Multiple Sclerosis and Related Disorders (2014) 3, 3–16

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journal homepage: www.elsevier.com/locate/msard

REVIEW

Vision and multiple sclerosis Simon J. Hickmana,n, Naz Raoofb, Rebecca J. McLeanc, Irene Gottlobc a

Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK Department of Ophthalmology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK c Department of Ophthalmology, University of Leicester, Leicester LE2 7LX, UK b

Received 20 February 2013; accepted 29 April 2013

KEYWORDS

Abstract

Multiple sclerosis; Vision; Optic neuritis; Diplopia; Nystagmus; Oscillopsia

Multiple sclerosis can affect vision in many ways, including optic neuritis, chronic optic neuropathy, retrochiasmal visual field defects, higher order cortical processing, double vision, nystagmus and also by related ocular conditions such as uveitis. There are also side effects from recently introduced multiple sclerosis treatments that can affect vision. This review will discuss all these aspects and how they come together to cause visual symptoms. It will then focus on practical aspects of how to recognise when there is a vision problem in a multiple sclerosis patient and on what treatments are available to improve vision. & 2013 Elsevier B.V. All rights reserved.

Contents 1. 2.

3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Causes of visual problems in multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1. Optic neuritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2. Chronic optic neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.3. Post-chiasmal visual field defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.4. Visuo-perceptual abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.5. Eye movement abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.6. Ocular problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Clinic measures of visual function in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Morbidity due to vision problems in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.1. Visual symptoms in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Abbreviations: EDSS, expanded disability status scale; EQ-5D, EuroQuol questionnaire; ETDRS, early treatment diabetic retinopathy study; MRI, magnetic resonance imaging; MS, multiple sclerosis; MSVQ-7, MS-specific vision questionnaire; NARCOMS, North American Research Committee on Multiple Sclerosis; NEI-VFQ 25, 25-Item National Eye Institute visual function questionnaire; NICE, National Institute of Health and Clinical Excellence; ONTT, Optic Neuritis Treatment Trial; OCT, optical coherence tomography; PML, progressive multifocal leucoencephalopathy; RNFL, retinal nerve fibre layer; UFOV, useful field of vision; UK, United Kingdom; VEP, visual evoked potentials n Corresponing author. Tel.: +44 114 2712619; fax: +44 114 2268946. E-mail addresses: [email protected] (S.J. Hickman), [email protected] (N. Raoof), [email protected] (R.J. McLean), [email protected] (I. Gottlob). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.04.004

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S.J. Hickman et al. 4.2. Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.3. Vision and limb function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.4. Driving. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.5. “Blindness” due to MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5. Management of vision problems due to MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.1. Patient assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.2. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 5.3. Low vision services and sight impairment registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1.

Introduction

Multiple sclerosis (MS) is a common disease in countries of higher latitudes. Much is known about the nature of ongoing physical disability due to chronic MS, although the impact of the disease on patients' vision has been less studied. Vision is, however, rated by MS patients as their second most important bodily function after walking (Heesen et al., 2008). Also, patients with visual impairment for whatever reason have reduced health-related quality of life scores on every dimension of the EuroQol questionnaire (EQ-5D) than the general population and patients with other chronic conditions such as type II diabetes, coronary artery disease and hearing impairment (Langelaan et al., 2007). Visual symptoms are very common in MS. In a population-based study of morbidity of MS, in the month before assessment 33% of MS patients reported blurred vision and 26% reported diplopia (Swingler and Compston, 1992). In a survey of patients on the North American Research Committee on Multiple Sclerosis (NARCOMS) register, 66.5% reported some visual disability with 14% reporting moderate, severe or total visual disability (Salter et al., in press).

2. Causes of visual problems in multiple sclerosis Vision in MS may be affected by a number of reasons, which are discussed below. These may occur in isolation, usually as a relapses, however, patients with chronic MS will often have a combination of problems, which can have an additive effect to impair vision.

2.1.

Optic neuritis

Optic neuritis causes acute, usually unilateral, visual impairment. It is a very common early manifestation of MS. In one series, isolated optic neuritis was the first presenting attack of MS in 21% of cases (Confavreux and Vukusic, 2006) and in another series, 46% of MS patients had an attack of optic neuritis at some point during their disease course (Burman et al., 2011). The presentation and differential diagnosis of optic neuritis has been reviewed elsewhere (Hickman et al., 2002, 2008). The long-term prognosis for vision following optic neuritis is generally good. The Optic Neuritis Treatment Trial (ONTT) followed up 294 of the original cohort of 454 patients for at

least 15 years following their initial presentation with a first episode of acute optic neuritis. 72% of the originally affected eyes had a visual acuity of ≥20/20 and 66% of patients had ≥20/20 acuity in both eyes. Six patients (2%) had a visual acuity ≤20/40 in both eyes but only 3 (1%) had a visual acuity ≤20/200 in both eyes (Optic Neuritis Study Group, 2008). Poor visual outcome was usually related to having recurrent attacks of optic neuritis (The Optic Neuritis Study Group, 2004). Also, patients who went on to develop MS during the course of the study had poorer visual function on testing than those who had remained with isolated optic neuritis, but the differences were small. Optic chiasmitis can occur in MS. The clinical features are similar to typical optic neuritis. In the days before magnetic resonance imaging (MRI) it was often mistaken for bilateral optic neuritis because the visual impairment affects both eyes. Typical bitemporal field defects may only be present early on in the presentation or during the convalescent phase (Hickman et al., 2008).

2.2.

Chronic optic neuropathy

It has been known for a long time that the optic nerves are affected by MS, even in the absence of having episodes of optic neuritis: visual evoked potentials (VEP) show delay in the P100 response, suggestive of demyelination (Halliday et al., 1973); optic nerve atrophy has been demonstrated with MRI (Davies et al., 1998) and axonal loss in the retinal nerve fibre layer (RNFL) has been demonstrated on both ophthalmoscopy (Frisén and Hoyt, 1974) and with optical coherence tomography (OCT) (Henderson et al., 2008). However, progressive loss of vision to blindness due to chronic optic neuropathy, akin to progressive locomotor disability, is extremely unusual. The reasons for this are not known. There may be more in built redundancy within the optic nerves compared with the corticospinal tracts, to preserve usable vision despite significant axonal loss (Frisén and Quigley, 1984). Walking requires the integration of the motor, co-ordination and sensory systems therefore locomotor disability may result from the additive effect of damage in the different systems. Lastly, plasticity and cortical remodelling may occur more readily in the visual than in the locomotor system (Toosy et al., 2005). There is a subset of MS patients though who develop profound visual loss. These are the MS patients who also carry the Leber's mutation, the so-called Harding's disease, after Anita Harding who first described the association

Vision and multiple sclerosis (Harding et al., 1992). The majority of reported cases have the 11778 mutation, but cases have also been reported with the 14484 and 3460 mutations. Most cases occur in females (unlike Leber's hereditary optic neuropathy alone which is more common in males) and, although the non-optic nerve features of the disease are typical for MS with relapses and remissions, they develop severe irreversible bilateral visual loss due to bilateral optic neuropathy (Palace, 2009).

2.3.

Post-chiasmal visual field defects

MS can affect the optic tracts, lateral geniculate nucleus and the optic radiations (Ormerod et al., 1987; Plant et al., 1992), although in the last case these are often asymptomatic (Hornabrook et al., 1992) unless they are large (Plant et al., 1992). The homonymous visual field defects that occur usually recover completely (Fig. 1) (Plant et al., 1992). Bilateral visual field defects due to bilateral optic radiation lesions have also been reported in MS, including bilateral inferior altitudinal defects, homonymous hemianopia with a contralateral quadrantinopia and crossed quadrant defects (Hickman, 2011). In a patient who is being treated with natalizumab, the development of a retrochiasmal visual field defect should raise suspicion that the patient had developed progressive multifocal leucoencephalopathy (PML). A review of 28 cases of natalizumabassociated PML found that five (18%) of them had an homonymous hemianopia at presentation (Clifford et al., 2010).

2.4.

Visuo-perceptual abnormalities

Visuo-perceptual abnormalities can occur, which are probably due to a combination of damage to the afferent visual pathways as well as to the primary visual cortex and beyond. In an unselected series of 49 patients with MS (mean expanded disability status scale [EDSS] score 5.93, range 2.0–9.0), significant visuo-perceptual abnormalities across a range of tests were found in 26% (Vleugels et al., 2000). The number of failed visuo-perceptual tasks correlated with the EDSS score, albeit weakly (r= 0.26, p= 0.04). In a further study on 291 MS patients by Benedict et al. (2006), significant abnormalities, when compared with controls, were found on the Judgement of Line Orientation Test and the Brief Visuospatial Memory Test-Revised for both total learning and delayed recall. As would be expected, performance on visuo-perceptual tasks deteriorates in line with deterioration in general cognition. In a study of object recognition, MS patients with generalised cognitive decline had difficulties in visual shape recognition and semantic-lexical processing (Laatu et al., 2001). Rarely, visual hallucinations may be perceived in association with other psychotic symptoms and are associated with plaques in the white matter of the frontal, temporal and occipital lobes (Fontaine et al., 1994).

2.5.

Eye movement abnormalities

One of the major causes of visual problems in MS is due to damage to the brainstem eye movement centres (Barnes and McDonald, 1992; Frohman et al., 2005). There have

5 been a range of eye movement abnormalities described. These can occur as part of relapses or can persist in progressive forms of the disease. Double vision has been reported to occur in 19.1–38.6% of MS patients at some point in their disease course (Kurtzke, 1970; Salter et al., in press). Isolated third, fourth and sixth cranial nerve palsies are relatively uncommon, since MS affects just the intra-axial structures, although they can occur due to both fascicular and nuclear lesions. An isolated abducens palsy can only occur due to a fascicular lesion, because a nuclear lesion will cause an ipsilateral gaze palsy (Barnes and McDonald, 1992; Frohman et al., 2005). One of the commonest eye movement abnormalities seen in MS is an internuclear ophthalmoplegia (INO). In one series, 53% of patients with clinically definite MS had a detectable INO (Kurtzke, 1970). It is due to a lesion of the medial longitudinal fasciculus which carries interneurons from the abducens nucleus to the medial rectus subnucleus of the contralateral oculomotor nucleus. It is frequently bilateral. An INO is characterised by limitation or slowing of the adducting eye relative to the abducting eye during conjugate horizontal eye movements. INOs are usually asymptomatic but they can cause visual disorientation, transient oscillopsia, diplopia, reading fatigue and loss of stereopsis (Frohman et al., 2005). INOs may be associated with a contralateral gaze palsy (the one-and-a-half syndrome) if the lesion also affects the paramedian pontine reticular formation and/or the sixth nerve nucleus. In a series of 14 patients with one-and-a half syndrome, Wall and Wray (1983) found that 12 had visual symptoms, including diplopia, blurring of vision, oscillopsia and difficulty looking to one side. Double vision can also occur due to skew deviations, which are supranuclear vertical ocular misalignments. The misalignment may remain the same in all positions of gaze or the degree of dissociation may vary. They can occur in isolation or can be seen in combination with other eye movement problems, such as an INO, or with a head tilt (Barnes and McDonald, 1992; Frohman et al., 2005). Attacks of diplopia may also be paroxysmal, lasting for less than a minute, probably due to axonal hyperexcitability (Barnes and McDonald, 1992; Frohman et al., 2005; Smith and McDonald, 1999). Disturbances of conjugate gaze are commonly seen, including prolongation of the saccadic latency, decreased saccadic velocity (usually seen with an INO), inaccurate saccades and saccadic intrusions of smooth pursuit movements (“broken pursuits”) (Barnes and McDonald, 1992; Frohman et al., 2005; Reulen et al., 1983). Nystagmus has been reported in 15–48% of cases of MS (Kurtzke, 1970; Sarvananthan et al., 2009; Swingler and Compston, 1992). Gaze-evoked nystagmus is a jerk nystagmus with a slow drift in one direction and a resetting saccade in the other direction and, as the name suggests, occurs with gaze. It occurs due to lesions affecting the neural integrators and their connections in the brainstem. The resulting nystagmus can be horizontal, vertical (upbeat or downbeat) or rotational. The amplitude of nystagmus increases with gaze in the direction of the nystagmus fast phase and diminishes with gaze in the opposite direction, which is known as Alexander's law (Doslak et al., 1979). It is

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Fig. 1 (a) Screening visual field test from a 34 year-old man with a four year history of MS who had developed blurred vision in both eyes. The visual field test demonstrates a left upper incongruous quadrantinopia. (b) Subsequent magnetic resonance imaging showed MS lesions including the symptomatic lesion in the right optic radiation (arrowed). (c) Visual field test performed 5 months later showing complete recovery.

often asymptomatic unless there is nystagmus in primary position, although gaze-evoked oscillopsia can occur (Shery et al., 2006). Pendular nystagmus is an ongoing sinusoidal oscillation of the eyes, which may be conjugate, dysconjugate or even uniocular. As it affects primary gaze it can cause oscillopsia

and can severely reduce visual acuity, primarily by retinal slip preventing adequate foveation (Barnes and McDonald, 1992; Frohman et al., 2005). In a series of 37 MS patients with pendular nystagmus, Barton and Cox (1993) found that 37 out of 74 eyes had a visual acuity of 20/200 or worse. The authors postulated that pendular nystagmus

Vision and multiple sclerosis results from a combination of both brainstem disease and chronic optic neuropathy with slowed conduction of visual information in the anterior visual pathways leading to abnormal feedback to the visual fixation system. Primary gaze can also be affected by saccadic intrusions including square wave jerks, macro- and micro-saccadic oscillations (ocular flutter) and opsoclonus. These can be asymptomatic, although ocular flutter and opsoclonus can be very visually disabling causing shimmering, jiggling, or wavy vision (Frohman et al., 2005). Eye movement abnormalities in MS often occur in combination with each other and can have an additive effect on visual dysfunction. In a study of 24 MS patients, Tilikete et al. (2011) found a significant correlation between the number of abnormal eye movements and both visual acuity (po0.01) and the composite score of the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) (po0.05).

7 metamorphopsia (distorted vision). Pooled results of clinical trials showed that it occurred in 0.4% of patients treated with the 0.5 mg dose and tended to occur in the first three to four months of treatment. It usually resolves after cessation of fingolimod treatment. Jain and Bhatti (2012) recommended that all patients have a dilated fundal examination by an Ophthalmologist before starting treatment and be warned as to what visual symptoms to look out for. They should then be re-assessed by an ophthalmologist three to four months after starting fingolimod, with a subsequent review after a further six months and then annually. At each visit, ancillary tests such as OCT and fluoroscein angiography can be performed at the discretion of the ophthalmologist. Patients with co-existent diabetes mellitus or uveitis are at increased risk of fingolimodinduced macular oedema and therefore require more intensive surveillance (Jain and Bhatti, 2012).

3. 2.6.

Clinic measures of visual function in MS

Ocular problems

There is an association between MS and some causes of ocular inflammatory diseases, including anterior uveitis, posterior uveitis, pars planitis and periphlebitis. Uveitis may be seen in approximately 0.65–1% of patients with MS. The onset of uveitis my precede, coincide with or come after the diagnosis of MS (Biousse et al., 1999; Le Scanff et al., 2008). It can cause significant visual impairment; in one series of uveitis in patients with MS, after a mean follow-up of 13.4 years, Biousse et al. (1999) found that 21 out of 50 affected eyes had a visual acuity of 20/50 or worse. Pars planitis is a form of intermediate uveitis affecting the pars plana and into the vitreous body. It affects vision less than other forms of uveitis but may lead to cataracts, epiretinal membrane formation or cystoid macular oedema (Donaldson et al., 2007). Retinal venous sheathing (periphlebitis) may be seen in up to 36% of patients with MS (Fig. 2). It is usually mild and does not affect vision. It may serve, however, as a surrogate marker for MS activity within the rest of the central nervous system (Engell, 1986; Tola et al., 1993). Fingolimod has been recently licensed as an oral treatment for highly active relapsing–remitting MS. One of the adverse reactions reported is macular oedema (Jain and Bhatti, 2012). This may or may not be symptomatic. The visual symptoms include insidious onset of painless decreased visual acuity in one or both eyes and

Fig. 2 Fundus photography demonstrating bilateral asymptomatic sheathing of the retinal vessels in a 21-year-old female who presented with right optic neuritis. An MRI of her brain showed characteristic changes of demyelination.

The standard measure of vision is Snellen visual acuity, which uses high contrast letters read at either 20 ft or 6 m. In a population-based study, 72% of MS patients had corrected visual acuities in one or both eyes of 20/30 or worse (Swingler and Compston, 1992). Snellen visual acuity is repeatable and easy to administer, however its measurements in MS show low sensitivity to change over time and any changes in visual acuity are poorly correlated with changes in the overall EDSS score (Rudick et al., 1997). In general patient populations, measures of low contrast vision show better correlations than Snellen visual acuity with measures of reading performance, face recognition and difficulty with daily tasks (Leat et al., 1999). Contrast sensitivity, as measured by low contrast Sloan letter charts, has been shown to be sensitive in detecting visual dysfunction due to MS. Therefore, low contrast acuity measurements are commonly used now in clinical trials in optic neuritis and MS (Galetta and Balcer, 2013). It has also been proposed that low contrast acuity should be incorporated into the Multiple Sclerosis Functional Composite rating scale (Balcer et al., 2003). In clinic, they may be of most use in assessing patients with visual symptoms despite good Snellen visual acuities. Colour vision abnormalities may be seen in 32.5–42.5% of MS patients when tested with the Farnsworth Munsell 100 Hue Test, even in the absence of previous optic neuritis (Harrison et al., 1987; Vleugels et al., 2000). When chromatic discrimination is measured, dysfunction has been detected in both red–green and blue–yellow axes, implying impairment in both parvocellular and koniocellular systems (Moura et al., 2008). Screening for colour vision abnormalities in the clinic can be performed using the Ishihara pseudoisochromatic plates. Although these were designed to pick up congenital colour deficiencies, when tested, 45– 60% of MS patients have been found to some deficit of colour vision when viewing the plates (Fredericksen et al., 1986; Harrison et al., 1987; Swingler and Compston, 1992) Visual field testing may pick up retrochiasmal defects as discussed above, however most deficits detected are due to optic nerve involvement. Optic neuritis may lead to any form of visual field defect, although diffuse abnormalities

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S.J. Hickman et al.

(48.2%), altitudinal defects (15%) and central or centrocaecal scotomata (8.3%) were most commonly seen in the ONTT (Keltner et al., 1993). Visual field defects can also be seen in the absence of previous optic neuritis. In one study, asymptomatic visual field defects on standard automated perimetric testing were detected in 63.6% of eyes in MS patients without a previous history of optic neuritis (Sisto et al., 2005). MRI of the optic nerves (Hickman, 2007), OCT measurements of the RNFL thickness (Henderson et al., 2008) and VEP measurements (Halliday et al., 1973) can help to confirm that there is damage to the visual pathways, however their use in the clinic is limited as they do not provide prognostic information and tend to just back up what is already known from measures of vision, although this is subject to debate (Costello and Van Stavern, 2012). They are of most use in research and clinical trials. Delay in VEP latencies is a common finding in MS (Halliday et al., 1973), with a reduction in amplitude occurring when vision is reduced, such as in acute optic neuritis (Youl et al., 1991). Careful clinical eye movement testing can pick up most abnormalities of eye movements, although eye movement recordings are more sensitive at picking up subtle eye movement abnormalities (Reulen et al., 1983). Often subclinical defects detected on recordings will not have a major effect on vision. However, in cases where there are subjective complaints of blurring or oscillopsia, eye movement recordings may reveal abnormalities, such as abnormal square wave jerks or smooth pursuit abnormalities which were not detected clinically (McLean and Gottlob, unpublished). Eye movement recordings are most used in laboratory studies and drug trials (Mehta and Kennard, 2012; Shery et al., 2006).

4.

Morbidity due to vision problems in MS

Vision in patients with MS can therefore be influenced by many factors, reflecting the myriad effects that MS can have on the eyes as well as the afferent and efferent visual pathways. There follows a discussion about visual symptoms,

Table 1

impairment due to visual dysfunction in MS and sight impairment registration due to MS.

4.1.

Visual symptoms in MS

Visual symptoms are very common in patients with MS and may be reported despite reasonable Snellen visual acuity. In a study of 80 MS patients with a median binocular Snellen visual acuity equivalent of 20/16 (range 20/12.5–20/250), the NEI-VFQ-25 scores were significantly worse in the MS group for the composite score and for 10 of 12 subscales compared with an eye disease-free reference group. Significant problems were reported with: feeling that vision is blurry, not clear, or “fuzzy”; difficulty reading; feeling that two eyes see differently; trouble focusing on or following moving objects; difficulty driving; double vision; difficulty with vision when eyes are tired and difficulty with vision at night. From the results a brief MS-specific vision questionnaire (MSVQ-7) was proposed to capture selfreported visual dysfunction with more relevance to the MS population than the more generic NEI-VFQ-25 (Ma et al., 2002). This is shown in Table 1. When administered to a hospital outpatient cohort of 24 patients with chronic MS (mean age 51, range 36–64; mean disease duration 18 years, range 10–29; mean EDSS score 4.85, range 3–8), the mean MSVQ-7 score was 14.8 (range 7–28). However, there was no correlation between the total score and EDSS, visual acuity, contrast sensitivity or colour vision. The most commonly reported difficulties were with ‘difficulty with vision when your eyes are tired’ (mean score 2.58/4) and ‘feeling that your vision is blurry, not clear or “fuzzy”’ (mean score 2.42/4) (Raoof and Hickman, unpublished). This suggests that patients experience a lot of visual symptoms, but that vision tests used in the clinic may not adequately reflect this. Many measures of patients' function are taken at a snapshot in time and therefore do not generally show the clear variation that can occur in patients' symptoms. MS is a disease defined by its variability, which can occur on a dayto-day and hour-to-hour basis, with many symptoms exacerbated by fatigue. Variability has been described with retesting visual fields in patients following optic neuritis (Wall et al., 1998). A saturation-like effect in vision can

The 7-item MS Vision Questionnaire (MSVQ-7). Adapted from Ma et al. (2002).

Visual symptom or activity

Difficulty with vision when your eyes are tired Difficulty with your vision in bright sunlight Feeling that your two eyes see differently Difficulty looking at or using a computer Feeling that your vision is blurry, not clear, or “fuzzy” Trouble focusing on or following moving objects Double vision

Problem severity scale No problem

Slight problem

Moderate problem

Severe problem

N/A

1 1 1 1 1 1 1

2 2 2 2 2 2 2

3 3 3 3 3 3 3

4 4 4 4 4 4 4

0 0 0 0 0 0 0

Instructions: For each symptom or visual activity mentioned, please indicate whether you currently have no problem (circle response 1), a slight problem (circle response 2), a moderate problem (circle response 3), a severe problem (circle response 4), or whether that aspect of vision is not applicable to you (circle response 0).

Vision and multiple sclerosis occur when exposed to high light levels (Enoch et al., 1979). This can be demonstrated by a biphasic widening of the VEP P100 response after exposure to intense large field illumination, even though the overall latency does not change. It suggests that there are a sub-population of nerve fibres within the optic nerve which are susceptible to high illumination and show increased conduction time (Campos et al., 1985). Patients can complain of letters dropping out while reading and of difficulty sustaining vision at higher light levels (Enoch et al., 1979; Tagami et al., 1984). Worsening of vision can also occur due to heat or when taking exercise. This is Uhthoff's phenomenon and is due to heat shortening the action potential duration and thereby reducing the safety factor for successful conduction of nerve impulses within demyelinated axons (Smith and McDonald, 1999). Lowering the body temperature has been shown to improve vision and shorten VEP delay in MS (Poyraz et al., 2010). The use of specialised cooling equipment in MS has also shown improvements in day-to-day physical activities such as walking (Meyer-Heim et al., 2007). If there is a relative delay in conduction between the two optic nerves then the patient may experience Pulfrich's phenomenon, which is the misperception of the trajectory of moving objects (O'Doherty and Flitcroft, 2007; Smith and McDonald, 1999).

4.2.

Reading

As has been discussed above, patients can complain of problems with reading. This may be caused by decreased visual acuity, fatigue (as outlined in Section 4.) and with problems with visual perceptual processing. Difficulty with reading and other aspects of cognitive impairment are significant factors in causing unemployment amongst patients with MS (Bruce et al., 2007; Chiaravalloti and DeLuca, 2008). There are also case reports of alexia without agraphia in MS due to lesions in the splenium of the corpus callosum (Mao-Draayer and Panitch, 2004).

4.3.

Vision and limb function

Patients with eye movement abnormalities have been demonstrated to have worse EDSS scores than those without eye movement abnormalities (median 5.2 versus 3.5, p= 0.02), even allowing for age and disease duration (Downey et al., 2002). The presence of eye movement abnormalities also predicted worsening disability when the patients were re-examined after two years (median 7.0 versus 5.0, po0.001) (Derwenskus et al., 2005). Mobility may be directly affected by visual dysfunction in MS. In a study of 12 MS patients who had had previous falls, vision factors associated with falling included double vision and uncertainty of eye and movement coordination (Nilsagård et al., 2009). Unsteady gaze fixation is also associated with poor eye–hand coordination and intention tremor on visually directed reaching (Feys et al., 2008).

4.4.

Driving

Visual impairment may affect driving performance in MS patients. However, one study did not find a difference in

9 depth perception, accident/violation rate or self-limited driving performance between those MS patients who reported visual difficulties and those MS patients who did not, or with a control group, however all patients had Snellen visual acuities that met the licensure requirement (Schultheis et al., 2010a). Measurement of the useful field of vision (UFOV) gives additional information as to the likelihood of poor driving performance. This tests visual information processing, divided attention and selective attention, to generate an overall composite score. MS patients with evidence of cognitive impairment using a standard battery of tests had worse UFOV scores and worse scores on a simulated Neurocognitive Driving Test. 29% of MS patients with cognitive impairment were rated as having a high risk of accident involvement from their scores on the UFOV test (Schultheis et al., 2001). A further study found that information processing speed and visuospatial learning and recall were also significant cognitive predictors of driving performance in community-dwelling drivers with MS (Schultheis et al., 2010b). All MS patients should be advised to consult their licensing authority to ensure that they are deemed safe to continue driving.

4.5.

“Blindness” due to MS

There are a lack of up-to-date data on the amount of overall visual impairment that exists due to MS. It is, however, relatively unusual to develop severe visual impairment. An historical cohort study of MS patients found a visual acuity of o20/50 in both eyes in only 5.2% of cases (Kurtzke, 1970). The number of registrations for sight impairment in England and Wales due to MS or optic neuritis is also very small. Out of 97,726 patients registered with a sight impairment from the years 2007–2011, only 59 (0.06%) were listed as showing MS or optic neuritis to be the cause (Bunce and Zekite, personal communication). This figure may, though, be an underestimate for a number of reasons: MS or optic neuritis as the cause or contributing factor may not be recorded on the Certificate of Vision Impairment (Bunce and Wormald, 2006); there may be a number of patients with MS and significant sight impairment who have gone unrecognised since many patients with MS have severe multiple impairments and therefore the patient, or their physician, do not feel that registration of low vision is of primary importance; patients sometimes refuse sight impairment registration and also there is no statutory requirement for it to be offered.

5. 5.1.

Management of vision problems due to MS Patient assessment

It is therefore important to consider visual problems when seeing patients with MS. The United Kingdom (UK) National Institute of Health and Clinical Excellence (NICE) (2003) have produced guidelines on MS management. The guidance as regards vision is shown in Table 2. It is recommended that patients with MS are screened for vision problems. One of the suggested questions to ask is: “Since you were last seen, have you developed any new problems with vision or your eyes?” Local implementation policies also need to be in

10

S.J. Hickman et al.

place to identify which local ophthalmologist has an interest in neuro-ophthalmology, where the nearest specialist lowvision service is and which is the social service team responsible for people with visual impairment. There is a danger of ascribing all vision complaints to MS and therefore not to look for other, potentially reversible problems. A study of 130 patients with MS, ocular comorbidity was found in 20%, including uncorrected refractive error, cataract and glaucoma (Polman et al., 2003). A NARCOMS questionnaire study found that, of 8983 respondents, 15.9% reported a visual comorbidity, including 12.0% with cataracts, 3.3% with uveitis and 3.2% with glaucoma. Among participants with visual comorbidities, 13.8% had two or more. In a multivariable Cox model the presence of visual comorbidities was associated with a higher risk of self-reported mild visual disability (HR 1.47; 95% confidence intervals: 1.37–1.59) (Marrie et al., 2011). It is often worth asking the patient to see their optometrist to see if their visual problems can be corrected by new spectacles following an up-to-date refraction. The optometrist can also provide initial screening for other ophthalmological conditions such as glaucoma and cataracts. If the optometrist cannot improve the visual acuity then the patient should be seen in a specialist ophthalmology clinic. The patient will need to be assessed for ocular comorbidities before ascribing the decrease in vision as being due to MS. The NARCOMS study found that in the past six months almost 23% of respondents reported visiting an ophthalmologist, while 20.1% saw an optometrist and 4.7% saw a neuroophthalmologist (Salter et al., in press). On reviewing the records of 33 patients seen in the joint neuro-ophthalmology clinic at the Royal Hallamshire Hospital, Sheffield, UK between 2007 and 2011 who already had a confirmed diagnosis of MS, seven had ophthalmological reasons for their visual complaints (two with refractive errors and one each of blepharitis, uveitis, pars planitis, retinal vasculitis and transient monocular blindness) and 26 had problems more directly related to their MS (eight with chronic optic neuropathy, seven with oscillopsia, three with optic neuritis, three with diplopia, two with INOs, two with retro-ocular pain and one with a retrochiasmal visual field defect) (Hickman, unpublished).

5.2.

Table 2 UK National Institute of Health and Clinical Excellence guidance on vision problems in MS. Adapted from NICE (2003). All recommendations are at grade D: Directly based on category IV evidence, or extrapolated recommendation from category I, II or III evidence. Recommendation Guidance number 1.7.10.1

1.7.10.2

1.7.10.3

1.7.10.4

1.7.10.5

Each professional in contact with a person with MS should consider whether the individual's vision is disturbed, by considering, for example, the individual's ability to read the text of a newspaper, book or other written material and to see the television. Any person with MS who is unable to read normal print or to see the television should be assessed for glasses by an optometrist. Any individual who experiences reduced visual acuity, despite using suitable glasses, should be assessed in a specialist ophthalmology clinic. Any person with MS who has nystagmus that causes reduced visual acuity or other visual symptoms should be offered a timelimited trial of treatment with oral gabapentin. This should be initiated and monitored by a suitable specialist. Any person with MS who is unable to read (due to low visual acuity) or to see television, despite all available treatment, should be:  assessed for low-vision equipment and adaptive technology  referred to the appropriate specialist social services team  registered as partially sighted.

Treatment

Treatment options for each of the specific problems that can affect vision in MS are listed in Table 3. If the visual symptoms occur as part of an MS relapse and are disabling then high dose glucocorticoids will speed up recovery (Frohman et al., 2005; Hickman et al., 2002, 2008). These are usually given as 1 g per day intravenous methylprednisolone for three days or 500 mg per day oral methylprednisolone for five days, either with or without an oral prednisolone taper. Results from a recent small trial in chronic optic neuropathy in MS found that 4-aminopyridine improved in VEP P100 latency compared with placebo and led to improvements in low contrast visual acuity in a subset of patients. Eyes with a RNFL thickness between 60 and 80 μm on OCT had the highest response rate (Horton et al., 2013). A larger study is needed before 4-aminopyridine can be recommended as a treatment option in chronic optic neuropathy.

Any patient with oscillopsia or diplopia should also have a full orthoptic assessment to provide baseline measurements and in recommending appropriate treatment. Out of a cohort of 137 MS patients attending a neuroophthalmology clinic, 34% obtained benefit from orthoptic treatment, including the use of prisms, convergence therapy and advice about using occupational safety glasses (Jenkins, 2007). There may be a role for strabismus surgery or botulinum toxin injections in the extra-ocular muscles in the management of symptomatic INOs, although this is limited and should only be carried out where there is expertise in this area (Adams et al., 2009; Murthy et al., 2007). Bilateral medical rectus resections with either unilateral or bilateral adjustable lateral rectus recession (s) have been reported to promote single vision for primary

Vision and multiple sclerosis

Table 3

11

Suggestions for how to manage specific problems causing visual symptoms in MS.

Problem

Lesion location(s)

Treatment options

Reference

Optic neuritis Chronic optic neuropathy

Optic nerve Optic nerve

Glucocorticoids acutely 4-aminopyridine Low vision services Glucocorticoids acutely

Hickman et al.( 2002, 2008) Horton et al. (2013) Margrain (2000) Plant et al. (1992)

Neuropsychology

Chiaravalloti and DeLuca (2008)

Glucocorticoids acutely Prisms

Frohman et al. (2005) Jenkins (2007)

Glucocorticoids acutely Convergence therapy Botulinum toxin Strabismus surgery Paramedian pontine reticular Glucocorticoids acutely formation or VIth nerve nucleus Central vestibular pathways Glucocorticoids acutely Prisms Central vestibular pathways Carbamazepine Acetazolamide Cerebellem Glucocorticoids acutely Brain stem Cerebellum Glucocorticoids acutely Central vestibular pathways Gabapentin Clonazepam, 3,4-diaminopyridine 4-aminopyridine Baclofen Anterior visual pathway Gabapentin Cerebellum Memantine Central vestibular pathways 7Strabismus surgery Cerebellar nodulus and uvula Baclofen

Adams et al. (2009) Frohman et al. (2005) Jenkins (2007) Murthy et al. (2007) Frohman et al. (2005)

Retrochiasmal visual field defect

Optic tract Lateral geniculate nucleus Optic radiation Visuo-perceptual problems Anterior visual pathway Visual cortex Association vision cortices III, IV or VI cranial nerve palsy Nerve fascicle Nerve nucleus (except VIth nerve) Internuclear ophthalmoplegia Medical longitudinal fasciculus

Gaze palsy

Skew deviation Paroxysmal diplopia or nystagmus Disturbances of conjugate gaze Gaze-evoked nystagmus

Pendular nystagmus

Periodic alternating nystagmus

Frohman et al. (2005) Jenkins (2007) Frohman et al. (2005) Frohman et al. (2005) Frohman et al. (2005) Mehta and Kennard (2012)

Frohman et al. (2005) Jain et al. (2002) Mehta and Kennard (2012) Frohman et al. (2005) Mehta and Kennard (2012)

Saccadic intrusions Square wave jerks Ocular flutter Opsoclonus

Cerebellem Brain stem

Glucocorticoids acutely Carbamazepine Baclofen

Frohman et al. (2005

Uveitis Anterior Pars planitis Posterior

Uveal tract of the eye

Topical glucocorticoids Systemic glucocorticoids Immunosuppression β-interferon

Becker et al. (2005) Donaldson et al. (2007)

position and reading post operatively in bilateral INO with exotropia (Adams et al., 2009). A recent single case report showed that treatment with 4-aminopyridine led to improvements in both subjective vision and saccadic conjugacy in an MS patient with bilateral INO (Serra et al., 2013). The NICE guidelines suggest that an initial trial of gabapentin should be tried for oscillopsia due to pendular nystagmus (see Table 4) (Averbuch-Heller et al., 1997; Bandini et al., 2001; Mehta and Kennard, 2012; NICE, 2003; Shery et al., 2006; Starck et al., 2010; Thurtell et al., 2010). Although this is an unlicensed indication, there is class B

evidence to recommend treatment with doses up to 2400 mg per day (Mehta and Kennard, 2012). The side effects reported include dizziness, somnolence and fatigue. Second-line treatment could be tried with memantine at doses of up to 40 mg per day (see Table 4 and Fig. 3) (Mehta and Kennard, 2012; NICE, 2003; Shery et al., 2006; Starck et al., 1997, 2010; Thurtell et al., 2010). Again, this is an unlicensed indication. One study, however, which was assessing whether memantine can improve cognition in MS, found that it could exacerbate MS symptoms, causing blurred vision, fatigue, severe headache, increased muscle

12

S.J. Hickman et al.

Table 4 The results of studies on the effects of gabapentin and memantine on visual acuity in MS patients with acquired pendular nystagmus. Drug

Number of patients

Trial design

Gabapentin 9 with MS in Double-masked crossover trial a larger trial with baclofen 5

Examiner-masked crossover trial with vigabatrin 13 Retrospective observational study 11 (20 eyes) Examiner-masked crossover trial with memantine 3 with MS in Double-masked crossover trial a larger trial with memantine

Memantine 10

Prospective observational study compared with scopolamine 3 Retrospective observational study 11 (20 eyes) Examiner-masked crossover trial with gabapentin 3 with MS in Double-masked crossover trial a larger trial with gabapentin

Dose per Benefit day (mg)

Study

900

Significant improvement in Landolt Averbuch“C” distance visual acuity (po0.006) Heller et al. (1997) 1200 Significant improvement in Snellen Bandini et al. visual acuity in 2 patients (2001) 900–2400 Snellen visual acuity improved in 31% Shery et al. of patients (2006) 1200 Near visual acuity on Nieden charts Starck et al. improved by at least 0.1 in 50% eyes (2010) 1200 Improved logMAR visual acuity in Thurtell et al. 2 patients (2010) 15–60

Significant improvement in Snellen visual acuity seen in 5 patients

Starck et al. (1997)

10–20

Snellen visual acuity improved in all patients Near visual acuity on Nieden charts improved by at least 0.1 in 65% eyes Improved logMAR visual acuity in all patients

Shery et al. (2006) Starck et al. (2010) Thurtell et al. (2010)

40–60 40

weakness, walking difficulties or an unstable gait (Villoslada et al., 2009). Of note, this phenomenon only occurred when memantine dose was escalated from the standard 20–30 mg/day. The authors' explanation was that their trial was the first placebo-controlled blinded trial, and that patients receiving memantine (even at higher doses) in a non-blinded fashion were more inclined to tolerate side effects. However, three subsequent placebo-controlled memantine trials in MS for spasticity, cognitive dysfunction and optic nerve neuroprotection in optic neuritis, all at doses of 20 mg/day, do not mention a transient exacerbation of MS symptoms as a serious adverse event (Esfahani et al., 2012; Lovera et al., 2010; Mehta et al., 2010). Interestingly, patients in the cognitive study, which did not show significant differences between memantine and placebo, did have some subjective worsening of neurological function (Lovera et al., 2010). All of these studies were of short duration, probably insufficient to assess longer term neuroprotection. It seems that memantine in MS is particularly suitable for patients with nystagmus without cognitive deficits who may benefit from memantine even at higher doses. In conclusion, memantine's use in MS patients therefore needs to be closely monitored, in particular in subjects with cognitive deficits. An approach of using a vertical Kestenbaum-type procedure to move the patient's nystagmus null point combined with gabapentin has been reported to be successful in an MS patient with acquired pendular nystagmus associated with a compensatory abnormal head posture (Jain et al., 2002). This type of surgery should only be undertaken in specialist centres. Other forms of nystagmus may respond to different drugs, although their study in MS has been limited. Downbeat

nystagmus may be treated with using clonazepam, 3,4diaminopyridine or 4-aminopyridine. Upbeat nystagmus may respond to baclofen or one of the aminopyridines. Periodic alternating nystagmus can be treated with baclofen (Mehta and Kennard, 2012). Occasionally, carbamazepine or acetazolamide will suppress some paroxysmal forms of nystagmus (Frohman et al., 2005). If the patient complains of visual fatigue then sensitivity may be restored by closing the eyes, lowering the light level or with the use of tinted spectacle lenses (Enoch et al., 1979; Tagami et al., 1984). A further study has suggested that reading speed and visual search can be improved with the use of coloured spectral overlays (Newman Wright et al., 2007). If the patient is complaining of Pulfrich's phenomenon then this can be alleviated by the use of a neutral density filter over the asymptomatic eye, to balance the VEP delay between the two eyes (O'Doherty and Flitcroft, 2007).

5.3. Low vision services and sight impairment registration If the patient's vision remains poor and cannot be corrected then the patient should be referred to a low vision clinic. In a study of 168 new referrals to a low vision clinic with various causes of poor vision, only 23% could read standard newsprint sized text (equivalent to N8 on a near vision chart). After provision of suitable reading aids 88% could read this size of text (Margrain, 2000). It is also important to offer sight impairment registration if the patient is eligible. In the UK, sight impairment registration entitles the claimant to a Disabled Person's Railcard, local travel and leisure

Vision and multiple sclerosis

13

Fig. 3 Eye movement recordings with an infra-red pupil tracker (Eyelink II), sampling at 500 Hz, before (A) and after (B) treatment with memantine in a 50 year old man with MS and oscillopsia. He had a disconjugate, pendular nystagmus, occurring in both the horizontal and vertical place, with the larger amplitude in the left eye. Post treatment (B) with 30 mg of memantine per day the amplitude of the nystagmus is significantly reduced, particularly in the vertical plane. He reported a significant improvement in oscillopsia with memantine treatment and his visual acuity approved by almost 1 line on the early treatment diabetic retinopathy study (ETDRS) chart from 0.86 logMAR (20/145 Snellen equivalent) to 0.78 logMAR (20/121 Snellen equivalent).

concessions and protection under the Disability Discrimination Act. In addition, severe sight impairment registration entitles the registrant to a number of additional benefits including the blind person's personal income tax allowance, free sight tests, reduced television licence fee and car parking concession under the Blue Badge Scheme when the patient is a passenger. Lastly, although sight impairment registration does not automatically qualify the registrant for other welfare benefits, such as Disability Living Allowance, the registration is taken into account as part of the claim (Royal National Institute of Blind People, 2012). Also, the World Health Organization stresses the importance of collecting within-country data on causes of visual impairment as this helps in priority-setting and resource allocation (Resnikoff et al., 2004).

6.

Conclusions

Although severe sight impairment is uncommon in MS, visual symptoms are common. Relapses, causing problems such as optic neuritis, will usually recover well, with recovery speeded up by the use of glucocorticoids, if appropriate. Chronic visual symptoms do occur though in all stages of the disease. These will often be treatable, as outlined above. It is therefore important when seeing MS patients to enquire whether they are having any trouble with their vision or eyes.

Conflict of interest S.J.H., N.R., R.J.M. and I.G. report no conflicts of interest.

Acknowledgements Thanks to Catey Bunce and Antra Zekite from Research and Development, Moorfields Eye Hospital NHS Foundation Trust, London, UK for providing the data on sight impairment registration for people with MS.

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Vision and multiple sclerosis.

Multiple sclerosis can affect vision in many ways, including optic neuritis, chronic optic neuropathy, retrochiasmal visual field defects, higher orde...
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