Journal of , Neurosurgery, and Psychiatry 1992;55:747-752 747 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.9.747 on 1 September 1992. Downloaded from REVIEW

The ocular manifestations of 1 Abnormalities of the afferent

W I McDonald, D Barnes

" [December 1822] . . . My eyes were so at which the patient is examined. Figures 2a attacked that when fixed upon minute objects and b show that occasionally a defect with a indistinctness ofvision was the consequence:- horizontal margin indistinguishable from that Until I attempted to read, or to cut my pen, I seen with ischaemic lesions may evolve over a was not aware of my Eyes being in the least week or two into a central scotoma. During the attacked. Soon after, I went to Ireland, and recovery phase, a typical central scotoma may without any thing having been done to my become patchy and later leave an enlarged Eyes, they completely recovered their strength with an arcuate scotoma (figs 3a, b); and distinctness of vision". fragments of this defect may persist indef- Augustus d'Este' initely.3 Rarely, clearing of central vision may first result in the temporary appearance of a Visual symptoms, sensory or motor, are ring scotoma (fig 4). amongst the commonest manifestations of Colour vision is almost invariably impaired demyelinating disease. More than one third of and there is a relative afferent pupillary defect. patients with multiple sclerosis (MS) present Fundal examination is normal in about 50% of with them and they occur at some stage in patients. In the remainder, variable swelling of almost all. This paper, and a companion paper the (papillitis) is present. After a on disorders ofeye movement are based on two month or so, pallor of the optic disc commonly decades of experience in the physician's clinic develops, with variable loss of the retinal at Moorfields Eye Hospital. We have not fibre layer. Haemorrhages occur in less than attempted to analyse the whole clinical mater- 5% of patients and are never profuse, and the ial, but present conclusions derived from itself close to the disc is unchanged; if numerous published studies based on it, eman- there is extensive peripapillary oedema with ating from Moorfields, the National Hospitals retinal folds and a macular star, the appear- Queen Square and MaidaVale and the Medical ances suggest the rare condition of neuro- Research Council's and Balance which may not have the same Unit. implications for the development of multiple sclerosis.4 In about a quarter of patients with there are varying combinations Acute optic neuritis of perivenous sheathing, leakage of fluorescein http://jnnp.bmj.com/ Optic neuritis is the commonest cause of at angiography, and cells in the media.5 The spontaneously reversible visual loss in young vascular changes are almost always confined to adults in populations of Northern European origin. It usually begins with discomfort around the eye which is increased by eye movement. Blurring of vision usually follows

within a few days though it may precede the on October 1, 2021 by guest. Protected copyright. , which is only rarely severe. Visual loss evolves over a week or so to reach a maximum which varies from the trivial to the profound (no of light). Colour vision is altered early, colours being broken up in a pointillist manner, as MacKarell,2 a profes- sional painter, has so poignantly illustrated. It soon fades so that the environment has a pale, Institute of Neurology, and the Moorfields grey, washed out appearance (fig 1). The Eye Hospital, London, general level of illumination appears low and UK depth perception is impaired. W I McDonald D Barnes Clinical findings Figure 1 The Grey Blanket "The next day, upon Correspondence to: waking I discovered that there was over the central zone of Professor McDonald, Examination at the height of the symptoms vision of ny right eye, what seemed like a grey asbestos Institute of Neurology, reveals a variable loss of acuity, though it is Queen Square, Lonon mat. Although there was I was disturbed WC1N 3BG, UK usually worse than 6/24. The classical field loss to note that the grey swab occluded all light. I switched on to the bedside light in the vain hope that intense lumination Received 23 August 1991 is a central scotoma, but .it is important would somehow disperse the fog. " (From Depictions of an and in revised form that a range of defects may be 31 December 1991. appreciate Odyssey, Peter MacKarell 1990, National Society for Accepted 8 January 1992 found, to some extent depending on the stage Education in Art and Design.) 748 McDonald, Barnes

Figure 2 Patient with A J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.9.747 on 1 September 1992. Downloaded from acute optic neuritis. Note how the early quadrantic field defect (a) evolved over two weeks into a central scotoma (b).

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the far periphery of the retina and are usually rarely be the presenting feature of multiple not readily visible without full dilation of the sclerosis. This variability in vision is associated

and the use of the indirect ophthalmo- with a reduction in amplitude of the visual on October 1, 2021 by guest. Protected copyright. scope. These changes may be seen in the evoked potential,7 and can be partly accounted asymptomatic or the symptomatic eye, indicat- for by the extreme sensitivity of conduction in ing that the retinal vascular involvement is partially demyelinated fibres to small changes probably not a direct consequence of the optic in temperature.8 neuritis itself, but an independent expression A of disorientation in moving traffic is of the multifocal perivenular inflammation experienced by some patients and is probably which is characteristic of multiple sclerosis. due to the Pulfrich effect, a phenomenon The is rarely symptomatic (see attributable to unequal latencies between the below). two eyes which can be experienced in normal individuals by placing a neutral density filter Transient phenomena over one eye: a pendulum swinging in one Three classes of short-lived symptoms are plane then appears to be describing an encountered. Phosphenes (flashes of light), elipse.9 10 often precipitated by eye movement are experi- enced by approximately one third of Course and prognosis patients." Deterioration of vision induced by The patient with optic neuritis is anxious to exercise, a hot meal or a hot bath (Uhthoffs have answers to two questions: "Will I get phenomenon) is usually not encountered in better?" and "Will it recur?" The physician the acute stage of optic neuritis, though it can (and sometimes the patient too) is also inter- Abnormalities of the afferent visual system 749

Figure 3 Following acute A J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.9.747 on 1 September 1992. Downloaded from optic neuritis in this patient, the large central scotoma (a) has resolved over six months to leave a discontinuous arcuate defect with an enlarged blind spot (b).

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Figure 4 During recovery from acute optic neuritis, an earlier central scotoma on October 1, 2021 by guest. Protected copyright. (not shown) has evolved into a ring scotoma.

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ested in the question: "Will the patient develop oligoclonal bands in the CSF increased the risk J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.9.747 on 1 September 1992. Downloaded from multiple sclerosis?" of subsequent development of multiple sclero- Between 85-95% of patients with acute sis.25 HLA typing is of no practical value: optic neuritis make an excellent recovery to an although associations with A3, B7, DR2 and acuity of 6/9 or better over a period of 1-3 DR3 have been described, the results are not months, though occasionally the recovery consistent.'5 26 27 period is longer. Even if the final acuity is normal, patients may be aware of a range of residual symptoms, which are not, however, Pathophysiology usually troublesome except when the patient's Recent work making use of gadolinium (Gd)- occupation or recreation requires optimum TPA enhanced MRI and evoked potentials has visual performance. Impairment of contrast shed light on the mechanism of symptom sensitivity and colour vision are common" and production in acute optic neuritis. There is impairment of depth perception may interfere good evidence that the occurrence of Gd- with playing ball games. DTPA enhancement in immune-mediated It is not possible to predict the likelihood of demyelinating disease indicates the presence of a residual deficit with any confidence on inflammation.28-30 The earliest detectable clinical grounds. Gould et al, for example, event in the development of a new lesion in found that the worst was unre- multiple sclerosis is an increase in permeability lated to the likelihood of a persisting deficit.'2 of the blood-brain barrier in association with Recently, MRI of the has provided inflammation.29 Over the next few weeks evidence that physically long lesions (more oedema develops and is often extensive.3 32 than 1 cm), particularly when they involve the Inflammation ceases after approximately one portion of the nerve in the optic canal, are month and over the next few weeks the oedema significantly associated with persistent visual resolves to leave a small residual area of impairment.'3 Recurrence of optic neuritis, in abnormal MRI signal. either eye occurs in 20-36% of patients.14-16 Youl et al studied visual function in relation to MRI with and without Gd-DTPA enhance- Risk of developing multiple sclerosis ment and visual evoked potentials in patients There is a considerable range of frequency of recruited within two weeks of the onset of developing MS world wide.'7 18 Not surpris- symptoms of optic neuritis.33 They found that ingly, the frequency is low in populations in Gd-DTPA enhancement (signifying inflamma- which multiple sclerosis is rare. For example, tion) was present in all optic examined in Japan a frequency of 8%,'9 and in a white at this early stage. After a month, enhancement population in Chile,20 a frequency of 4-3% (1 had ceased in the majority. The presence ofthe of 23 patients) has been reported. In popula- main clinical features (visual loss, field defects, tions of Northern European origin living at an afferent pupillary defect and pain) corre- high latitudes, however, multiple sclerosis is lated significantly with the presence of inflam- more frequent. In the United Kingdom prob- mation. Of particular interest were the visual ably about 75% of patients ultimately develop evoked potential (VEP) findings: there was a multiple sclerosis, the majority doing so within strong relationship between optic nerve the first five years after presentation.'52' A enhancement and reduction inVEP amplitude number of risk factors for the development of (signifying conduction block). When enhance- multiple sclerosis has been identified, but none ment subsided, however, the VEP showed http://jnnp.bmj.com/ is a wholly reliable guide. Rizzo and Lessell consideable recovery, though with persistent found that in Massachusetts the 15 year delay presumably signifying demyelination. calculated risk for developing multiple sclerosis The dependence of visual acuity on intact was 74% in females, but only 34% in males.'6 optic nerve conduction as assessed by VEP The presence of perivenous sheathing carries a amplitude, but not latency, is well estab- relative risk of 14 for developing multiple lished .34 These experiments lead to the con-

sclerosis after a mean follow up of 3-5 years.5 clusion that the inflammatory process per se on October 1, 2021 by guest. Protected copyright. Multiple silent cerebral lesions on MRI at impairs conduction and that its resolution presentation carries a high risk for the early makes an important contribution to visual development of multiple sclerosis: Miller et al recovery. The possible mechanisms involved found a nearly seven fold increase in risk of are reviewed by Youl et al.33 developing multiple sclerosis within a year.22 Demyelination probably does, however, con- Five year follow up has revealed that 3/4 of tribute to some symptoms. The Pulfrich effect patients with silent lesions at presentation have can be accounted for by slowing of conduction developed the disease compared with less than in one optic nerve, and the phosphenes on eye 10% with normal brain MRI (S Morrissey; movement by abnormal excitability ofdemyeli- unpublished data). It must be emphasised, nated .35The high risk ofpersistent visual however, that multiple cerebral lesions on MRI impairment with lesions in the optic canal may (most of which eventually disappear) may be be due to the occurrence of inflammation with seen with monophasic acute disseminated accompanying oedema in a region where there encephalomyelitis, following which the risk of is little room for expansion of the nerve. The developing multiple sclerosis is very low.2324 ophthalmic artery also runs through the canal, The diagnosis of multiple sclerosis cannot and it is possible that the lasting deficit results therefore be made on the basis of a single from the addition of an ischaemic element to unenhanced MRI, and follow up is mandatory. the direct effects of inflammation and demye- Moulin et al found that the presence of lination. Abnormalties of the afferent visual system 751

Treatment tosis or raised protein content or both. MRI J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.9.747 on 1 September 1992. Downloaded from Given that approximately 90% of patients shows that occasional cases presenting with make an excellent spontaneous recovery it will optic neuritis have bilateral cerebral lesions be difficult to demonstrate a therapeutic effect showing a marked tendency to resolution, the end-point of which is a reduction in the typical of acute disseminated encephalomyeli- number of patients with persisting visual loss. tis.24 Exceptionally, such cases may be seen in This is indeed the case, and no completed adult life.46 The prognosis for vision is excel- study is large enough to demonstrate such an lent: in a follow up of up to 32 years effect. One might, however, expect steroids to persistently impaired acuity was found in only be helpful in view of their anti-inflammatory one eye in 19 patients.40 properties and their capacity to reverse the The risk ofmultiple sclerosis after childhood blood-brain barrier defect (albeit temporarily) optic neuritis is much lower than in adults,45 in multiple sclerosis.36 Several studies have not exceeding 15% in the United Kingdom shown that treatment with ACTH3738 and where, as noted above, the risk for adults with retrobulbar triamcinolone"2 shortens the dura- unilateral optic neuritis is approximately tion of . In view of the 75%. influence that length of the lesion and involve- ment of the nerve in the bony optic canal have on prognosis, a controlled trial of high dose Progressive optic neuritis intravenous methylprednisolone in this sub Though it occurs, progressive optic neuritis, group has been initiated. A large multicentre unilateral or bilateral is rare and the diagnosis trial of oral prednisone on unselected cases of should only be made after careful exclusion of optic neuritis is being carried out in the United a compressive cause and long term follow up. States. Such patients should be kept under review indefinitely. Rarely, multiple sclerosis may present as progressive bilateral visual loss.47 Acute bilateral optic neuritis We have so far dealt only with acute unilateral optic neuritis. In adults, acute bilateral simul- Involvement of the posterior visual path- taneous optic neuritis is much less common ways than unilateral or sequential optic neuritis, and At necropsy the , tracts and published studies are based on small numbers. radiations commonly contain lesions. In the Hierons and Lyle reported 11 cases who were two thirds of patients with acute optic neuritis reviewed after up to 30 years by Parlin et having multiple silent cerebral MRI lesions at al. 39 40 The visual prognosis was poorer than presentation, the optic radiations are almost for unilateral optic neuritis. Only two patients always involved.48 Occasionally, however, fulfilled the criteria for a diagnosis of multiple symptomatic acute homonymous hemianopias sclerosis, suggesting that this disease may be are encountered, and a recent MRI study less common after simultaneously bilateral provides evidence that in such cases the lesions optic neuritis than after unilateral optic neu- are unusually large.49 We have not seen a ritis. Nevertheless, we see a few cases each year clinically manifest bitemporal hemianopia as in whom multiple sclerosis follows acute bilat- described by Traquair,50 though we have seen eral simultaneous optic neuritis. The numbers patients with acute unilateral optic neuritis in this study were small and the possibility that who have evidence of involvement of the http://jnnp.bmj.com/ some of the patients were isolated cases of ipsilateral chiasm from Gd-DTPA enhance- Leber's could not, at that ment or an abnormal evoked potential from time, be excluded. The diagnostic assessment the contralateral temporal field. The reasons of such patients should now include both MRI for the infrequency of symptomatic posterior (additional silent cerebral lesions are absent in defects-which include the relationship typical Leber's hereditary optic neuropathy in between the anatomical disposition of the

males),4' and examination of mitochondrial fibres and the perivenular orientation of the on October 1, 2021 by guest. Protected copyright. DNA.42 43 lesions, as well as the usual size ofplaques-are discussed elsewhere.49 Childhood optic neuritis In children optic neuritis, when it is recog- nised, is usually bilateral. Small children with As previously mentioned, subclinical ocular unilateral visual loss may not show behavioural inflammatory changes are found in about one change sufficient to attract the attention of quarter of patients with acute optic neuritis.5 their parents. There is a number of clinical Sheathing occurs in a slightly smaller propor- differences from adult optic neuritis.'7394445 tion of patients with established MS.5" These The illness follows an infection such as retinal changes are only occasionally sympto- measles, chicken pox and infectious mononuc- matic52 though we have seen one patient with leosis in nearly half of cases and, not surpris- clinically definite disease in whom recurrent ingly, there is a seasonal variation with the was so severe as to neces- greatest number presenting in April. Evidence sitate vitrectomy Confusion with sarcoidosis of more generalised CNS involvement is not occasionally arises; spontaneous and more or infrequently present in the form of drowsiness less lasting remission of visual loss (the rule in or fleeting neurological signs. The CSF is optic neuritis) is much against the diagnosis of usually normal but may show a modest pleocy- granulomatous optic neuropathy.53 752 McDonald, Barnes

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1125-30. Neurol Neurosurg Psychiatry 1989;52:1360-3. on October 1, 2021 by guest. Protected copyright. 27 Compston DAS, Batchelor JR, Earl CJ, McDonald WI. 52 Bamford CR, Granley JP, SibleyWA, Laguna JM. Uveiitis, Factors influencing the risk of multiple sclerosis develop- perivascular sheathing and multiple sclerosis. Neurology ing in patients with optic neuritis. Brain 1978;101: (NY) 1978;28 (suppl II): 119-24. 495-511. 53 Graham EM, Ellis CJK, Sanders MD, McDonaldWI. Optic 28 Hawkins CP, Munro PMG, MacKenzie F, et al. Duration neuropathy in sarcoidosis. J Neurol Neurosurg Psychiatry and selectivity of blood-brain barrier breakdown in 1986;49:756-63.