Journal of Neurology, Neurosurgery, and Psychiatry 1992;55:747-752

REVIEW

The ocular manifestations of multiple sclerosis

1 Abnormalities of the afferent visual system

W I McDonald, D Barnes

" [December 1822] . . . My eyes were soattacked that when fixed upon minute objectsindistinctness ofvision was the consequence:-Until I attempted to read, or to cut my pen, Iwas not aware of my Eyes being in the leastattacked. Soon after, I went to Ireland, andwithout any thing having been done to myEyes, they completely recovered their strengthand distinctness of vision".

Augustus d'Este'

Visual symptoms, sensory or motor, areamongst the commonest manifestations ofdemyelinating disease. More than one third ofpatients with multiple sclerosis (MS) presentwith them and they occur at some stage inalmost all. This paper, and a companion paperon disorders of eye movement are based on twodecades of experience in the physician's clinicat Moorfields Eye Hospital. We have notattempted to analyse the whole clinical mater-ial, but present conclusions derived fromnumerous published studies based on it, eman-ating from Moorfields, the National HospitalsQueen Square and MaidaVale and the MedicalResearch Council's Hearing and BalanceUnit.

Institute of Neurology,and the MoorfieldsEye Hospital, London,UKW I McDonaldD BarnesCorrespondence to:Professor McDonald,Institute of Neurology,Queen Square, LononWC1N 3BG, UKReceived 23 August 1991and in revised form31 December 1991.Accepted 8 January 1992

Acute optic neuritisOptic neuritis is the commonest cause ofspontaneously reversible visual loss in youngadults in populations of Northern Europeanorigin. It usually begins with discomfortaround the eye which is increased by eyemovement. Blurring of vision usually followswithin a few days though it may precede thepain, which is only rarely severe. Visual lossevolves over a week or so to reach a maximumwhich varies from the trivial to the profound(no perception of light). Colour vision isaltered early, colours being broken up in apointillist manner, as MacKarell,2 a profes-sional painter, has so poignantly illustrated. Itsoon fades so that the environment has a pale,grey, washed out appearance (fig 1). Thegeneral level of illumination appears low anddepth perception is impaired.

Clinical findingsExamination at the height of the symptomsreveals a variable loss of acuity, though it isusually worse than 6/24. The classical field lossis a central scotoma, but .it is important toappreciate that a range of defects may befound, to some extent depending on the stage

at which the patient is examined. Figures 2aand b show that occasionally a defect with ahorizontal margin indistinguishable from thatseen with ischaemic lesions may evolve over aweek or two into a central scotoma. During therecovery phase, a typical central scotoma maybecome patchy and later leave an enlargedblind spot with an arcuate scotoma (figs 3a, b);fragments of this defect may persist indef-initely.3 Rarely, clearing of central vision mayfirst result in the temporary appearance of aring scotoma (fig 4).

Colour vision is almost invariably impairedand there is a relative afferent pupillary defect.Fundal examination is normal in about 50% ofpatients. In the remainder, variable swelling ofthe optic disc (papillitis) is present. After amonth or so, pallor of the optic disc commonlydevelops, with variable loss of the retinal nervefibre layer. Haemorrhages occur in less than5% of patients and are never profuse, and theretina itself close to the disc is unchanged; ifthere is extensive peripapillary oedema withretinal folds and a macular star, the appear-ances suggest the rare condition of neuro-retinitis which may not have the sameimplications for the development of multiplesclerosis.4 In about a quarter of patients withoptic neuritis there are varying combinationsof perivenous sheathing, leakage of fluoresceinat angiography, and cells in the media.5 Thevascular changes are almost always confined to

Figure 1 The Grey Blanket "The next day, uponwaking I discovered that there was over the central zone ofvision of ny right eye, what seemed like a grey asbestosmat. Although there was peripheral vision I was disturbedto note that the grey swab occluded all light. I switched onthe bedside light in the vain hope that intense luminationwould somehow disperse the fog. " (From Depictions of anOdyssey, Peter MacKarell 1990, National Society forEducation in Art and Design.)

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Figure 2 Patient withacute optic neuritis. Notehow the early quadranticfield defect (a) evolvedover two weeks into acentral scotoma (b).

A

Correctio_ nphO = clOD. Refractio: - - -. -.nh- -cl

- - -

B

OD. RCractb: nph0 dy

the far periphery of the retina and are usuallynot readily visible without full dilation of thepupil and the use of the indirect ophthalmo-scope. These changes may be seen in theasymptomatic or the symptomatic eye, indicat-ing that the retinal vascular involvement isprobably not a direct consequence of the opticneuritis itself, but an independent expressionof the multifocal perivenular inflammationwhich is characteristic of multiple sclerosis.The uveitis is rarely symptomatic (seebelow).

Transient phenomenaThree classes of short-lived symptoms areencountered. Phosphenes (flashes of light),often precipitated by eye movement are experi-enced by approximately one third ofpatients." Deterioration of vision induced byexercise, a hot meal or a hot bath (Uhthoffsphenomenon) is usually not encountered inthe acute stage of optic neuritis, though it can

rarely be the presenting feature of multiplesclerosis. This variability in vision is associatedwith a reduction in amplitude of the visualevoked potential,7 and can be partly accountedfor by the extreme sensitivity of conduction inpartially demyelinated fibres to small changesin temperature.8A sense of disorientation in moving traffic is

experienced by some patients and is probablydue to the Pulfrich effect, a phenomenonattributable to unequal latencies between thetwo eyes which can be experienced in normalindividuals by placing a neutral density filterover one eye: a pendulum swinging in oneplane then appears to be describing anelipse.9 10

Course and prognosisThe patient with optic neuritis is anxious tohave answers to two questions: "Will I getbetter?" and "Will it recur?" The physician(and sometimes the patient too) is also inter-

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Abnormalities of the afferent visual system

Figure 3 Following acuteoptic neuritis in thispatient, the large centralscotoma (a) has resolvedover six months to leave adiscontinuous arcuatedefect with an enlargedblind spot (b).

A

B

wphO dey

Figure 4 During recoveryfrom acute optic neuritis,an earlier central scotoma(not shown) has evolvedinto a ring scotoma.

co- -- -nw-O -__ _

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ested in the question: "Will the patient developmultiple sclerosis?"Between 85-95% of patients with acute

optic neuritis make an excellent recovery to anacuity of 6/9 or better over a period of 1-3months, though occasionally the recoveryperiod is longer. Even if the final acuity isnormal, patients may be aware of a range ofresidual symptoms, which are not, however,usually troublesome except when the patient'soccupation or recreation requires optimumvisual performance. Impairment of contrastsensitivity and colour vision are common" andimpairment of depth perception may interferewith playing ball games.

It is not possible to predict the likelihood ofa residual deficit with any confidence onclinical grounds. Gould et al, for example,found that the worst visual acuity was unre-lated to the likelihood of a persisting deficit.'2Recently, MRI of the optic nerve has providedevidence that physically long lesions (morethan 1 cm), particularly when they involve theportion of the nerve in the optic canal, aresignificantly associated with persistent visualimpairment.'3 Recurrence of optic neuritis, ineither eye occurs in 20-36% of patients.14-16

Risk of developing multiple sclerosisThere is a considerable range of frequency ofdeveloping MS world wide.'7 18 Not surpris-ingly, the frequency is low in populations inwhich multiple sclerosis is rare. For example,in Japan a frequency of 8%,'9 and in a whitepopulation in Chile,20 a frequency of 4-3% (1of 23 patients) has been reported. In popula-tions of Northern European origin living athigh latitudes, however, multiple sclerosis ismore frequent. In the United Kingdom prob-ably about 75% of patients ultimately developmultiple sclerosis, the majority doing so withinthe first five years after presentation.'52' Anumber of risk factors for the development ofmultiple sclerosis has been identified, but noneis a wholly reliable guide. Rizzo and Lessellfound that in Massachusetts the 15 yearcalculated risk for developing multiple sclerosiswas 74% in females, but only 34% in males.'6The presence of perivenous sheathing carries arelative risk of 14 for developing multiplesclerosis after a mean follow up of 3-5 years.5

Multiple silent cerebral lesions on MRI atpresentation carries a high risk for the earlydevelopment of multiple sclerosis: Miller et alfound a nearly seven fold increase in risk ofdeveloping multiple sclerosis within a year.22Five year follow up has revealed that 3/4 ofpatients with silent lesions at presentation havedeveloped the disease compared with less than10% with normal brain MRI (S Morrissey;unpublished data). It must be emphasised,however, that multiple cerebral lesions on MRI(most of which eventually disappear) may beseen with monophasic acute disseminatedencephalomyelitis, following which the risk ofdeveloping multiple sclerosis is very low.23 24The diagnosis of multiple sclerosis cannottherefore be made on the basis of a singleunenhanced MRI, and follow up is mandatory.Moulin et al found that the presence of

oligoclonal bands in the CSF increased the riskof subsequent development of multiple sclero-sis.25 HLA typing is of no practical value:although associations with A3, B7, DR2 andDR3 have been described, the results are notconsistent.'5 26 27

PathophysiologyRecent work making use of gadolinium (Gd)-TPA enhanced MRI and evoked potentials hasshed light on the mechanism of symptomproduction in acute optic neuritis. There isgood evidence that the occurrence of Gd-DTPA enhancement in immune-mediateddemyelinating disease indicates the presence ofinflammation.28-30 The earliest detectableevent in the development of a new lesion inmultiple sclerosis is an increase in permeabilityof the blood-brain barrier in association withinflammation.29 Over the next few weeksoedema develops and is often extensive.3 32Inflammation ceases after approximately onemonth and over the next few weeks the oedemaresolves to leave a small residual area ofabnormal MRI signal.Youl et al studied visual function in relation

to MRI with and without Gd-DTPA enhance-ment and visual evoked potentials in patientsrecruited within two weeks of the onset ofsymptoms of optic neuritis.33 They found thatGd-DTPA enhancement (signifying inflamma-tion) was present in all optic nerves examinedat this early stage. After a month, enhancementhad ceased in the majority. The presence of themain clinical features (visual loss, field defects,an afferent pupillary defect and pain) corre-lated significantly with the presence of inflam-mation. Of particular interest were the visualevoked potential (VEP) findings: there was astrong relationship between optic nerveenhancement and reduction inVEP amplitude(signifying conduction block). When enhance-ment subsided, however, the VEP showedconsideable recovery, though with persistentdelay presumably signifying demyelination.The dependence of visual acuity on intactoptic nerve conduction as assessed by VEPamplitude, but not latency, is well estab-lished .34 These experiments lead to the con-clusion that the inflammatory process per seimpairs conduction and that its resolutionmakes an important contribution to visualrecovery. The possible mechanisms involvedare reviewed by Youl et al. 33

Demyelination probably does, however, con-tribute to some symptoms. The Pulfrich effectcan be accounted for by slowing of conductionin one optic nerve, and the phosphenes on eyemovement by abnormal excitability ofdemyeli-nated axons.35The high risk ofpersistent visualimpairment with lesions in the optic canal maybe due to the occurrence of inflammation withaccompanying oedema in a region where thereis little room for expansion of the nerve. Theophthalmic artery also runs through the canal,and it is possible that the lasting deficit resultsfrom the addition of an ischaemic element tothe direct effects of inflammation and demye-lination.

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Abnormalties of the afferent visual system

TreatmentGiven that approximately 90% of patientsmake an excellent spontaneous recovery it willbe difficult to demonstrate a therapeutic effectthe end-point of which is a reduction in thenumber of patients with persisting visual loss.This is indeed the case, and no completedstudy is large enough to demonstrate such an

effect. One might, however, expect steroids tobe helpful in view of their anti-inflammatoryproperties and their capacity to reverse theblood-brain barrier defect (albeit temporarily)in multiple sclerosis.36 Several studies haveshown that treatment with ACTH3738 andretrobulbar triamcinolone"2 shortens the dura-tion of visual impairment. In view of theinfluence that length of the lesion and involve-ment of the nerve in the bony optic canal haveon prognosis, a controlled trial of high doseintravenous methylprednisolone in this subgroup has been initiated. A large multicentretrial of oral prednisone on unselected cases ofoptic neuritis is being carried out in the UnitedStates.

Acute bilateral optic neuritisWe have so far dealt only with acute unilateraloptic neuritis. In adults, acute bilateral simul-taneous optic neuritis is much less common

than unilateral or sequential optic neuritis, andpublished studies are based on small numbers.Hierons and Lyle reported 11 cases who were

reviewed after up to 30 years by Parlin et

al. 39 40 The visual prognosis was poorer thanfor unilateral optic neuritis. Only two patientsfulfilled the criteria for a diagnosis of multiplesclerosis, suggesting that this disease may beless common after simultaneously bilateraloptic neuritis than after unilateral optic neu-

ritis. Nevertheless, we see a few cases each year

in whom multiple sclerosis follows acute bilat-eral simultaneous optic neuritis. The numbersin this study were small and the possibility thatsome of the patients were isolated cases ofLeber's optic neuropathy could not, at thattime, be excluded. The diagnostic assessmentof such patients should now include both MRI(additional silent cerebral lesions are absent intypical Leber's hereditary optic neuropathy inmales),4' and examination of mitochondrialDNA.42 43

Childhood optic neuritisIn children optic neuritis, when it is recog-nised, is usually bilateral. Small children withunilateral visual loss may not show behaviouralchange sufficient to attract the attention oftheir parents. There is a number of clinicaldifferences from adult optic neuritis.'7394445The illness follows an infection such as

measles, chicken pox and infectious mononuc-leosis in nearly half of cases and, not surpris-ingly, there is a seasonal variation with thegreatest number presenting in April. Evidenceof more generalised CNS involvement is notinfrequently present in the form of drowsinessor fleeting neurological signs. The CSF isusually normal but may show a modest pleocy-

tosis or raised protein content or both. MRIshows that occasional cases presenting withoptic neuritis have bilateral cerebral lesionsshowing a marked tendency to resolution,typical of acute disseminated encephalomyeli-tis.24 Exceptionally, such cases may be seen inadult life.46 The prognosis for vision is excel-lent: in a follow up of up to 32 yearspersistently impaired acuity was found in onlyone eye in 19 patients.40The risk of multiple sclerosis after childhood

optic neuritis is much lower than in adults,45not exceeding 15% in the United Kingdomwhere, as noted above, the risk for adults withunilateral optic neuritis is approximately75%.

Progressive optic neuritisThough it occurs, progressive optic neuritis,unilateral or bilateral is rare and the diagnosisshould only be made after careful exclusion ofa compressive cause and long term follow up.Such patients should be kept under reviewindefinitely. Rarely, multiple sclerosis maypresent as progressive bilateral visual loss.47

Involvement of the posterior visual path-waysAt necropsy the optic chiasm, tracts andradiations commonly contain lesions. In thetwo thirds of patients with acute optic neuritishaving multiple silent cerebral MRI lesions atpresentation, the optic radiations are almostalways involved.48 Occasionally, however,symptomatic acute homonymous hemianopiasare encountered, and a recent MRI studyprovides evidence that in such cases the lesionsare unusually large.49 We have not seen aclinically manifest bitemporal hemianopia asdescribed by Traquair,50 though we have seenpatients with acute unilateral optic neuritiswho have evidence of involvement of theipsilateral chiasm from Gd-DTPA enhance-ment or an abnormal evoked potential fromthe contralateral temporal field. The reasonsfor the infrequency of symptomatic posteriordefects-which include the relationshipbetween the anatomical disposition of thefibres and the perivenular orientation of thelesions, as well as the usual size ofplaques-arediscussed elsewhere.49

Retinal vasculitisAs previously mentioned, subclinical ocularinflammatory changes are found in about onequarter of patients with acute optic neuritis.5Sheathing occurs in a slightly smaller propor-tion of patients with established MS.5" Theseretinal changes are only occasionally sympto-matic52 though we have seen one patient withclinically definite disease in whom recurrentretinal haemorrhage was so severe as to neces-sitate vitrectomy Confusion with sarcoidosisoccasionally arises; spontaneous and more orless lasting remission of visual loss (the rule inoptic neuritis) is much against the diagnosis ofgranulomatous optic neuropathy.53

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