Disorders and Nystagmus€¦ · Disorders and Nystagmus JANET C. RUCKER Introduction Clinical Approach and Diagnostic Tools Ophthalmoparesis Extraocular Muscles The Neuromuscular

13 Acquired Ocular MotilityDisorders and NystagmusJANET C. RUCKER

Introduction

Clinical Approach andDiagnostic Tools

OphthalmoparesisExtraocular MusclesThe Neuromuscular JunctionCranial Nerve PalsiesBrainstem Disorders

Supranuclear Ocular MotilityControl

Abnormal Spontaneous EyeMovementsNystagmusSaccadic Intrusions

References

Key Points

� Eye movement disorders may be considered in two categories: those that causeincomplete eye movements (ophthalmoparesis) and those that cause excessiveeye movements (saccadic intrusions and nystagmus).

� Central to an understanding and correct diagnosis of abnormal eye movements isthe evaluation of ocular alignment, ocular motility, and each functional class ofeye movements: optokinetic, vestibular, vergence, smooth pursuit, and saccades.

� Ophthalmoparesis is caused by dysfunction of extraocular muscles, theneuromuscular junction, cranial nerves, cranial nerve nuclei, and internuclearand supranuclear connections.

� The initial pathologic eye movement in nystagmus is a slow drift of the eyeaway from the desired position, whereas the initial pathologic eye movementin saccadic intrusions is an inappropriate saccade that intrudes on fixation.

� Identification of the characteristics of nystagmus (physiologic versus pathologic,jerk versus pendular) is necessary for diagnostic evaluation and treatment.

Introduction

The goal of all normal eye movements is to place and maintain an object ofvisual interest on each fovea simultaneously to allow visualization of a stable,single object. Any deviation from normal eye movements may degrade vision.The spectrum of ocular motility disorders ranges from absent or inadequate

312

ocular motor function (ophthalmoplegia or ophthalmoparesis) to excessive ocu-lar motor function (spontaneous eye movements). This chapter is divided intothree sections; the first details those aspects of the history and examinationrequired for an accurate diagnosis of abnormal ocular motility, the second con-cerns acquired disorders of ophthalmoparesis, and the third concerns acquiredabnormal spontaneous eye movements.

Clinical Approach and Diagnostic Tools

Ophthalmoparesis results in ocular misalignment; hence an object of visualinterest falls on the fovea in one eye and on an extrafoveal location in the othereye, leading to the subjective appreciation of binocular diplopia (Fig. 13–1).When there are abnormal spontaneous eye movements, illusory motion of thevisual world (oscillopsia) occurs if the subjective experience of retinal motionis in excess of that normally tolerated by the visual system (up to about5 degrees per second for Snellen optotypes).1 An understanding of the natureand pathophysiology of these symptoms allows the correct identification andlocalization of an ocular motility disorder. Binocular diplopia may result fromdysfunction of extraocular muscles, the neuromuscular junction, cranial nerves,cranial nerve nuclei, and internuclear and supranuclear connections. Oscillopsiamay result from nystagmus and saccadic intrusions.

When diplopia is present, it is essential to determine if the diplopia resolveswith covering each eye in turn (binocular diplopia). If it persists with monocularcovering (monocular diplopia), it is not attributable to ocular misalignment butrather to refractive error or other ocular causes.2–4 It should be determined ifbinocular diplopia is horizontal, vertical, or oblique; worse in a particular direc-tion of gaze; and worse at distance or near. Horizontal diplopia is caused byimpaired abduction or adduction and vertical diplopia by impaired elevation

Figure 13–1 Fixation with normal ocularalignment is represented by solid black lines. Animage of the feather falls on each fovea simulta-neously and a single object is seen. Binoculardiplopia, which develops with an ocular mis-alignment (lateral deviation of the right eye asdepicted by the dashed arrow), occurs becausethe image of the feather falls on an extrafoveallocation in the deviated right eye (dashed lines).(Adapted from Leigh RJ, Zee DS: The Neurologyof Eye Movements, 3rd ed. Oxford, OxfordUniversity Press, 1999, p 337.)

31313 � Acquired Ocular Motility Disorders and Nystagmus

or depression. Worsening diplopia in a particular gaze direction suggests thatmotility in that direction is impaired. The temporal course of the diplopia andany associated neurologic symptoms should be assessed; proximal muscle weak-ness, difficulty swallowing, and shortness of breath, for example, suggest neuro-muscular dysfunction, and a deterioration of monocular vision and proptosissuggest an orbital process. These historical features are also important in theevaluation of patients with oscillopsia and spontaneous eye movements.

The neurologic and visual systems should be carefully examined in all patientswith diplopia, ophthalmoparesis, oscillopsia, or abnormal spontaneous eyemovements.5 The eye movement examination should include an assessment ofocular alignment and motility, as described in Chapter 1 (Fig. 13–2). In addition,stability of gaze fixation should be assessed with the eyes close to central position,viewing near and far targets, and at eccentric gaze angles. Prolonged observationfor up to 2 minutes is necessary, as some types of nystagmus periodically changedirection. Observation of the effect of removal of fixation on eye stability is alsoimportant, as nystagmus caused by peripheral vestibular dysfunction may onlybe visible under this circumstance. This can be achieved by transient coverageof the fixating eye during ophthalmoscopy in a dark room.

Each functional class of eye movements should be examined in both horizon-tal and vertical directions. Optokinetic nystagmus occurs reflexively during self-rotation and can be elicited at the bedside with visual tracking of an optokineticdrum or tape with alternating black-and-white vertical stripes. It consists of slowtracking, smooth pursuit movements alternating with quick resetting saccadicmovements.6 Vestibular eye movements hold an image steady on the fovea bymeans of compensatory eye movements during brief, nonsustained head move-ments, such as during walking. These eye movements may be evaluated clini-cally with passive head thrusts during which the examiner applies a low-amplitude, high-acceleration head rotation while the patient fixates a target.7,8

If vestibular function is normal, the patient will maintain fixation of the targetduring and after the head movement. If vestibular function is impaired, thepatient will not be able to maintain fixation and a corrective saccade back tothe target is seen following the head rotation. Examiner-applied passive headthrusts are more sensitive than patient-initiated active head thrusts for identify-ing vestibular dysfunction.9 Vergence eye movements consist of disconjugateconvergent and divergent eye movements that maintain stability of a visualimage during near and far gaze shifts. Smooth pursuit is a slow eye movement

A

B

C

D

Figure 13–2 Corneal light reflection test. A, Normalocular alignment—a light shined in the center of one pupilfalls in the center of the other pupil. B, Exotropia—a lightshined in the center of one pupil falls medial to the pupilcenter in the other eye. C, Esotropia—a light shined inthe center of one pupil falls lateral to the pupil centerin the other eye. D, Right hypertropia—a light shined inthe center of the pupil in the left eye falls below the pupilcenter in the right eye.

314 Neuro-Ophthalmology: Blue Books of Neurology

(velocity 20 to 50 degrees/second), which functions to hold the image of amoving target steady on the fovea and which can be assessed by having thepatient follow a slowly moving target. Saccades are fast eye movements (velocity300 to 500 degrees/second) that rapidly shift gaze to place an object of visualinterest on the fovea.10 Saccades present a challenging task to the brain, as theirexecution requires a sudden, intense neural discharge to effect a high-velocityeye movement and to overcome the elastic, damping orbital pull of extraocularmuscles and suspensory ligaments.10 This intense neural discharge is providedby brainstem neurons called burst neurons.

Ophthalmoparesis

EXTRAOCULAR MUSCLES

Thyroid ophthalmopathy is typically painless and bilateral, although it may beasymmetric. It tends to affect the inferior and medial rectus muscles first, leadingto restrictions of elevation and abduction. Although it is useful to obtain thyroidfunction studies (thyroid-stimulating hormone, triiodothyronine, and thyroxine),it may be associated with hyperthyroid, hypothyroid, or euthyroid states.Thyroid-stimulating antibodies correlate with the presence of thyroid eye diseaseand can be an important disease marker in the setting of a serologic euthyroidstate.11–13 Orbital computed tomography (CT) or magnetic resonance imaging(MRI) scans demonstrate enlargement of involved extraocular muscle bodies withrelative sparing of muscle tendon insertions at the globe (Fig. 13–3A). Coronalimages are best, because muscle enlargement may be underestimated if only axialimages are acquired. Treatment options include corticosteroids, radiation, andorbital decompression surgery, as discussed in Chapter 3. Discontinuation ofsmoking should be strongly advised, as smoking may worsen thyroid ophthal-mopathy and lessen treatment effect.14,15

Orbital pseudotumor is typically painful and unilateral. Any extraocularmuscle may be involved; orbital CT or MRI scans demonstrate enlargement of

Figure 13–3 A, Axial T1-weighted magnetic resonance imaging scan with gadolinium showingenlargement of the extraocular muscles from thyroid eye disease. Involvement is asymmetric, withgreater muscle enlargement in the left orbit than in the right. Muscle tendon insertions at the globeare relatively spared. B, Contrast-enhanced computed tomography scan showing enlargement ofthe left medial rectus muscle body and muscle tendon insertion from orbital pseudotumor.


involved extraocular muscle bodies and muscle tendon insertions at the globe(Fig. 13–3B), in contrast to that seen in thyroid ophthalmopathy, in which thereis sparing of the tendon insertions (Fig. 13–3A). The posterior sclera and orbitalfat may also be radiographically abnormal. Spontaneous resolution is common.Nonsteroidal anti-inflammatory medications and steroids relieve pain, hastenrecovery, and decrease the risk of recurrence.16

Infiltration by amyloid or infections and inflammation in sarcoidosis andWegener’s granulomatosis may also cause this phenotype. Lymphoid malignanciesare the most common orbital neoplasms.17 Metastasis of other neoplasms toextraocular muscles is rare. Orbital disease is covered in detail in Chapter 3.

Chronic progressive external ophthalmoplegia (CPEO) causes a slowly pro-gressive, bilateral, symmetric ocular immobility and bilateral ptosis. The pupilsare not affected, but the orbicularis oculi typically is. Characteristically the sac-cadic velocities are reduced throughout the movement, making it more easilydifferentiated from neuromuscular junction disorders. The extraocular musclesare sometimes seen to be atrophic on orbital imaging. Patients are often asymp-tomatic because of the slowly progressive, bilateral nature of the disease. Mito-chondrial genetic defects are the most common etiology, in which deletions orduplications arise. The phenotype may occur on its own or with cardiac pro-blems and retinitis pigmentosa and other disorders such as Kearns-Sayre syn-drome. It may also arise within a myodonic epilepsy with ragged red fibers(MERFF) and a mitochondrial encephalopathy, lactic acidosis, and strokelikeepisodes (MELAS) disorder. A CPEO phenotype may also be seen in oculophar-yngeal dystrophy, myotonic dystrophy, congenital myopathies such as myotubu-lar myopathy, and in association with neuropathies such as Refsum’s andStephen’s syndromes and abetalipoproteinemia.

THE NEUROMUSCULAR JUNCTION

Myasthenia gravis (MG) is the most common disease of the neuromuscular junc-tion. Ocular motility dysfunction in MG can mimic nearly any abnormal eye move-ment; it may resemble internuclear ophthalmoplegia, cranial nerve or nuclearpalsies, but the pupil is only very rarely involved. Features strongly suggestive ofneuromuscular junction impairment include moment to moment or visit to visitvariability in ocular motility, eyelid or extraocular muscle fatigue with prolongedupgaze, Cogan’s lid twitch, the peek sign, orbicularis oculi weakness, ptosis, andenhanced ptosis.18–20 Upgaze should be maintained for at least 2 minutes to assessadequately the appearance orworsening of ptosis or impaired ability tomaintain eyeelevation. Cogan’s lid twitchmay be seenwith saccadic return of the eyes to the cen-tral position following a few seconds of sustained downgaze.18 The upper eyelidmay elevate excessively, twitch, and become ptotic again. The peek sign is positivewhen prolonged eye closure allows orbicularis oculi weakness to cause lid separa-tion and globe exposure, despite initial complete eye closure.19 Enhanced ptosis isseen when ptosis in a less or nonptotic eyelid increases on manual elevation of themore ptotic lid.20 This phenomenon is based on Hering’s law of equal neural inner-vation to both eyelids;whenmaximal innervation is applied to a severely ptotic lid inan attempt to hold it open, the samemaximal innervationmayminimize the appear-ance of ptosis in a contralateral less or nonptotic lid. Manual elevation of the more


ptotic lid decreases the innervation of both lids, allowing the contralateral lid tobecome more ptotic (Fig. 13–4). Another phenomenon attributable to Hering’slaw is that of lid retraction in the eye contralateral to a ptotic lid. Frontalis overactiv-ity resulting from the attempt to hold ptotic lids open is often seen.

A positive edrophonium chloride test (Fig. 13–5) provides diagnostic supportfor MG.21 It is most useful when there is a defined deficit such as significantptosis or a fixed ocular motility defect that may be monitored for improvement.Edrophonium chloride is a reversible acetylcholinesterase inhibitor thatdecreases breakdown of acetylcholine in the synaptic cleft, thereby improvingneuromuscular transmission. Sensitivity and specificity of the edrophoniumtest in the setting of ocular MG are 60% to 80% and 86%,22,23 respectively. Rarepotential test risks include cardiac arrhythmias, syncope, respiratory failure, andseizures; however, this risk is approximately 0.16%.24 In one series a meandose of only 3.3 mg edrophonium resulted in improvement of ptosis or an ocularmotility defect, thereby minimizing test risk.25 The ice pack test is an alternativeto the edrophonium test; an ice pack is lightly placed over a closed ptotic eye for2 minutes, followed by observation for improvement of ptosis. The premise ofthis test is that neuromuscular transmission is improved by cold temperatures.26

Sensitivity is as high as 80% when partial ptosis is present but may be lowerwith complete ptosis.27

Acetylcholine receptor antibodies consist of three types: binding, blocking,and modulating. In generalized MG, binding and modulating antibodies havea prevalence of 89% and blocking antibodies of 52%28; in ocular MG it is lowerat 50%. Although anti-muscle specific receptor tyrosine kinase (anti-MuSK)

Figure 13–4 Enhanced ptosis. A, At rest, the left eyelid exhibits significant ptosis. B, Manualelevation of the left eyelid results in increased ptosis of the right eyelid.


antibodies are positive in some patients previously considered to have seronega-tive generalized MG, they are only rarely associated with ocular MG.29–32 A 20%or greater decrement of the compound muscle action potential with repetitivesuprathreshold stimulation has a sensitivity of only 42% in ocular MG,33 butthe diagnostic yield is increased with single-fiber electromyogram, with up to100% sensitivity.33

Standard treatments for MG include the long-acting acetylcholinesteraseinhibitor pyridostigmine, corticosteroids, and steroid-sparing immunosup-pressive agents such as azathioprine and mycophenolate mofetil.34,35 Pyridostig-mine is primarily used for symptom relief, whereas the others provide treatmentof the underlying disease process. In ocular MG, pyridostigmine is more effec-tive for ptosis than for diplopia.36 Corticosteroids are highly effective for bothptosis and diplopia and may successfully render the patient asymptomatic. Thereis some evidence that they may also diminish the risk of progression of ocular MGto generalized MG.25,36

Botulism results from exposure to an anticholinergic toxin produced byClostridium botulinum. Exposure is acquired by ingestion of toxin in contami-nated food; from wound infections; and, in infants, from gastrointestinal produc-tion of toxin. The clinical features are of a subacute ophthalmoparesis withpupillary involvement, particularly paralysis of accommodation, and muscleweakness without sensory loss elsewhere. It is said to be difficult to distinguishfrom ophthalmoplegia from MG; however, pupillary light-near dissociation andimpaired accommodation are common with botulism.

Ocular motility is rarely affected with the Lambert-Eaton myasthenic syn-drome, a presynaptic neuromuscular junction disorder caused by voltage-gatedcalcium channel antibodies. The clinical features are of autonomic disturbances,ptosis, and pupillary light-near dissociation in association with weakness else-where.37 The disorder may be paraneoplastic but can also occur independently.

EDROPHONIUM TEST METHOD

1. Identify an examination parameter to observe forimprovement after edrophonium administration.

2. Establish IV access.

3. Prepare edrophonium (10 mg in 1 cc syringe),1 mg atropine, saline flush (10 cc), blood pressureand heart rate monitoring equipment, video camera(optional).

4. Inject 1 mg edrophonium test dose, flush IV,observe for improvement or side effects for1 minute.

5. Monitor blood pressure and heart rate.

6. Repeat steps 4 and 5 every 1–2 minutes untilimprovement of chosen parameter, side effects,or 10 mg of edrophonium administered.

Figure 13–5 Edrophonium testmethod for diagnosis in myastheniagravis.


CRANIAL NERVE PALSIES

Third Nerve Palsy (Oculomotor Nerve)

The oculomotor nerve innervates the medial, inferior, and superior recti mus-cles; the inferior oblique muscle; the levator palpebrae superioris; the pupillarysphincter muscle; and the ciliary body.38,39 Identification of a complete thirdnerve palsy is typically straightforward on examination, when there is ptosis,an eye that is deviated “down and out,” and a dilated pupil. Elevation, depres-sion, and adduction of the eye are impaired. Identification of a partial thirdnerve palsy can be more challenging, especially if the pupil is spared.

Although a lesion anywhere along the oculomotor nerve pathway may result inthird nerve dysfunction, the two most common causes are compression of thenerve by a posterior communicating artery aneurysm within the subarachnoidspace and microvascular ischemia. Lesions of the third nerve fascicle in the brain-stem, cavernous sinus, and superior orbital apex are readily localized whennearby structures are also involved. Meningeal infiltration of the cavernous sinusor superior orbital apex by infectious, neoplastic, or autoimmune processes andcompression of the third nerve by an internal carotid artery aneurysm withinthe cavernous sinus are common diagnostic considerations. Hemorrhage into apituitary adenoma (pituitary apoplexy) may cause sudden onset unilateral orbilateral third nerve dysfunction, often accompanied by vision loss, nausea, orheadache.40 Onset of a third nerve palsy following minor trauma should promptinvestigation for an underlying posterior communicating artery aneurysm,41

although one may not always be found.42 Third nerve palsies may also arisein raised intracranial pressure, when the nerve is stretched as it passes acrossthe tentorial edge.

Elevation of the eyelid or constriction of the pupil during adduction or depres-sion of the eye is suggestive of aberrant regeneration (anomalous axon innerva-tion) (Fig. 13–6). When aberrant regeneration develops following an acutethird nerve palsy, a compressive posterior communicating artery aneurysm ortraumatic etiology should be considered.43 When aberrant regeneration occursspontaneously, without a preexisting acute third nerve palsy, a cavernous sinusmeningioma, or an internal carotid artery aneurysm is likely,44–46 although anunruptured posterior communicating artery aneurysm may also be responsible.47

Fourth Nerve Palsy (Trochlear Nerve)

Cranial nerve IV innervates the superior oblique, which depresses the adductedeye and intorts the eye. Each trochlear nerve innervates the superior obliquecontralateral to its nucleus. With a fourth nerve palsy, the affected eye is higherthan the contralateral eye (hypertropia) and vertical diplopia increases withdowngaze and adduction of the affected eye and reduces when a contralateralhead tilt places the affected eye in an extorted position. There may be a restinghead tilt in the direction away from the paretic eye. It is helpful to examine oldphotographs of the patient to determine if a head tilt is present, which suggestslong-standing misalignment such as that seen with congenital fourth nervedysfunction. Congenital fourth nerve palsies are relatively common and neuro-imaging may not be necessary if a long-standing nature can be confirmed byhistory.


The dorsal location of the brainstem exit near the tentorium makes the troch-lear nerves particularly prone to traumatic injury, which may cause unilateral orbilateral trochlear dysfunction.48 Microvascular fourth nerve palsies are lesscommon than microvascular third and sixth nerve palsies. Schwannomas ofthe fourth nerve, although very rare, are more common than those of the thirdand sixth nerves (Fig. 13–7).49

Figure 13–6 Aberrant regeneration following a traumatic left oculomotor nerve palsy. A, Incentral position, there is slight left ptosis and pupillary dilation. B, In right gaze, there is incom-plete adduction of the left eye and increased elevation of the left eyelid.

Figure 13–7 Axial T1-weightedmagnetic resonance imaging withgadolinium showing a left fourthnerve schwannoma in the sub-arachnoid space.


Sixth Nerve Palsy (Abducens Nerve)

Cranial nerve VI innervates the lateral rectus. A sixth nerve palsy results in pare-sis of abduction of the ipsilateral eye and esotropia. The amount of esotropia isgreatest in the direction of action of the weak muscle. The patient usually com-plains of binocular horizontal diplopia.

As the nerve passes through Dorello’s canal,50,51 it is prone to become affected,often bilaterally, by elevations in intracranial pressure. Relatively minor headtrauma may result in sixth nerve dysfunction.48 MG and restrictive medial rectusinvolvement in thyroid eye disease often mimic the sign of a sixth nerve palsy.

Investigation of Cranial Neuropathy Causing Diplopia

Intracranial magnetic resonance angiography (MRA) or CT angiogram (CTA)is commonly obtained to evaluate for an intracranial aneurysm in the setting,for example, of an acute onset, pupil-involving third nerve palsy. Ninety-twopercent of posterior communicating artery aneurysms causing third nerve palsiesare larger than 5 mm.52 MRI detects aneurysms larger than 5 mm with 97% sen-sitivity and aneurysms smaller than 5 mm with 54% sensitivity. The rupture riskof an aneurysm less than 10 mm is 0.05% per year.53,54 Approximately 1.5%of third nerve palsy-causing aneurysms that eventually rupture may not bedetected by MRA. It is often prudent to proceed with conventional intracranialangiogram to exclude an aneurysm definitively if MRA or CTA are equivocal.Gadolinium-enhanced MRI with high resolution, thin cuts through the brain-stem increases diagnostic yield, especially after an aneurysm is excluded byMRA or CTA. If MRI is unremarkable, lumbar puncture may be required toassess for cerebrospinal fluid abnormalities. Acute onset of a painful, pupil-sparing third nerve palsy and sixth nerve palsy may represent microvascularischemia to the nerve, especially in older patients with vascular risk factors.55

Spontaneous resolution over 8 to 12 weeks is typical. Investigation of the othercauses noted in the table should also be undertaken.

Multiple Cranial Neuropathies

Lesions at the cavernous sinus are associated with third, fourth, and sixth nervepareses in combination with signs of involvement of the first and second divi-sions of the trigeminal nerve and sympathetic fibers. Primary tumors such asparasellar meningiomas, lymphoma, and pituitary adenomas and secondarytumors including nasopharyngeal carcinoma and myeloma; vascular disorderssuch as carotid-cavernous fistula and intracavernous internal carotid artery aneu-rysm; and inflammatory disorders such as Tolosa Hunt syndrome, Wegener’sgranulomatosis, Rosai-Dorfman syndrome, and hypertrophic pachymeningitismay all cause cavernous sinus syndromes (Table 13-1). Lesions at the orbital apexmay affect the oculomotor, trochlear, and abducens nerves in combination withthe first division of the trigeminal nerve and the optic nerve. Proptosis, chemosis,and conjunctival injection are often present. Inflammation, including orbitalpseudotumor and those noted previously, infection from the sphenoid and eth-moid sinuses, particularly aspergillosis and mucormycosis, and primary andsecondary neoplastic disease may all cause orbital apex syndromes.


Multiple ocular motor nerves may be affected in Guillain-Barre syndrome or inthe Miller-Fisher variant of Guillain-Barre. The classic triad of Miller-Fisher syn-drome is ophthalmoplegia, ataxia, and areflexia. In addition to ophthalmoplegia,pupillary light-near dissociation is common. Anti-GQ1b antibodies are present ingreater than 90% of patients with Miller-Fisher syndrome and are associated withCampylobacter jejuni infections. Treatment if required is with plasma exchange orintravenous immunoglobulin, as for Guillain-Barre syndrome

BRAINSTEM DISORDERS

Cranial Nerve Nuclei

As has been noted in Chapter 1, nuclear lesions differ in clinical appearance fromtheir corresponding cranial neuropathies. A third nerve nuclear lesion causesbilateral impairment of ocular elevation (resulting from contralateral innerva-tion of the superior rectus) and bilateral ptosis (resulting from a single midlinelevator palpebrae subnucleus that innervates both levator muscles).56,57 Veryrarely, a third nerve nuclear lesion may result in isolated weakness of a singlemuscle such as the inferior or superior rectus.58,59

A fourth nerve nuclear lesion causes a superior oblique palsy clinically similarto a fourth nerve lesion; however, the superior oblique weakness is contralateral to

TABLE 13-1 Causes of Third, Fourth, and Sixth Cranial Nerve Paresis

Site Disorder

Brainstem InfarctionHemorrhageDemyelinationTumorInfection/abscess

Subarachnoidcourse

AneurysmMeningitis, including carcinomatous and leukemic infiltration,infectious including bacteria, spirochetes, and asepticmeningitis

Microvascular infarctionTumor

Cavernous sinus/orbital apex

Internal carotid aneurysmCaroticocavernous fistulaPituitary lesionsMeningiomaMetastasisMicrovascularSphenoid and ethmoid mucocelesTolosa-Hunt syndrome, Wegener’s granulomatosis and otherinflammatory disorders

Herpes zosterOrbit Trauma

InfectionsTumor


the nuclear lesion because of the fourth nerve decussation after dorsal emergencefrom the midbrain. In addition, a fourth nerve nuclear lesion is almost invariablyaccompanied by a Horner’s syndrome ipsilateral to the lesion because of the prox-imity of the preganglionic sympathetic fibers to the dorsally placed fourth nervenucleus.60

A sixth nerve nuclear lesion causes an ipsilateral horizontal gaze palsy.61–63

Although rare cases of isolated horizontal gaze palsy are reported,63 it is nearlyalways accompanied by an ipsilateral seventh cranial nerve palsy with lowermotor neuron facial weakness (because of the anatomic proximity of the seventhcranial nerve fascicle to the sixth nerve nucleus, which it wraps around).

SUPRANUCLEAR OCULAR MOTILITY CONTROL

Supranuclear eye movement abnormalities result from dysfunctional cerebral,cerebellar, and brainstem afferent connections to the ocular motor cranial nervenuclei. Because of the excessive demands that saccadic eye movements place onthe neural network, a clinical hallmark of supranuclear eye movement disordersis disproportionate involvement of saccadic eye movements relative to smoothpursuit. Vestibular eye movements are typically intact. In contrast, a nuclearor infranuclear process impairs saccades, smooth pursuit, and vestibular eyemovements to the same extent.

Burst neurons in the brainstem provide the sudden, intense neural dischargerequired to initiate a high velocity saccade and to overcome dampening, orbital elas-tic forces. Burst neurons for horizontal saccades are located in the paramedian pon-tine reticular formation (PPRF) and, for vertical saccades, in the rostral interstitialmedial longitudinal fasciculus (riMLF) in the midbrain (Chapter 1). A lesion ofthe PPRF causes slow or absent horizontal saccades and a lesion of the riMLF causesslow or absent vertical saccades. Burst neurons must be inhibited; otherwiseconstant saccades would occur and disrupt vision. This is provided to both thehorizontal and vertical burst neurons by omnipause neurons located in the pons.Dysfunction of these neurons results in excessive back-to-back saccades in eitherthe horizontal directions (ocular flutter) or in all directions (opsoclonus) (see later).

The dorsal midbrain syndrome is comprised of a supranuclear upgaze palsy,convergence-retraction nystagmus, lid retraction (Collier’s sign), and pupillarylight-near dissociation. The most common etiologies are a pineal gland cyst orhemorrhage and hydrocephalus. A supranuclear upgaze palsy with forced down-ward deviation of the eyes (“peering at the tip of the nose”) may result from athalamic lesion that extends into the midbrain.64 Thalamic esotropia, in whichthe eyes are deviated medially on both sides, arises because of excessive conver-gence tone with compression or involvement of the dorsal midbrain.65

Gaze deviation is a common manifestation of a supranuclear disorder. Thefrontal eye fields (FEF) project to the contralateral PPRF; a destructive lesionof the FEF, for example, following cerebral infarction, results in ipsiversive bilat-eral gaze deviation; the patient “looks at the lesion.” With an irritative lesion, forexample, seizure or hemorrhage, there is contraversive deviation; the patient“looks away from the lesion.” A thalamic lesion, however, may cause “wrongway eyes” in which the patient “looks away” from a destructive lesion.66

Degenerative brainstem diseases such as progressive supranuclear palsy,Parkinson’s disease, spinocerebellar degenerations, and Huntington’s disease


and metabolic disorders such as Wilson’s disease and lipid storage diseases mayall show distinctive abnormalities of supranuclear ocular motility control.

Internuclear ophthalmoparesis (INO) results from a lesion of the medial longi-tudinal fasciculus (MLF), which carries signals from the abducens nucleus to thecontralateral medial rectus subnucleus of the oculomotor nucleus. These signalsallow conjugate horizontal eye movements with co-contraction of the ipsilaterallateral rectus and contralateral medial rectus muscles. A unilateral INO leads toimpaired adduction of the eye ipsilateral to the MLF lesion and dissociated nys-tagmus of the contralateral abducting eye. Despite adduction weakness on directhorizontal motility testing, adduction of the eye ipsilateral to the MLF lesion isintact with convergence eye movements because direct vergence signals to themedial rectus motor neurons do not pass through the MLF.67 The eye movementsmay appear normal with bedside smooth pursuit testing and the presence ofan INO diagnosed only by the identification of a decreased velocity of the adduct-ing eye compared with the abducting eye during saccadic testing, known asadduction lag.68 Multiple sclerosis; vascular lesions such as infarction, hemor-rhage, and arteriovenous malformations; and tumors are the most common causesof INO.69,70 Bilateral INO is usually because of multiple sclerosis and may beassociated with a marked exotropia; the “walled eyed” bilateral INO.

Because the PPRF and MLF lie in close proximity within the brainstem oneach side, lesions in this region may affect both structures, leading to the “oneand a half syndrome” coined by Miller-Fisher. The coexistence of an INO andan ipsilateral horizontal gaze palsy results in there being only abduction in thecontralateral eye and no other horizontal eye movement.

Skew deviation is a vertical misalignment of the visual axes. Patients havea hypertropia, which may be concomitant (the same in all directions of gaze),or incomitant. It may be difficult to differentiate incomitant skews from otherocular motility problems such as ophthalmoparesis because of dysfunction ofcranial nerves III or IV, but there should be other signs of brainstem or cerebellardysfunction. It occurs when a disorder causes a mismatch between inputs to thebrainstem from the otoliths on both sides.

Some patients may have an INO as well. Others may show the ocular tiltreaction (OTR), in which there is a tilt of the head to the side contralateral to thelesion. It is assumed that this reflects a compensation by the brainstem for the lossof vestibular input; the patient’s position of center of gravity has been shifted. TheOTR may be paroxysmal or sustained. Skew deviation with or without the OTRmay arise with lesions in the cerebellum, midbrain (particularly lesions of thedorsal midbrain which include the interstitial nucleus of Cahal), and pons.

Abnormal Spontaneous Eye Movements

NYSTAGMUS

Nystagmus is a repetitive to-and-fro movement of the eyes that can be congenitalor acquired, physiologic or pathologic. Physiologic nystagmus is sometimes evidentat a bedside motility examination and consists of low-amplitude, high-frequencygaze-evoked nystagmus present only in extremes of horizontal gaze. The nystagmuswill resolve when the eyes are moved to a slightly less eccentric gaze position.


Pathologic acquired nystagmus is described as jerk or pendular; jerk nystag-mus is characterized by a to-and-fro oscillation whose phases are of unequalvelocity, termed the slow and fast phases, whereas in pendular nystagmus thephases have equal velocity. Although the direction of jerk nystagmus is namedafter the direction of the fast phase, the underlying mechanism generating theabnormal eye movement is the slow phase, or slow drift of the eyes away fromthe desired position. The fast phase is a rapid, corrective movement in the oppo-site direction. There are three primary mechanisms by which an image is main-tained on the fovea: fixation, the vestibulo-ocular reflex, and eccentric gazeholding. Nystagmus may result from disruption of any one of these mechanisms.

Nystagmus Associated with Visual Loss

Visual loss of any cause may disrupt fixation and be associated with nystagmus;that resulting from optic nerve disease is more commonly pendular and thatresulting from retinal disease more commonly of jerk type. In the Heimann-Bielchowsky phenomenon, the nystagmus is more prominent in the eye withthe greater visual loss71–74 or may arise when the visual loss is only in oneeye. This is usually pendular and is more prominent in the vertical direction.

Acquired Pendular Nystagmus

Acquired pendular nystagmus (APN) is one of the most visually disabling typesof nystagmus. It is a pendular nystagmus that may have horizontal, vertical, ortorsional components. APN may occur in the setting of visual loss because ofoptic neuritis, but it is more commonly seen in brainstem lesions, for example,because of multiple sclerosis;75 Pelizaeus-Merzbacher disease; lysosomal storagediseases; brainstem infarction; Whipple’s disease76 (when it is associated withoculomasticatory myorhythmia); spinocerebellar degenerations; toluene abuse;77

or as a component of oculopalatal myoclonus (oculopalatal tremor),78 in whichpendular nystagmus with a prominent vertical component associated with a syn-chronous palatal tremor develops months after brainstem or cerebellar infarction.Others brainstem signs are invariably present, such as INO and skew deviation.

Treatment of APN

A double-blind, placebo-controlled, cross-over study comparing gabapentinand baclofen found gabapentin to be highly effective in minimizing oscillopsiaand ocular oscillations in patients with APN.79 The known role of gamma-aminobutyric acid (GABA)-ergic neural transmission in control of the neuralintegrator, which functions to maintain stability of the eyes in eccentric gazepositions, suggests altered GABA transmission as a mechanism for APN. Meman-tine, clonazepam, valproate, and scopolamine may also be tried.80,81 Patientswith oculopalatal tremor may respond to carbamazepine.82,83

Nystagmus from Vestibular Imbalance

Nystagmus from vestibular imbalance may be caused by disease of peripheral orcentral vestibular pathways. With peripheral vestibular disease, asymmetric ves-tibular inputs result in jerk nystagmus because the unaffected and unopposed


contralateral vestibular nucleus drives the eyes slowly toward the side of thelesion, and hence the direction of the nystagmus is away from the lesion. Animportant feature of peripheral vestibular nystagmus is that it is accentuatedby, and indeed may only be detected with, elimination of fixation, for example,with Frenzel goggles. The nystagmus is usually of mixed torsional and horizon-tal direction. Most nystagmus from acute peripheral vestibular impairment suchas benign paroxysmal positional vertigo or acute labyrinthitis resolves spontane-ously; however, if oscillopsia or vertigo are significantly debilitating, acute man-agement with pharmacologic agents such as diphenhydramine or promethazinemay be beneficial.

Imbalance of central vestibular connections may result in vertical or torsionalnystagmus. Elimination of fixation tends not to influence the severity of thenystagmus appreciably. Downbeat nystagmus, in which the slow phase is in anupward direction and which is accentuated looking down and to either side,may arise because calcium channel-rich cerebellar Purkinje cells inhibit thevestibular nucleus mediating downward, but not upward, eye movements. Thiscauses a relative decrease in inhibition of upward eye movements, with a resultantslow drifting of the eyes upward and fast corrective downward eye movements.84

Other signs of cerebellar dysfunction, such as abnormal vestibulo-ocular reflex,are also seen.

Upbeat nystagmus is usually present in the primary position of gaze and, likedownbeat nystagmus, increases when the eye is moved in the direction of thenystagmus. It is not, however, accentuated by looking to either side. Verticalnystagmus is almost always associated with a central cause, although a periph-eral vestibular lesion can occasionally be associated with upbeating nystagmus,usually with a torsional component.

Either downbeat or upbeat nystagmus may result from a variety of otherbrainstem or cerebellar pathologies such as vascular disorders, tumors, enceph-alitis, inherited and acquired causes of cerebellar degeneration, multiple sclero-sis and other inflammatory diseases, and metabolic states such as drugintoxication with lithium and anticonvulsants, Wernicke’s encephalopathy, andvitamin B12 deficiency. Downbeat nystagmus may also be caused by structurallesions of the craniocervical junction, such as Arnold-Chiari malformation(Fig. 13–8),85 Paget’s disease and basilar invagination, and foramen magnumlesions such as meningioma. Pure torsional nystagmus is rare and is associatedwith the brainstem diseases noted previously.

Treatment

The potassium channel blockers 3,4-diaminopyridine and 4 aminopyridineare effective treatments for downbeat nystagmus.86,87 Clonazepam, baclofen,and gabapentin may also be useful.88,89

Periodic Alternating Nystagmus

Periodic alternating nystagmus (PAN) is a horizontal jerk nystagmus that sponta-neously reverses direction every 60 to 90 seconds. It is often missed if the exam-iner does not watch the eyes for long enough. At the time of direction-reversal,there may be a transition period in which vertical nystagmus or a series of squarewave jerks may arise, before the horizontal nystagmus changes direction and


continues. It may occur in multiple sclerosis, cerebellar degenerations or masslesions, brainstem infarction, anticonvulsant toxicity, meningoencephalitis, andtrauma. In an animal model, PAN results from ablation of the cerebellar nodulusand uvula, structures known to use GABA B inhibitory pathways to control rota-tionally induced nystagmus.90 Both experimental and clinical PAN respond wellto the GABA B agonist baclofen.91

Seesaw Nystagmus

This is a rare nystagmus in which one eye elevates and intorts while the othermoves down and extorts, then the movement reverses. It occurs in patients withchiasmal visual loss due, for example, to pituitary and other parasellar lesionsbut may also arise in brainstem lesions that involve the interstitial nucleus ofCahal in the midbrain. Treatment of the parasellar lesion usually improves thecondition, as do baclofen, clonazepam, and alcohol.

Gaze-Evoked Nystagmus

Gaze-evoked nystagmus is the most common type of nystagmus, is absent incentral position, and beats in the direction of eccentric gaze. It is the result ofimpairment in eccentric gaze holding mechanisms from a variety of causes,including anticonvulsant or sedative medications and brainstem lesions thathave impaired the function of the diffuse gaze-holding neural network. Becauseit is absent in central position, it is generally not visually disabling and, there-fore, does not require treatment.

SACCADIC INTRUSIONS

In contrast to nystagmus, in which the initial abnormal movement is a slow driftof the eyes away from their desired position, the initial abnormal eye movement

Figure 13–8 Sagittal T1-weightedmagnetic resonance imaging withgadolinium showing an Arnold-Chiari type I malformation.


with saccadic intrusions is a sudden saccadic movement that abolishes steadyfixation. The spectrum of saccadic intrusions ranges from abnormal intrusivesingle saccades (macrosquare wave jerks) to sustained saccadic oscillations(ocular flutter and opsoclonus). Back-to-back saccades with no saccadic intervalin the horizontal plane are termed ocular flutter, whereas similar saccadic intru-sions in all directions are termed opsoclonus. Ocular flutter and opsoclonusarise because of disease of pontine omnipause neurons that normally inhibit sac-cadic burst neurons.92 Many causes of ocular flutter and opsoclonus, such asviral parainfectious encephalitis, meningitis, and medication toxicity, resolvespontaneously. Others, such as paraneoplastic syndromes, stroke, or tumor,may not and clonazepam or gabapentin may be tried but are not very effective.

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