuropathies. Orbicularis ‘‘peek’’ sign Small palpebral fissure widening with scleral show following a brief period of lid apposition against a patient’s gentle closure. Seen in 3 of 25 patients with ocular myasthenia gravis and 0 of 200 control subjects.34

36% with purely ocular symptoms at with ocular myasthenia without onset, but all subsequently generalized.38 thymoma should undergo thymectomy However, some case reports have de- has yet to be conclusively determined. scribed chronic MuSK-related ocular In a recent retrospective study of 115 myasthenia without generalization, in Chinese patients with ocular myasthe- one case over a 10-year period without nia who underwent transsternal thy- immunosuppression.39 The manage- mectomy, none developed generalized ment of ocular myasthenia remains disease over a mean follow-up of 44.5 controversial. Since 50% to 80% of months, suggesting a role for the patients progress to generalized myas- surgery even in purely ocular patients, thenia, prevention of this transforma- but prospective, controlled trials are tion is a central goal of treatment, in needed to more conclusively confirm addition to ocular symptom control. the benefits of thymectomy.42 Several studies have suggested that treatment of ocular myasthenia with Cranial Neuropathies steroids may decrease the conversion Disease of the cranial nerves is cov- rate to generalized myasthenia,40,41 al- ered in detail in the article ‘‘Diplopia though the conclusion is tempered by Due to Ocular Motor Cranial Neurop- the retrospective, nonrandomized na- athies’’ by Wayne T. Cornblath, MD, ture of these studies. Whether patients FAAN, in this issue of .

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KEY POINT h In the presence of a complete third nerve palsy, fourth nerve function may be examined by looking for intorsion of the globe during combined abduction-depression.

FIGURE 8-9 Ocular myasthenia. Eye appearance at rest (A) with prominent, nearly complete left ptosis. Demonstration of enhanced ptosis or curtaining (B) shows development of right ptosis with manual elevation of the left lid. Eye appearance after a few seconds of upgaze (C) shows left ptosis, but inferior third of the pupil and iris are visible. Eye appearance after 120 seconds of upgaze (D) shows increased left ptosis with nearly complete coverage of the pupil and iris. E, Positive edrophonium test. Resolution of left ptosis 15 seconds after administration of 1 mg of edrophonium.

Courtesy of Janet C. Rucker, MD.

The presence of an oculomotor, trochlear, results in paralysis of the medial rectus, or abducens palsy may reflect compres- it is difficult to test for ipsilateral sion, infiltration, inflammatory disease, or, superior oblique weakness since it acts especially in older patients, ischemia to in the vertical plane during adduction. the nerve. Multiple cranial neuropathies To test its function, the practitioner suggest disease of the brainstem, sub- may instead bring the eye into the arachnoid space, cavernous sinus, or, in abducted position and ask the patient the presence of an optic neuropathy, the to look down, which should result in orbital apex. Infectious, inflammatory, or intorsion of the globe if the superior neoplastic meningitic processes may oblique is functional. Identifying con- present with diplopia due to infiltration comitant trochlear nerve palsy along- of one of the ocular motor cranial side an oculomotor nerve palsy is nerves, as evidenced by a case of primary crucial, in that it is unlikely to be the CNS lymphoma presenting with a third result of the common and relatively nerve palsy (Case 8-1). benign microvascular etiology43 and Checking for trochlear nerve palsy suggests a localization either at the in the presence of a third nerve palsy. orbital apex or within the cavernous When a complete third nerve palsy sinus.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 8-1 A 78-year-old woman with hypercholesterolemia presented with diplopia and ptosis. The ptosis began 1 year ago and worsened later in the day. Two weeks ago, she awoke in the morning and noticed an oblique diplopia (the second image was higher and over to the right) that resolved with closure of either eye. She had tenderness over the head, intense fatigue, and a history of mild pain with chewing that had since resolved. A noncontrast brain MRI was reported as normal. On examination, there was an esotropia on left gaze consistent with a left abducens palsy. An exotropia on right gaze was consistent with a left medial rectus palsy, and a left hypotropia worse in upgaze (and present in both adduction and abduction) indicated left superior rectus and inferior oblique weakness. Together with mild left ptosis, these findings suggested a left oculomotor palsy. Serum tests for temporal arteritis were normal. An MRI of the brain and orbits, with and without contrast, revealed bilateral enlargement and enhancement of the oculomotor, trigeminal, and facial nerves (Figure 8-10). Spine MRI demonstrated diffuse nerve root enhancement. Gangliosides to asialo monosialotetrahexosylganglioside (GM)1 and GM2 were mildly elevated. Lumbar puncture revealed 74 white blood cells/2L (93% lymphocytes), an elevated protein level of 101 mg/dL, a normal glucose level of 56 mg/dL, and elevated "2-microglobulin level, but cytology and flow cytometry were negative. Over the next month, two more lumbar punctures were performed, both with similar profiles and negative cytology, but a gene rearrangement analysis of the third sample was consistent with a primary T-cell CNS lymphoma.

FIGURE 8-10 Imaging studies of the patient in Case 8-1. Enhancement and enlargement of bilateral oculomotor nerves is seen in an axial contrast-enhanced T1-weighted MRI (A, red arrows). B, Coronal contrast-enhanced T1-weighted MRI demonstrates enlargement and enhancement of the bilateral oculomotor nerves (red arrows) and facial nerves (yellow arrows).

Comment. This case demonstrates that diplopia may be one of the first and only symptoms of life-threatening disease, such as primary CNS lymphoma. Multiple diagnostic challenges were faced, including nonspecific symptoms suggestive of temporal arteritis and a reported fatigable ptosis, which, as shown here, may be present in third nerve palsies in addition to ocular myasthenia. The oblique nature of the patient’s double vision helped predict the examination finding of a pupil-sparing oculomotor palsy, which in this age group is often microvascular. However, the examination revealed the unexpected finding of a concomitant abducens palsy. Once multiple cranial neuropathies were discovered, a leptomeningeal process was suspected. Finally, the limitation of noncontrast brain MRI in the diagnosis of diplopia is evidenced by the fact that a contrast MRI revealed obvious pathology of the cranial nerves soon after a noncontrast MRI was negative.

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Aberrant regeneration. Longstanding strictor pupillae muscles, resulting in lid oculomotor nerve palsies may eventu- elevation or pupillary constriction, re- ally result in regrowth of nerve fibers to spectively, during adduction. The pres- the wrong target. Thus, the fibers ence of such aberrant regeneration meant for the medial rectus might confirms the chronicity of the injury innervate the levator palpebrae or con- and rules out a benign microvascular

FIGURE 8-11 A 23-year-old man presented with a left abduction defect (A) accompanied by a right gaze palsy (B). C, Fluid-attenuated inversion recovery (FLAIR) MRI (left) revealed a hyperintense mass lesion, which showed contrast enhancement on postcontrast T1-weighted MRI (right) within the pons. D, Funduscopic examination revealed evidence of a prior posterior uveitis. Further history revealed a history of chronic mouth ulcers. A diagnosis of neuro-Behçet disease was made. In addition to oral and genital ulcers, Behçet disease can cause a retinal vasculitis and brainstem inflammatory lesions. The clinical and radiologic examinations improved with steroid treatment (not shown).

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS etiology (Supplemental Digital Content which case it is known as one-and-a-half h 44 Internuclear 8-4, links.lww.com/CONT/A126). syndrome. Alternatively, a conjugate ophthalmoplegia gaze palsy may occur in one direction reflects a lesion of the Supranuclear and Internuclear due to parapontine reticular formation medial longitudinal Diplopia injury, with an abducens palsy in the fasciculus and results in There are essentially two main causes of other direction due to injury of the failure of adduction of supranuclear or internuclear diplopia, abducens nerve fascicle (Figure 8-11). the contralateral eye in whicharediscussedingreaterdetailin Skew deviation. In the vertical attempted gaze to one the article ‘‘Supranuclear Eye Movement plane, skew deviation is a vertical mis- side. When found in Abnormalities’’ by Eric R. Eggenberger, alignment of the eyes resulting from association with a DO, MSEpi, FAAN, in this issue of inappropriate utricular-vestibular-ocular contralateral gaze palsy, it is termed a one-and-a- . output, essentially mimicking the phys- half syndrome. Internuclear ophthalmoplegia. In the iologic vertical deviations that normally h horizontal plane, disruption of the medial compensate for head or body tilt. As When vestibular output longitudinal fasciculus (Figure 8-1) can be seen in Figure 8-2 (red dashed from the utricle regarding tilt of the head or body resultsinfailedadductionoftheipsilat- line with arrows), the responsible path- is disrupted on one side, eral eye in contralateral gaze, with an ways emanating from the medial vestib- the result is a pathologic abducting nystagmus of the contralateral ular nucleus decussate in the pons, vertical misalignment of eye, together termed an internuclear after which they travel along the medial theeyesknownasa ophthalmoplegia. Sparing of conver- longitudinal fasciculus, so that a mesen- skew deviation. The gence, if present, confirms internuclear cephalic skew is frequently accompanied misalignment is often, but ophthalmoplegia, as it would not be by an internuclear ophthalmoplegia not always, comitant (equal spared with dysfunction of the oculo- where the internuclear ophthalmoplegia in all directions of gaze). motor nerve or the medial rectus is on the side of the higher eye. Because h When skew deviation muscle. Pontine disease may also affect of this pontine decussation, a medullary results from a medullary the abducens nucleus or parapontine skew will result in the ipsilateral eye being lesion, the ipsilateral eye is reticular formation, resulting in a conju- lower, while a mesencephalic skew will lower; when it results from gate gaze palsy in the direction opposite result in the ipsilateral eye being higher. a mesencephalic lesion, to the internuclear ophthalmoplegia, in Figure 8-12 shows an example of skew. the ipsilateral eye is higher.

FIGURE 8-12 Skew deviation. A 22-year-old woman presented with a vertical diplopia and a left hypertropia. A, Trochlear nerve palsy was initially suspected until examination revealed a comitant hypertropia and improvement in the supine position, consistent with skew. Additional findings included a torsional nystagmus, right facial and left body numbness, and ocular-lateropulsion (a conjugate movement of the eyes toward the side of the lesion when the eyes are closed) all pointing to a right Wallenberg syndrome. MRI showed a fluid-attenuated inversion recovery (FLAIR) hyperintense (B, arrow) and enhancing (C, arrow) lesion in the right lateral medulla. Note that the lower eye was on the side of the lesion, which is the rule for medullary skew. Multiple sclerosis was diagnosed with the development of a subsequent lesion.

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FIGURE 8-13 A framework for the assessment of the patient with diplopia. (1) Differentiate monocular from binocular diplopia. (2) If binocular, use history to predict localization. (3) Screen for fatigability and ptosis. If present, consider myasthenia. (4) If extraocular motility is limited, look for signs of orbital disease such as restriction, proptosis, or positive forced ductions. (5) If no restriction occurs, use the pattern of limitation to diagnose cranial neuropathy or internuclear ophthalmoplegia. (6) If extraocular motility is not limited but there is a tropia, use cover testing or Maddox rod to deduce the pattern of misalignment in multiple fields of gaze. (7) If vertical tropia is present, test for improvement in supine, indicative of skew. Note that exotropia or esotropia that is comitant in all directions suggests an infantile strabismus. Alternatively, an infantile esotropia or exotropia may be comitant in the horizontal plane, but worsen in upgaze or downgaze. When an exotropia is worse in upgaze (or an esotropia is worse in downgaze), it is termed a V pattern. When an exotropia is worse in downgaze (or an esotropia is worse in upgaze), it is termed an A pattern. These patterns are suggestive of infantile strabismus. IV = fourth nerve palsy; III = oculomotor nerve palsy; Hx = history; INO = internuclear ophthalmoplegia; B/L = bilateral; CI = convergence insufficiency; VI = abducens palsy; EOM = extraocular movements; EXO = exotropia; ESO = esotropia; HYPER = hypertropia; A/V = A pattern or V pattern; DI = divergence insufficiency; IOO = Inferior oblique overaction.

KEY POINT Distinguishing a skew deviation supine position, as the utricle is taken h The amplitude of the from a trochlear nerve palsy. While out of the plane of gravity.45 vertical misalignment appears to improve in the typical pattern of skew deviation is Convergence insufficiency. With the supine position in comitant (meaning that the ocular Parkinson disease, or rarely with advanc- skew deviations but not misalignmentisthesameinalldirec- ing age, convergence may become lim- with trochlear nerve tions of gaze and in both directions of ited, and adduction of the dominant eye palsies. head tilt), alternative patterns may occur, may be substituted, with the fellow eye and distinguishing skew from a fourth left in primary position. Convergence nerve palsy may be difficult. Some insufficiency is also common in children, evidence suggests that the hypertropia resulting in difficulty reading, often of skew may improve in amplitude in the accompanied by horizontal diplopia. In

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT childhood convergence insufficiency, localization of diplopia can be found h Convergence improvement occurred in 73% of pain Figure 8-13. insufficiency in children tients receiving office-based vergence/ often responds to accommodative therapy with home re- VIDEO LEGENDS office-based vergence/ inforcement versus 35% with placebo Supplemental Digital Content 8-1 accommodative therapy therapy.46 Prism glasses may be useful in Testingofversionsinamanwithaleftorbital with home apex syndrome. Video shows a 75-year-old man adults with convergence insufficiency. reinforcement, while who developed gradually progressive proptosis adult patients with and ptosis in his left eye accompanied by an Trends oblique diplopia. Visual field loss and a relative lesions of the An esotropia at distance in patients over afferent pupillary defect ensued in the left eye as convergence centers often 65 years old in the absence of lateral well. Neuro-ophthalmic examination reveals that require prismatic therapy. rectus weakness has been termed dis- the left eye is depressed and deviates laterally in primary gaze. Testing of versions show a lack of tance esotropia of the elderly. A recent adduction and elevation of the left eye, and study suggests that this entity may prog- limited depression which, along with ptosis, is ress over time, although the etiology for consistent with a left oculomotor palsy. Abduction this condition remains unknown.47 of the left eye is also limited, consistent with a left The sensitivity of the third step of abducens palsy. the Parks-Bielschowsky Three-Step The presence of a left oculomotor palsy and Test for true bilateral superior oblique an ipsilateral abducens palsy is suggestive of either cavernous sinus syndrome or orbital apex syn- paresis was found to be only 40% in drome. In this case, however, the presence of an one study, although this limitation may opticneuropathy(not shown), which would not in part result from false-positive errors occur from a cavernous sinus lesion, is the clue using the study’s criteria for the condi- that the site of the lesion is the orbital apex. The tion which was the observation of proptosis is also most consistent with an orbital apex mass, and MRI with contrast (see axial and bilateral fundus extorsion (both fundi coronal images at end of video) revealed a large were observed to be rotated along the left orbital apex meningioma in this patient. coronal plane so that the top of the links.lww.com/CONT/A124 48 retina was closer to the nose). B 2014 American Academy of Neurology. A recent study reviewed 34 patients presenting to the emergency depart- Supplemental Digital Content 8-2 ment with painful ophthalmoplegia. Alternate cover test. This video of the same The authors found that third and sixth patient as in Supplemental Digital Content 8-1 shows an exotropia (reflective of left medial nerve palsies were the most common rectus weakness) and a left hypotropia (reflective etiology, each accounting for 35% of the of left superior rectus and inferior oblique patients. Of note, CT and MRI of the weakness). Notice how the movements of the head demonstrated low sensitivities for right eye are greater than the left eye during the responsible etiologies (14% and 50%, test, even though it is not the paretic eye; the left eye is unable to move because of paresis. The respectively), while an erythrocyte sedi- deviation of the right eye (there is both an mentation rate of greater than 50 mm/h exotropia and hypertropia) is an example of a was 100% sensitive for temporal arteritis, secondary deviation and results from the Hering and pupillary mydriasis was 100% sen- law of equal innervation, which states that an sitive for aneurysmal causes.49 equal force is provided to each eye. links.lww.com/CONT/A125 A ROADMAP FOR DIPLOPIA B 2014 American Academy of Neurology. Using the principles of history taking Supplemental Digital Content 8-3 and examination discussed in this Enhanced ptosis (curtaining). When the ex- article, the neurologist should able to aminer lifts the right eyelid, the left eyelid falls diagnose even the most challenging further, and when the left lid is lifted, the case of diplopia. An algorithm for the apparently normal right lid begins to droop,

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