J'ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:863-868

REVIEW

The ocular manifestations of multiple sclerosis

2 Abnormalities of eye movements

D Barnes,W I McDonald

"[October 17th, 1827] ... At Florence I beganto suffer from a confusion of sight; about the6th November the malady increased to theextent of my seeing all objects double. Eacheye had its separate vision . . . the malady ofmy Eyes abated, I again saw all objects actuallyin their single state."

Augustus d'Este

Institute of Neurology,and the MoorfieldsEye Hospital, London,UKD BarnesW I McDonaldCorrespondence to:Dr Barnes, Institute ofNeurology, Queen Square,London WC 1N 3BG

Received 23 August 1991and in revised form31 December 1991.Accepted 8 January 1992

The first part of this review described afferentvisual disturbances in multiple sclerosis.' Inthis second part we discuss the abnormalitiesof eye movements that may be encountered.The accurate control of eye movements,authoritatively reviewed by Zee and Pierrot-Deseilligny, depends upon the integration ofactivity of many separate components of thenervous system, most importantly at the levelof the brainstem and cerebellum.2 The multi-focal nature of multiple sclerosis, and itspredilection for the posterior fossa explain whypatients with this disease are so commonlysubject to defects in eye movement control.Diplopia is experienced by one third, nystag-mus occurs in two thirds, and some eyemovement disorder is present in more thanthree quarters of multiple sclerosis patientsduring their illness.4-6A careful assessments of eye movements in

every patient suspected of having multiplesclerosis is necessary, both for decidingwhether an abnormality is present (and thusperhaps providing the evidence for a separatelesion crucial to the diagnosis), and definingits nature. The examination must be systematicif abnormalities are not to be missed. It isparticularly important to examine the eyes inthe primary position to detect spontaneousinvoluntary movements such as square wave

jerks, ocular flutter and second degree nys-tagmus. Prolonged inspection in conjugatedeviation is required to detect periodicalternating nystagmus (see below). Occasion-ally small amplitude movements are best seenwhen examining the fundus ophthal-moscopically. Patients with clinically normaleye movements frequently show abnormalitieson electroculography (EOG),7 8 which is a

valuable investigation, complementary tobrainstem evoked potentials for detectingsubclinical lesions.5The range of symptoms is narrow. Blurring

of vision relieved by closure of either eye,diplopia, and oscillopsia are obvious pointersto disorders of ocular motor control, but lessclearcut symptoms such as a feeling of unstea-

diness or simply "tired eyes" may be the onlycomplaint, and some patients have no symp-toms at all.With a few exceptions, for example lesions of

the medial longitudinal fasciculus (MLF), theclinical examination usually allows onlyapproximate localisation of a lesion responsiblefor an eye movement disorder. The advent ofcontrast-enhanced MRI using Gadolinium-DTPA has provided a means of highlightingand accurately delineating the lesion responsi-ble in most multiple sclerosis patients in acuterelapse." This technique has now been suc-cessfully applied to patients with disorderedeye movements, allowing precise clinico-ana-tomical correlation in patients with abnormalhorizontal gaze." 1 There are still manyabnormalities where the anatomical location ofthe lesion responsible is uncertain, but withfurther experience in multiple sclerosis andother diseases, MRI should provide con-siderable insight into these problems.

Types of eye movement disturbancePractically all known types of eye movementdisorder have been described in multiple scle-rosis (table 1), but the commonest are bilateralinternuclear ophthalmoplegia (11O), abnor-malities compatible with damage to the cere-bellum or its connections, and pendularnystagmus.'4 '5 While these disturbancesshould alert the clinician to the diagnosis ofmultiple sclerosis, it cannot be too stronglyemphasised that no particular clinical patternis specific to this, or any other disease. In what

Table Simplified classification of eye movementabnormalities in multiple sclerosis

1 Isolated ocular motor nerve palsies

2 Abnormalities of voluntary gaze-Ocular dysmetria and gaze impersistence-lesions of the medial longitudinal fasciculus-horizontal gaze palsy-one-and-a-half syndrome-dorsal midbrain syndrome-skew deviation

3 Abnormalities of slow phase eye movements

4 Nystagmus-horizontal-vertical-pendular-periodic alternating

5 Paroxysmal disorders of eye movements-ocular flutter-square wave jerks-opsoclonus

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follows we have tried to indicate the relativefrequency with which the various eye move-ment abnormalities occur in multiple sclero-S1S.

1 ISOLATED OCULAR MOTOR NERVE PALSIES

Truly isolated ocular motor palsies are uncom-mon in multiple sclerosis; careful examinationoften reveals other defects such as nystagmuson upgaze. When they do occur, the VIth andIlIrd nerves are most commonly involved. Wehave only seen one patient with isolatedinvolvement of the trochlear nerve. PartialIIIrd nerve palsies, either fascicular or nuclear,may occur, and precise lesion localisation isoften possible by careful analysis of the clinicalsigns. '6 More uncommonly, brainstemdemyelination can cause an upper or lowerdivisional IlIrd nerve palsy usually associatedwith more distal lesions.'7 Ivers and Goldsteinfound only two cases of isolated lateral rectuspalsy in 144 multiple sclerosis patientsreviewed at the Mayo Clinic.'8 Similarly, in astudy of 1000 cases of isolated ocular motorpalsies, Rush and Younge found only 27(2 7%) to be due to multiple sclerosis: involve-ment of the IIIrd alone occurred in eightpatients, the IVth in none, the VIth in 18, andmultiple nerves were affected in one patient."Moster et al, however, examined 49 patientsunder the age of 50 with isolated lateral rectuspalsies and found demyelination to be thecause in 12%, the third commonest aetiol-ogy.2" Furthermore, in most studies about 1/4of cases remain undiagnosed,'9 21 and it ispossible that some of these patients may havehad an episode of demyelination.

In one multiple sclerosis patient with anisolated lateral rectus palsy, MRI showed alesion corresponding to the site where the VIthnerve emerges from the ventral paramedianpons.22 Similarly, in the series of Bronstein etal,'2 isolated lateral rectus palsy in multiplesclerosis was shown by MRI to be associatedwith lesions involving the fascicular portion ofthe nerve: if the nucleus was involved anipsilateral gaze palsy, more marked in theabducting eye, was seen. Thus while isolatedpalsies are relatively uncommon in multiplesclerosis, this diagnosis should be borne inmind in a young patient with no other obviouscause.

2 ABNORMALITIES OF VOLUNTARY GAZE

Disturbances of conjugate gaze, either volun-tary saccades or, as decribed below, smoothpursuit, are the commonest eye movementabnormalities caused by multiple sclerosis,although they are frequently subclinical. Theirdetection often provides evidence of dissem-ination of lesions in the nervous system,allowing a definite diagnosis to be made. In adetailed EOG study of saccades and smoothpursuit in 84 patients with definite, probable orpossible multiple sclerosis, Reulen et al foundabnormalities in 85%, 77% and 60% of casesrespectively.4 Similar studies have confirmedthe high incidence of saccadic and pursuit eyemovement defects: they are present in abouttwo-thirds of patients in whom the diagnosis is

not yet definite, but are frequently sub-clinical.23 24 Several authors emphasise theimportance of measuring as many separateparameters of saccades as possible for lesionlocalisation, as for example, a prolonged sac-cadic initiation time alone can result fromdelay in any part of the afferent or efferentvisual system.2" The findings of these studiesemphasise that, in experienced hands, EOG isoften helpful in the evaluation of patients withpossible multiple sclerosis.

Lesions of the medial longitudinal fasciculus(MLF)The best known clinical eye movement abnor-mality in multiple sclerosis is the INO. Thecardinal feature of an INO is slow, or lesscommonly, incomplete adduction of the eyeipsilateral to the affected MLF. Slowing ofadducting saccades may become more obviousduring rapidly repeated lateral gaze move-ments (with the examiner looking at theglabella). Although INOs are most commonlydue to multiple sclerosis, it is important toremember that they may be seen in otherdisorders such as brainstem infarction, gliomasand anticonvulsant toxicity.26 An INO is pres-ent in 34-53% of patients, and is oftenbilateral, especially later in the course of thedisease.46 Dysconjugation of the two eyes isoften compounded by overshooting of thecontralateral abducting eye (followed by a fewbeats of "ataxic" nystagmus in about 50% ofpatients), and also by overshoot on recenteringof the abducted eye. Ataxic nystagmus is rarelysustained, and its mechanism is unclear,although Zee et al showed that in three out offour patients, it represented an adaptiveresponse to weak adduction in the affected eye,as predicted by Hering's law of equal inner-vation."

Other abnormalities which may be foundwith an MLF lesion include vertical gaze-evoked nystagmus, impairment of verticalgaze, hypertropia most commonly ipsilateral(skew deviation-see below), and unilateral orbilateral slowing of abduction.28 The verticalgaze disorders probably reflect disruption ofconnections with the rostral interstitial nucleusof the MLF. Convergence is usually spared,but in those patients in whom it is impairedthere is a correlation with the clinical severityof the INO suggesting a more extensive (par-ticularly rostral) lesion. Furthermore, INOsare frequently associated with an increase insaccadic latency suggesting that the lesionresponsible extends beyond the MLF to otherbrainstem structures involved in the program-ming of saccades.4 This impression was con-firmed by Bronstein et al who studied 28patients (14 had multiple sclerosis) with anINO by MRI, and found that in all patients thelesions showed similar MRI appearances, andfrequently extended beyond the MLF toinvolve neighbouring pontine or mid-brainstructures. 1' Interestingly, the anatomicalextent of the MRI abnormalities did notcorrelate with the presence of associatedabduction and convergence defects, althoughpatients with these features tended to have

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2 Abnormalities of eye movements

more severe INOs clinically. In some patientswith bilateral INOs, fixation is disrupted byoccasional abducting saccadic bursts in one orother eye, the adduction deficit preventingconjugate movement of the fellow eye. Thisphenomenon is thought to signify a lesionextending beyond the MLF, and disrupting thesupranuclear control of omnipause cells in thenucleus raphe interpositus.29 30

Other less common clinical eye movementdisorders are now described which may resultfrom demyelinating lesions in the pon-tomesencephalic region: conjugate gazepalsy,3' 32 the "one-and-a-half' syndrome,33 34

gaze-alternating skew deviation35 and the dor-sal midbrain syndrome36 all occur, but areuncommon in isolation.

Horizontal gaze palsyHorizontal gaze palsies may theoretically resultfrom lesions of: (1) the ipsilateral paramedianpontine reticular formation (PPRF) rostral tothe abducens nucleus; (2) the abducensnucleus; (3) both one and two, and (4) boththe VIth nerve fascicle and contralateral MLF.The first three of these possibilities weredocumented by Bronstein et al in their MRIstudy.'3 Functionally, the abducens nucleusmay be the caudal end of the PPRF. Completegaze palsies which result from lesions of thePPRF alone may be distinguished clinicallyfrom those involving the nucleus because in theformer, the eyes can still be driven to the sideof the palsy by oculocephalic stimulation(Doll's eye manouevre) because the vestibulo-ocular reflex (VOR) does not rely on an intactPPRF. Incomplete palsies, however, are lesseasy to differentiate.

Isolated gaze palsies do occasionally occur inmultiple sclerosis, but are more commonlyassociated with other defects such as an INO.When isolated, they are assumed to be due tolesions confined to the PPRF-abducens com-plex, and this assumption has so far beenborne out by a small number of MRI stud-ies.'2 13 22 32 Although gaze palsies are usuallypartial, they may be complete. For example, apatient recently presented to us with bilateralINOs that developed into complete horizontalgaze palsies over one week, and other similarpatients are reported.3' 32 In patients withbilateral gaze palsies, MRI consistently shows asingle midline lesion in the pons, probablydamaging both PPRFs and the ventral raphearea.13 32

The "one-and-a-half" syndromeThe "one-and-a-half' syndrome was first des-cribed with pathological correlation by MillerFisher in 1967.37 It is the combination of ahorizontal gaze palsy with an ipsilateral INOdue to a lesion involving both the PPRF-abducens complex and MLF on the same side:thus the patient has a gaze palsy to the side ofthe lesion ("one") with impaired adduction onattempted contralateral gaze ("and-a-half').As with an isolated INO, there may be asso-ciated abnormalities of vertical gaze. Martynand Kean described a patient with multiplesclerosis and a "one-and-a-half' syndrome in

Figure T2-weighted axial MRI showing a right sideddorsal pontine and cerebellar lesion in a patient withmultiple sclerosis and a right "one-and-a-half "syndrome.(Ormerod et al. Brain 1987;110:1597. By permissionof Oxford University Press).

whom MRI confirmed that the lesion wassituated on the appropriate side of the dorsalpons (figure) .38 This syndrome was wellreviewed by Pierrot-Deseilligny et al withdescriptions of five cases of their own and areview of the 17 previously reported cases: ofthese 22 patients, the majority had vasculardisease and only two had multiple sclerosis.3"In 1983, however, Wall and Wray added afurther 20 cases to the literature, of whom 12had definite, and two suspected multiple scle-rosis.34 Of these 14 patients, 12 had visualsymptoms, most commonly diplopia, but blur-ring, oscillopsia and difficulty looking to oneside were also noticed. Associated findingsincluded gaze-evoked upbeat nystagmus in 13,downbeat nystagmus in two, and skew devia-tion in five (ipsilateral hypertropia in onlythree). From this report it seems that, inkeeping with our own experience, the "one-and-a-half' syndrome may be a more commonmanifestation of demyelination than was pre-viously thought.

The dorsal midbrain syndromeThe dorsal midbrain syndrome describes aconstellation of eye signs. Upward gaze isaffected most consistently, but eyelid retractionor ptosis, near-light dissociation of the pupils,accomodation paralysis or spasm, convergenceparalysis or spasm, convergence-retractionnystagmus, skew deviation (see below) andparesis of downgaze are also characteristic.Clinically, it is usually incomplete, but itsrecognition has considerable localising value.It is most commonly due to masses in thepineal region or vascular disease.37 There are afew reported cases in multiple sclerosis, how-ever, and this diagnosis should be consideredin young patients without an alternative

36cause.

Skew deviationSkew deviation refers to a supranuclear verticaldissociation of the eyes, and the first clue to its

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presence may be a head tilt. In midbrainlesions, the hyperdeviated eye is usually ipsi-lateral, whereas with more caudal lesions it iscontralateral, although exceptions do occur.The degree of dissociation may vary with eyeposition. When the higher eye reverses withgaze to either side, it is called gaze-alternatingskew (hyper-) deviation. This abnormality ismost commonly associated with lesions in thepretectal region and craniocervical junc-tion,404' but has no precise localising value.While acute lesions of the posterior fossa (forexample, hydrocephalus and strokes) areusually responsible,40 it is not uncommon inmultiple sclerosis, particularly in associationwith INO. Clinically, alternating skew may beconfused with some childhood squints, andwith bilateral lesions of the IVth or, lesscommonly, IIlrd nerves.

Lesions of the cerebellum and its connectionsLesions of the cerebellum or its connectionsare extremely common in multiple sclerosis,and produce characteristic eye movementabnormalities, often in association with othersymptoms and signs of cerebellar dysfunction.A cerebellar eye movement disorder is presentin about one-third of patients; saccadic under-shoot or overshoot dysmetria, pendular nystag-mus (see below) and fixation instability beingthe commonest. Saccadic dysmetria is mosteasily seen by asking the patient to centrequickly from a position of lateral deviation, andwhen it is the sole eye movement abnormalityit indicates a lesion in the cerebellar vermis.Truncal or limb ataxia or both frequentlycoexist."

Gaze-paretic, rebound (recentring after15-30 seconds of lateral gaze produces a fewbeats of nystagmus in the opposite direction)and less commonly centripetal (fast phasetowards the position of primary gaze on lateralgaze) nystagmus are typical of lesions in thevestibulo-cerebellum, and represent attemptsto compensate for defective cerebellar fixationmechanisms. Leech et al described the furtherabnormalities of failure to maintain lateral gazein darkness, and slow drifting of the eyes awayfrom the primary position in the absence offixation, attributing both to cerebellar diseaseon the basis of observations in cerebellec-tomised animals.43 These deficits may be morecommon than suspected in multiple sclerosis,but are difficult to detect clinically.

3) ABNORMALITIES OF SLOW PHASE EYE

MOVEMENTSDisordered smooth pursuit and a correspond-ingly abnormality of optokinetic nystagmus(OKN) are found in more than 50% ofpatients. It must be borne in mind, however,that smooth pursuit is likely to be abnormal inany tired, visually handicapped or uncooper-ative subject, or in one taking sedative drugs.These caveats limit the usefulness of testingsmooth pursuit clinically,44 but when theexamination is unequivocally abnormal, andthese complicating factors are absent, itremains a valuable diagnostic sign. The VOR,which maintains target fixation during head

movement, can be voluntarily suppressedwhen tracking a moving target. VOR suppres-sion is related to, but not entirely dependent onsmooth pursuit, and may be easily testedclinically by asking the patient to turn the headfrom side to side while watching an object suchas the thumb held fixed relative to the face. It isabnormal in up to 75% of patients, and usuallyparallels disturbances of smooth pursuit, buthas no precise localising value. In a fewpatients, however, VOR suppression may beabnormal in the absence of a defect in pursuit,and this finding suggests a cerebellar lesion.45

4) NYSTAGMUS

Limitation of eye movements in multiple scle-rosis is commonly associated with saccadicinstability, manifested clinically as involuntarymovements such as nystagmus or spontaneousjerks. Such movements may also be seen inisolation, and some have enough localisingvalue to be helpful in making the diagnosis.EOG examination is invaluable for character-ising these abnormalities when there is doubtat the bedside. Nystagmus of various types isvery common in multiple sclerosis; it may beapparent only on attempted gaze, or be presentin the primary position. In the latter case itmay only be detected during ophthalmoscopy,when the retinal vessels will appear to oscil-late.

Pendular nystagmusAcquired pendular nystagmus occurs fre-quently in multiple sclerosis46 47 and is charac-terised by sinusoidal involuntary oscillations ofone or both eyes: if both eyes are involved, themovements may be conjugate or dysconjugate.Oscillations may occur in any plane, and resultin linear, elliptical, circular or torsional move-ments of the globe. Pendular nystagmus issometimes associated with rhythmical move-ments of other parts of the body, such as thelimbs or palate, at a similar frequency. In thestudy of Gresty et al 12 out of 16 patients withacquired pendular nystagmus had multiplesclerosis.47 In each, there was an associateddefect of convergence, and half had bilateralINOs. Traditionally, the lesion responsible forpendular nystagmus has been thought toinvolve the dentato-rubro-olivary (Guillain-Mollaret) triangle. Gresty argued that thisascription is incorrect in demyelination, first,because stimulation of the cerebellum resultsin binocular eye movements whereas pendularnystagmus may be monocular, secondlybecause less than half of his patients hadunequivocal evidence of truncal or limb ataxia,and thirdly because the association with INOsplaces the lesion in the brainstem. In amultifocal disease like multiple sclerosis, thepossibility that neurological abnormalitiesassociated with pendular nystagmus, such ascerebellar ataxia, are due to separate lesionscannot be excluded until MRI studies areavailable. The prognosis for suppressing oscil-lopsia due to pendular nystagmus is poor.

Vertical nystagmusBoth upbeating and downbeating nystagmus

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can occur in multiple sclerosis, although theyare more commonly seen in other diseases.Primary position upbeating nystagmus is asso-ciated with abnormal vertical gaze, particularlyupwards, and attempted convergence and lat-eral gaze may enhance or attenuate the nys-tagmus. Fisher et al described 11 patients withprimary position upbeating nystagmus, ofwhom two had multiple sclerosis: in the fourpatients with a discrete lesion, two weresituated in the ponto-medullary, and two in theponto-mesencephalic junction.48

Overall, downbeating nystagmus is morecommon than upbeating nystagmus, and isusually associated with an Arnold-Chiari mal-formation or cerebellar degeneration.49 Down-beating nystagmus is usually accentuated byhorizontal deviation of the eyes on downgaze,and may be associated with impaired down-ward pursuit, directional preponderence ofOKN downwards and impairedVOR suppres-sion. In the Arnold-Chiari malformation, atorsional component to the nystagmus indi-cates the presence of an associated syrinx.50Downbeating nystagmus is very uncommon

in multiple sclerosis, although two patientswere described by Masucci and Kirtzke.5' Inone series of 62 patients, none were thought tohave multiple sclerosis, although the cause wasnot established in 27.49Following the advent ofMRI, however, the diagnostic precision inpatients with downbeating nystagmus hasimproved, and in a recent series of 24 casesfrom the National Hospital, a definite diag-nosis was made in 18.50 In this series twopatients with multiple sclerosis were identified,both of whom had unusually extensive cere-bellar abnormalities, especially subjacent tothe flocculus and paraflocculus. If such wide-spread damage to the cerebellum is required toproduce downbeating nystagmus, this findingprobably accounts for its rarity in multiplesclerosis.

Other types of nystagmusA number of other types of nystagmus areoccasionally encountered, such as horizontalperiodic alternating nystagmus. On forwardgaze this disorder is manifested as beats ofincreasing then decreasing amplitude to oneside, followed after a pause by a similar cycle tothe other side. The periodicity is constant andusually between one and six minutes, with aquiescent interval of 20 seconds betweenperiods: it may therefore be missed withoutprolonged observation.52 The periodicity maybe shorter, however, as in the atypical exampledescribed by Rudge and Leech in whom it wasonly 10 seconds.53 The anatomical site ofdamage in periodic alternating nystagmus hasnot been determined with certainty, althoughit is likely that a bilateral disturbance of theinhibitory connections between the cerebellumand vestibular nuclei is required.54 In keepingwith this localisation, Keane described apatient with multiple sclerosis and a combina-tion of periodic alternating and downbeatingnystagmus who, at necropsy, showed symmet-rical lesions involving the inferior vestibularnuclei and inferior cerebellar peduncles.58

Affected patients complaining of oscillopsiaoften respond to baclofen.56

Positional nystagmus, usually of the "cen-tral" type (immediate onset, non-fatiguablewith fast phase beating upwards), is notuncommon in patients complaining of ver-tigo,57 but a mass lesion in the region of theIVth ventricle should always be excluded,particularly if the patient complains of head-ache.

5) PAROXYSMAL DISORDERS OF EYEMOVEMENTS

Sometimes, more obtrusive and disturbinginvoluntary eye movements can interfere withvision, and some may represent paroxysmaldisorders of the type well recognised in multi-ple sclerosis. A number of case reports havedescribed paroxysmal diplopia, with or withoutassociated neurological deficits. For example,Todman reported on a 24 year old womanwhose first symptom of multiple sclerosis wasparoxysmal diplopia and hemiplegia.58 Eachattack lasted 20 seconds and recurred everythree minutes. Her symptoms resolved afterfive days of anticonvulsant therapy.

Ocular flutter, opsoclonus and square wavejerks are also occasionally seen in multiplesclerosis. Ocular flutter consists of brief burstsof uniplanar saccades which are not separatedby a saccadic interval, and may be exacerbatedby voluntary eye movement. Francis andHeron observed repetitive bursts of ocularflutter in a 23 year old girl with probablemultiple sclerosis, and her symptoms and signsresponded favourably to carbamazepine.59Gresty et al described a variant of ocular flutterin a patient in whom horizontal and verticalflutter movements were temporally linked toproduce sporadic bursts of rotatory nystag-mus.60 Unlike ocular flutter, opsoclonus ischaracterised by chaotic multiplanar conjugatesaccades. It is also occasionally caused bymultiple sclerosis, though is much more com-monly paraneoplastic or follows viral infec-tions. Finally, we have seen a few patients withsquare wave jerks, in which the involuntary eyemovements away from, and back to, theintended position of gaze are separated by asaccadic interval.

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