Review

The neuro-ophthalmology of multiple sclerosis

Elliot M Frohman, Teresa C Frohman, David S Zee, Roderick McColl, Steven Galetta Lancet Neurol 2005; 4: 111–21
Department of Neurology
Multiple sclerosis (MS) is the most common disabling neurological disease in young people. Most CNS lesions involve (E M Frohman MD PhD,
T C Frohman BA), Department
neuroanatomically non-eloquent zones that often do not result in symptomatic complaints. By contrast, tissue-injury
of Ophthalmology
mechanisms involving inflammatory demyelination can involve more eloquent sites, such as the optic nerve and (E M Frohman MD PhD), and
brainstem, which can correspondingly produce the development of well recognised syndromes such as optic neuritis Department of Radiology
and internuclear ophthalmoplegia, respectively. In this review we discuss the broad landscape of abnormalities that (R McColl PhD), University of
Texas Southwestern Medical
affect the afferent visual system and the ocular motor apparatus, and emphasise relevant features, the recognition and
Center at Dallas, TX, USA;
treatment of which are of importance to general neurological practice. The commonness of visual sensory and eye Departments of Neurology and
movement abnormalities in MS highlights the importance of understanding the principles addressed in this review. Ophthalmology, Johns Hopkins
Hospital, Baltimore, MD, USA
(D S Zee MD); Departments of
Owing to the disseminated nature of the disease process MS from 22% to 56%, which may have implications for Neurology and
in MS, there are several distinct neuro-ophthalmological therapy (see below). When the clinical course is typical, Ophthalmology, University of
syndromes that span both the visual sensory and the other diagnostic studies such as fluorescence Pennsylvania, PA, USA
ocular motor systems. The principal objective of this treponemal antigen antibodies, anti-nuclear antibodies, (S Galetta MD)

review is to provide a framework for understanding the angiotensin converting enzyme, Lyme titre, chest Correspondence to:
Dr Elliot M Frohman, Department
neuro-ophthalmic signs and symptoms that occur in radiograph, and lumbar puncture are of limited use in
of Neurology, University of Texas
patients with multiple sclerosis (MS). Particular eliminating other causes of optic neuropathy.4 A more Southwestern Medical Center at
emphasis is placed on understanding currently aggressive assessment should be considered when non- Dallas, 5323 Harry Hines Blvd,
proposed mechanisms that give rise to disorders of typical features of optic neuritis are present, including a Dallas, TX 75235, USA
elliot.frohman@
visual processing and ocular motility. very swollen optic nerve, retinal exudates, absence of utsouthwestern.edu
visual recovery within 30 days, and absence of pain.
Part I: the afferent visual system in MS Tests for Lupus, Lyme disease, sarcoid, syphilis, West
Optic neuritis Nile virus,7 ehrlichiosis,8 and Leber’s optic neuropathy
Acute idiopathic demyelinating optic neuritis is should be considered in the appropriate clinical setting.
frequently the initial clinical manifestation of multiple Demyelinating optic neuritis can be occasionally
sclerosis. Although there is a broad age range for onset, difficult to distinguish from anterior ischaemic optic
most patients with acute demyelinating optic neuritis neuropathy (table 1). The two entities may have
are young, age 20–50 years. There is a gender difference: overlapping clinical features, including the rate and range
women are three times as likely as men to develop optic of visual deterioration.9–11 An altitudinal defect (visual field
neuritis. The incidence of acute demyelinating optic suppression either above or below the horizontal) alone
neuritis is about three per 100 000 people in the USA; in may not be reliable in distinguishing optic neuritis from
low-risk regions such as Japan, the incidence approaches ischaemic optic neuropathy, since up to 10–15% of
one per 100 000 population per year.1,2 patients with optic neuritis may present with an altitudinal
defect.9–11 Although imaging is rarely necessary to
Clinical characteristics distinguish these two entities, orbital MRI will show optic
The patient with typical demyelinating optic neuritis nerve enhancement in most patients with optic neuritis.12
usually experiences a decline in vision over a 7–10-day Subclinical or chronic forms of demyelinating optic
period. The progression of visual loss beyond 2 weeks is neuritis—in which the patient notices a gradual decline in
distinctly unusual.3 In the Optic Neuritis Treatment vision instead of acute vision loss followed by
Trial,4 92% of patients had pain, particularly with eye improvement—may also develop. These patients may
movements. In the patient with typical optic neuritis, show abnormalities on neuro-ophthalmological
some recovery of vision should occur within 30 days of examination, including field loss, pupillary abnormalities,
onset. Clinical features that suggest non-typical optic and disc pallor.13 Diagnosis of chronic optic neuritis is
neuritis include the presence of retinal haemorrhages, a based on exclusion and considerations could include
markedly swollen nerve, retinal exudates, the absence of superimposed glaucoma (either chronic or acute), an
pain, and the presence of no light perception vision at underlying mass lesion, or an infiltrative process.
onset.5 These patients have a lower risk of developing
MS, particularly when a baseline MRI scan is normal.5,6 Demyelinating optic neuritis Anterior ischaemic optic neuropathy
Age (years) 20–50 >50 years
Diagnostic assessment Disc swelling A third of patients, typically no haemorrhages Present, many sectoral, nerve-fibre layer
or exudates haemorrhages
Patients with demyelinating optic neuritis should Pain Common (>90%) Uncommon (<10%)
undergo a brain MRI scan to establish their risk of MS. Field defect Typically central, but highly variable Typically altitudinal
According to the 10 year longitudinal optic neuritis
Table 1: Clinical differentiation of optic neuritis and ischaemic optic neuropathy
study, even one white-matter lesion increases the risk of

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Vision testing
Panel 1: The components of the afferent bedside neuro- Visual-field (Humphrey 30-2, contrast sensitivity [Pelli-
ophthalmological exam Robson]), visual-acuity (ETDRS charts) and colour-vision
Visual acuity testing (Ishihara pseudoisochromatic plates and
Spectacle correction Farnsworth-Munsell 100 hue test) were the main visual
Pinhole correction outcome measures used in the Optic Neuritis Treatment
Near card or distance Trial.3 In the Optic Neuritis Treatment Trial,4 visual-
Visual fields (confrontation) acuity abnormalities were reported in 89·5% of patients
Monocular testing at baseline. Visual-field defects (97·5%) and contrast-
Static versus dynamic sensitivity abnormalities (98·2%) were present in almost
Consider formal fields to characterise central defects all patients. Recently, low-contrast letter acuity testing
has been used to identify binocular visual dysfunction in
Colour
patients with MS; studies have suggested that this
Colour plates
assessment may be an ideal visual measure for
Red-green desaturation
incorporation into the Multiple Sclerosis Functional
Pupils Composite.15,16 In routine clinical practice, computer
Shape and position fields (24-2 or 30-2), using sita fast or full threshold
Anisocoria? algorithms may be used to document the visual-field
Reactivity defect in patients with optic neuritis. So far, contrast
Relative afferent papillary defect? sensitivity testing has been used primarily in clinical
Funduscopic exam trials to detect subtle visual dysfunction in patients with
Disc oedema/haemorrahge? multiple sclerosis. Although there are several bedside
Disc pallor assessment strategies that can be used to define
Nerve fibre loss? abnormalities of the anterior visual system, most
Occult nystagmus? neurologists in general practice will limit the routine
Perivenular phlebitis (peripheral retina)? assessments to acuity, confrontational fields, pupillary
light reflexes, and examination with an ophthalmoscope
(panel 1).
Although visual evoked potential testing may show
evidence of optic nerve dysfunction, optic neuritis Neuroimaging
should be clinically diagnosed. Multifocal visual evoked Around 50–70% of patients with optic neuritis will
testing may be useful in select patients, particularly have periventricular white-matter abnormalities
when the distinction between optic nerve and retinal consistent with demyelination on an initial MRI
disease is in question, or when evidence of subclinical scan.17–20 10 years after acute optic neuritis, the
optic nerve dysfunction is sought.14 presence or absence of MRI lesions was the main
factor in determining the risk of multiple sclerosis.5
56% of patients with one or more white-matter lesions
on their baseline brain MRI scan developed MS,
whereas 22% of patients with a normal baseline MRI
developed MS at 10 years.
The percentage of patients with optic nerve
enhancement in the acute stage may approach 90%
(figure 1).12 Newer MRI techniques—such as diffusion
tensor imaging, magnetic transfer imaging and
spectroscopy—may improve our ability to detect
demyelinating abnormalities in the brain.21,22
Criteria for the diagnosis of MS now incorporate MRI
findings.23,24 Application of these criteria to one group of
patients with demyelinating disease more than doubled
the 1 year diagnosis of MS.25 In another study of 56
patients with clinically isolated syndromes (eg, optic
neuritis), the presence of new T2 lesions 3 months after
presentation was useful in predicting the diagnosis of
clinically definite MS.26 In a report of 115 patients with
Figure 1: Axial T1-weighted gadolinium-enhanced orbital MRI scan in a
clinically isolated optic neuritis, 70% of the patients had
patient with acute optic neuritis of the left eye abnormal brain lesions shown by MRI scan and 27%
Note the enlargement and enhancement of the left optic nerve. had spinal-cord lesions.27

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Treatment
The Optic Neuritis Treatment Trial is the largest Optic neuritis
randomised study to examine the issue of corticosteroid
treatment for optic neuritis. The trial has used three
treatment groups: (1) intravenous methylprednisolone for Typical Atypical
3 days followed by an oral prednisone taper, (2) oral (Pain, retrobulbar or mild (No pain, retinal exudates,
disc swelling, visual loss retinal haemorrhages,
prednisone, and (3) oral placebo.3 In terms of visual acuity does not progress beyond severe disc swelling, no
recovery, final visual outcome at 6 months was the same 2 weeks, age 20–50 years) visual recovery after 1 month)
for all groups, although there were significant differences
favouring the intravenous group for contrast sensitivity Consider
(p=0·026) and colour vision (p=0·033) at 6 months.3 At
1 year, there were no statistical differences in any of the
Ischaemic optic neuropathy
four measures of visual function including visual acuity,
visual-field colour vision, and contrast testing.28 The Optic Brain MRI Infiltrative optic neuropathy
Neuritis Treatment Trial also reported that visual recovery Inflammatory (sarcoid, lupus)
may also be hastened by intravenous steroids as
determined by visual field and contrast sensitivity Normal
Infection
Abnormal (syphilis, lyme, viral, cat scratch)
measurements. However, no significant difference was (consistent with
reported for visual acuity recovery (p=0·09).3 A meta- demyelination) Compressive optic neuropathy
analysis of 12 randomised controlled clinical trials of
steroid treatment in MS and optic neuritis showed that
corticosteroids were potentially useful in improving short- Consider intravenous Intravenous corticosteroids, Magnetic resonance and serological
corticosteroids on consider immunomodulatory studies as appropriate
term visual recovery, but had no long-term benefit.29 case-by-case basis therapy
In the Optic Neuritis Treatment Trial, the use of oral
corticosteroids was associated with an increased risk of
Figure 2: An algorithm for the assessment and treatment of optic neuritis
recurrent optic neuritis.30 5 years after an initial bout of
optic neuritis, patients who received oral prednisone
(1 mg/kg) had the highest rate of recurrence (41%) monosymptomatic cohort had to have two or more
compared with those who received methylprednisolone white-matter lesions on a baseline brain MRI scan.34 All
or placebo (25% for both groups). At 10 years, there was patients received intravenous methylprednisolone for
no longer a significant difference in the risk of recurrent 3 days followed by a 2 week oral prednisone taper.
optic neuritis when comparing the oral prednisone and Patients who received interferon beta-1a (Avonex) had a
placebo groups (p=0·07).31 A small prospective 44% reduction in the 3 year risk of clinically definite MS
controlled clinical trial of oral methylprednisolone when compared with those who received placebo
(500 mg every day for 5 days) did not indicate an (p=0·02). Patients in the interferon group also had fewer
increased rate of demyelinating attacks.32 new and enhancing brain MRI lesions.34 Similarly, the
In patients with acute optic neuritis and an abnormal Early Treatment of Multiple Sclerosis (ETOMS) study
baseline brain MRI scan, we recommend treatment with also showed that interferon beta-1a is associated with a
a 3 day course of high-dose (1 g/day) intravenous short-term reduction in the conversion to clinically
corticosteroids followed by an oral prednisone taper, definite MS over 2 years.35
which may delay the onset of clinically definite MS over The potential long-term benefit of initiating interferon
a 2 year period.33 However, many patients with isolated beta-1a therapy in the high-risk monosymptomatic
optic neuritis and a normal baseline MRI scan will have patient is suggested by data from the CHAMPIONS
spontaneous and excellent recovery of vision without the study (an extension study of the CHAMPS study). The
use of corticosteroids. In this group of patients, we think CHAMPIONS study showed that patients initially
the decision to use intravenous corticosteroids followed randomly assigned to interferon beta-1a had 35% less
by an oral taper should be made between the patient and conversion to clinically definite MS over a 5 year follow-
the treating physician. We have a low threshold for the up versus placebo-treated patients.36 Given that the
initiation of corticosteroid treatment for those patients primary endpoint of the CHAMPS study was the
with severe unilateral visual loss because corticosteroids conversion to clinically definite MS after a
may hasten visual recovery by several weeks (figure 2). monosymptomatic event and because patients were no
longer kept in their assigned groups after clinically
Interferon beta-1a treatment in patients with optic neuritis definite MS developed, it is not surprising that an effect
The Controlled High Risk Multiple Sclerosis Prevention on disability was not seen. The Queen’s Square Study37
study (CHAMPS) was a randomised, double-blind, also shows the potential importance of initiating
placebo-controlled trial that enrolled patients with a first immunomodulatory therapy at the presentation of a
demyelinating event (eg, optic neuritis). Patients in this clinically isolated syndrome and an abnormal MRI. In a

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14 year follow-up study of 71 patients, 88% of patients symptoms, this type of ocular inflammation may result
with an abnormal baseline MRI scan developed MS, in vision loss caused by cataract or epiretinal membrane
while only 19% of patients with a normal baseline MRI formation, or macular oedema.
scan converted to MS. Of interest, stratifying Periphlebitis is a sheathing or cuffing of the retinal
radiographic severity by the number of baseline MRI veins by lymphocytes and plasma cells.44–47 The
lesions did not predict different risk rates for MS. On the prevalence of periphlebitis in MS has been estimated to
basis of the above data, we favour the initiation of be in the range of 10–36%, but large prospective studies
immunomodulatory therapy for the high-risk are lacking.48–50 More aggressive forms of retinal
monosymptomatic patient with typical clinical and brain periphlebitis may be seen in other disorders such as
MRI findings. For those high-risk patients who do not Eale’s disease, sarcoid, idiopathic uveitis, toxoplasmosis,
start immunomodulatory therapy, we recommend serial and syphilis.44 The perivascular inflammation that
brain MRI after intervals of 3–6 months to check for new occurs in the CNS also manifests in the retina, and may
disease activity. indeed serve as a surrogate marker of disease activity.48,51
In a study of 103 high-risk monosymptomatic patients,
including those with an abnormal brain MRI and Part II: ocular motor pathophysiology in MS
positive CSF oligoclonal bands, Berger and colleagues38 The clinical–radiological paradox
found that the presence of serum antimyelin antibodies Most CNS lesions in MS are not associated with
predicted the conversion to clinically definite MS. identifiable clinical findings. This is perhaps related to a
However, other studies have shown only low high predilection of tissue damage within non-eloquent
concentrations of antibodies to myelin oligodendrocyte zones of cerebral white matter, including the cerebral
glycoprotein in patients with MS and controls.39 periventricular zones, the centrum semiovale, and corona
radiata. By contrast, there are discrete neuroanatomically
Other afferent neuro-ophthalmological problems in MS eloquent sites where the pathological process in MS
In addition to the optic nerve, any part of the visual results in stereotyped and easily recognised syndromes
sensory pathway can be affected, including the chiasm, such as internuclear ophthalmoplegia.52
tracts, radiations, and striate cortex. Any type of field
defect may occur, depending on the location of the Assessment of the ocular motor system and disorders of
demyelinating lesion.40,41 Symptomatic homonymous fixation in MS
field defects are infrequent in MS, occurring in less than When done carefully, the bedside neuro-
1% of patients.41 Such defects are uncommon in MS ophthalmological examination can detect most
because of the large lesions required to produce them, abnormalities within both the visual sensory and ocular
their fleeting nature, and the tendency for inflammation motor systems of patients with MS (panels 1 and 2).
to be centred around venules and not fibre tracts. Correspondingly, MRI shows up most lesions
Symptomless or unrecognised homonymous field corresponding to the eye movement abnormalities
defects may occur more commonly than symptomatic recognised in MS. Proton density and T2-weighted
homonymous field defects in MS. In the Optic Neuritis sequences (with thin 3 mm cuts) have been seen to be
Treatment Trial, 13·2% of patients had evidence of a superior to FLAIR studies in detecting lesions.53,54
chiasmal or retrochiasmal field defect when serially
screened at nine visits over 1 year. Of those, 5·1% had Nystagmus
bitemporal defects while 8·9% showed homonymous The classification of nystagmus is perhaps best
field defects.42 Of note, 75·7% of patients who developed approached by considering the disorders of the gaze-
a retrochiasmal field defect had an abnormal baseline holding networks themselves in the brainstem and
MRI scan compared with 46% without such defects. cerebellum, and the inputs to them which can become
Ocular inflammation may occasionally be seen in imbalanced (for example, in the vestibular system).
patients with MS. Manifestations may include anterior The critical structures for gaze-holding—which act as a
uveitis, posterior uveitis, pars planitis, and periphlebitis. neural integrator—are located in the medulla for
Uveitis is ten times more common in patients with MS horizontal gaze (the medial vestibular nuclei and the
than in the general population.40,43 Anterior uveitis as a adjacent nucleus prepositus hypoglossi) and in the
complication in MS is typically granulomatous in midbrain for vertical gaze (the interstitial nucleus of
nature, and it may manifest before any other clinical Cajal).55,56 The superior vestibular nuclei probably also
evidence of MS.40 Because symptomatic anterior uveitis influence vertical gaze-holding through their connection,
is rare in MS, it is essential to exclude other via the medial longitudinal fasciculus (MLF), to the
inflammatory causes of anterior uveitis such as syphilis, interstitial nucleus of Cajal. The paramedian tracts of the
sarcoidosis, Lyme disease, tuberculosis, rheumatological midline pons also contain neurons that are important for
disorders, and Bechet’s disease. ocular motor integration. These brainstem integrators
Pars planitis is inflammation that occurs along the are connected to the cerebellar flocculus and
pars plana of the eye. Although it generally has no paraflocculus (tonsils), which in turn are the key

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cerebellar structures involved in the fine tuning of the

Panel 2: Components of the bedside ocular motor exam brainstem integrators for optimum function.
Pathological nystagmus on eccentric gaze, gaze-
Ocular alignment
evoked nystagmus, refers to a “jerk” nystagmus with a
Tropia?
slow drift in one direction and a resetting saccade in the
Crosscover for phorias
other. This commonly indicates failure of the neural
Hyper?
integrators. Not surprisingly, gaze-evoked nystagmus is
Skew deviation?
common in MS because of the high number of
Ptosis?
brainstem lesions.
Head tilt?
Pendular nystagmus (nystagmus in which there is a
Motility back and forth slow-phase oscillation) can also arise from
Ductions (monocular motility) disturbances in the neural integrators, usually involving
Versions (binocular motility) critical feedback pathways that interconnect brainstem
Diplopia? networks and the cerebellum.57,58 Pendular nystagmus is
Maddox rod/red glass testing? especially common in MS, and is also particularly
CN VI>III>IV distressing because it can severely disrupt vision
(primarily via retinal slip).58,59 Examples include elliptical
Intrusions
nystagmus and the ocular oscillations associated with
Visual and fundus inspection
palatal myoclonus (now called ocular palatal tremor).60
Square wave jerks
Pendular nystagmus may arise, in part, from increases in
Oscillations
conduction time on demyelinated fibres. Another
Flutter/opsoclonus
contributing factor to pendular nystagmus may be visual
Smooth pursuit loss.61 Pendular nystagmus can also arise from lesions in
Saccadic/cogwheeling the Guillian-Mollaret triangle (dentate nucleus, superior
High gain cerebellar peduncle, red nucleus, central tegmental tract,
Attention/concentration? inferior olive, inferior cerebellar peduncle) and may be
associated with palatal tremor (previously referred to as
Saccades
palatal myoclonus).60 An unusual form of horizontal
Latency
pendular nystagmus has been described in MS in which
Velocity
convergence evokes a conjugate pendular nystagmus.62
Accuracy
Several drugs, including gabapentin (with a GABA-like
Ipsipulsion/contrapulsion?
action) and memantine (with NMDA-blocking, AMPA-
Internuclear ophthalmoplegia?
receptor-modulating, and dopaminergic action) may
Dysconjugate nystagmus?
ameliorate the visually disabling pendular nystagmus
Gaze palsies
that is so commonly observed in MS.63–67 Recent studies
Nystagmus suggest that downbeat nystagmus can be decreased
Visual inspection using 3,4-diaminopyridine, or fampridine.63,64
Funduscopic exam (occult nystagmus?) Clonazepam is sometimes helpful for diminishing
Primary position nystagmus? downbeat nystagmus. Periodic alternating nystagmus
Gaze evoked nystagmus? can be treated effectively with baclofen. Occasionally
Monocular movements (eg, superior oblique myokymia) carbamazepine or acetazolamide suppresses some
Rebound nystagmus? paroxysmal forms of nystagmus.65
Periodic alternating nystagmus?
Upbeat or downbeat nystagmus? Saccadic intrusions
Pendular nystagmus? Disorders of pause-cell neurons, which are located in the
Positional nystagmus (as with BPPV)? pontine raphe between the abducens nuclei and
tonically inhibit saccadic premotor burst neurons in the
Vestibular
paramedian reticular formation of the pons and
Slow vestibulo-ocular reflex
midbrain, may produce impaired fixation due to
Head thrusts to assess vestibulo-ocular-reflex gain
extraneous saccades (table 2). The most common of
Vestibulo-ocular-reflex suppression
these are square-wave jerks, characterised by 1–5-degree
Head tilt (as with skew)
eye movements away and back from the neutral
Vestibular nystagmus (in primary position and increasing
position, and punctuated by an intrasaccadic latency.
amplitude with gaze in direction of fast phase)
Larger movements of 10–40 degrees in excursion are
Positional nystagmus (as with BPPV)
referred to as macrosquare-wave jerks. Large to-and-fro
BPPV=benign paroxysmal positioning vertigo eccentric movements across the midline represent
macrosaccadic oscillations.

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Disorder Characteristics Localisation Treatment

movements, however, are generally seen only on
ophthalmoscopy or on eye-movement recordings.66
Saccadic intrusions Square wave jerks Cerebellum Anticonvulsants
Macro square waves Brainstem Baclofen
Patients typically complain of shimmering, jiggling, or
Macro saccadic oscillations Pause cells? wavy vision. This disorder should be differentiated from
Ocular flutter superior oblique myokymia, which is strictly monocular
Opsoclonus
and characterised by a strong torsional component.66
Microsaccadic flutter
INO Adduction slowing MLF Steroids acutely Patients with MS will on occasion experience steady
Adduction limitation fixation interrupted by paroxysmal episodes of
Abduction nystagmus diplopia.67,68
Low vertical pursuit gain
Low vertical VOR gain
Vertical nystagmus (in some) Cerebellar regulation of eye movements
Skew deviation (in some) The dorsal vermis and the posterior fastigial nuclei are
Vertical saccades preserved key cerebellar structures concerned with the control of
Vergence preserved in most
saccadic accuracy by calibration of the size of the saccadic
WEBINO Wall-eyed and bilateral INO Rostral midbrain involving bilateral
Loss of convergence MLF and vergence pathways or CN III pulse. Saccadic dysmetria can occur after demyelinating
pathways to medial rectus muscles lesions within these structures and is characterised by
Saccadic dysmetria Overshoots and undershoots Cerebellum Steroids acutely hypermetric (if the deep nuclei are involved) or
Ipsipulsion Brainstem
hypometric (if the vermis alone is involved) saccades.
Contrapulsion
VOR suppression Can’t suppress VOR during Cerebellar flocculus None Macrosaccadic oscillations (large repetitive, back-and-
head/eye tracking forth saccades that cross the point of attempted fixation)
Saccadic long Slow initiation Anywhere in apparatus None are an extreme example of saccadic hypermetria.
latency
Saccadic slowing Reduced pulse (velocity) PPRF None
Demyelinating lesions within the cerebellar peduncles
CN palsies Complete or partial VI>III>IV Prisms can produce hypermetric saccades towards the side of a
Isolated lateral medullary lesion, involving the pathways through
In conjunction with other features Prisms the inferior cerebellar peduncle (ipsipulsion) or
Gaze palsies Decreased velocity and or PPRF Steroids acutely
(unilateral or amplitude of gaze to left, right, Abducens (VI) nucleus
hypermetric saccades away from a lesion localised to the
bilateral) or both VI + INO Hook Bundle region near the superior cerebellar
One-and-a-half Gaze palsy to one side PPRF and/or VI nucleus Steroids acutely peduncle.69,70
syndrome INO to the other and MLF on same side Floccular (and parafloccular—the tonsils in human
Paralytic pontine exotropia
Horizontal Absent or diminished adduction VI fascicle + MLF on same side. Steroids acutely
beings) lesions produce horizontal gaze-evoked
monocular failure and abduction nystagmus, primary-position downbeat nystagmus,
Pursuit Low gain or saccadic Pursuit circuitry None impaired (low gain) pursuit requiring corrective
Abnormalities High gain Attention/concentration saccades, rebound nystagmus (eg, a transient jerk
Skew deviation Vertical misalignment Anywhere in vestibular system that
Vertical diplopia can affect the linear otoliths
nystagmus that occurs on returning the eyes to straight
Often with INO (eg, utriculus) ahead after sustained attempted eccentric gaze-holding
Head tilt-away from hyper Hyper on side of pontine lesion in with the slow phase of rebound nystagmus is in the
Subjective vertical deviation most direction of prior attempted lateral gaze-holding), post-
Ocular counter-roll Hyper on side opposite of a
medullary lesion in most
saccadic drift (glissades), and a loss of vestibulo-ocular
Nystagmus Gaze evoked Cerebellum Gabapentin reflex cancellation. All of these are commonly seen in
Multidirectional Brainstem Memantine patients with MS.65
Upbeat and downbeat Vesitibular apparatus either central Baclofen
Vestibular or peripheral (as with BPPV) 3,4-diaminopyridine
Dysconjugate (with INO) Fampridine Internuclear ophthalmoplegia
Rebound (cerebellar) Prisms Internuclear ophthalmoplegia is characterised by slowing
Pendular types Botox or limitation of the adducting eye during horizontal
Occult (with ophthalmoscopy) Particle repositioning
saccades and is the result of damage to the MLF within
Periodic alternating manoeuvres for BPPV
the dorsomedial pontine or midbrain tegmentum,
INO=internuclear ophthalmoplegia; WEBINO=Wall-eyed and bilateral internuclear ophthalmoplegia; VOR=vestibulo-ocular adjacent to the fourth ventricle and cerebral aqueduct,
reflex; PPRF=paramedian reticular formation of the pons; CN=cranial nerve.
respectively (table 2). During horizontal saccades, the
Table 2: Ocular motor manifestations of MS burst cells in the paramedian reticular formation of the
pons innervate the abducens nucleus, which contains two
Ocular flutter is a saccadic intrusion characterised by distinctive sets of neurons. Axons from abducens motor
horizontal back-to-back saccades without an intersaccadic neurons innervate the ipsilateral lateral rectus muscle and
latency (by contrast with square-jerks in which there is an the axons of abducens interneurons cross the midline to
intersaccadic interval). Opsoclonus is similar but is become the MLF and subsequently innervate the medial
characterised by both horizontal and vertical back-to-back rectus subnucleus of the occulomotor complex (cranial
saccades. Finally, microsaccadic flutter is a binocular nerve nucleus III). Despite adduction weakness,
condition with similar back-to-back saccades. These convergence is generally intact, consistent with integrity

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Figure 3: Internuclear ophthalmoplegia (INO)

This patient exhibits the most typical type of INO, characterised by adduction slowing
without ocular limitation. Top: he gazes straight ahead (note the vertical midpupillary
marker line). Bottom: on attempted right gaze, the right abducting eye achieves the
target earlier than the left adducting eye (observe that the left pupil has not moved
off of the vertical marker). By the end of the saccade, both eyes achieved the fixation
target (not shown).

of the vergence pathways. If the lesion is sufficiently

rostral to involve the vergence circuitry or medial rectus
motor neurons themselves, then convergence is
compromised, potentially producing divergence of the
eyes and bilateral internuclear ophthalmoplegia (wall-
eyed, bilateral internuclear ophthalmoplegia).71
In the most subtle form of internuclear
ophthalmoplegia, the range of adduction is normal
whereas only the velocity is reduced (figure 3). We
assessed the accuracy of clinical detection of
internuclear ophthalmoplegia by 279 physicians.72 With
infrared oculography one can validate the presence of
internuclear ophthalmoplegia by specific criteria and Figure 4: Rostral tegmentum
quantitatively characterise the association between the Top: axial T2-weighted MRI shows a rostral pontine tegmentum lesion that
encompasses the region containing the MLF. Bottom: axial proton-density-weighted
severity of the syndrome and the accuracy of clinical MRI shows a rostral midbrain tegmentum plaque just ventral to the cerebral aqueduct.
detection.72–76 The detection rates were highly accurate Both of these patients were seen to exhibit bilateral INO.
across all physician groups when the degree of
adduction slowing was severe. Mild to moderate cases (either of which, or both, can be present in an individual
of internuclear ophthalmoplegia were not identified by patient) are an adaptive response to overcome the
most physicians. weakness of the contralateral medial rectus and a
Internuclear ophthalmoplegia is commonly associated dissociated gaze-evoked nystagmus.77
with a lesion within the MLF at the level of the dorsal
pons or midbrain (figure 4). In one study of 58 patients Abduction slowing in internuclear ophthalmoplegia
with MS and internuclear ophthalmoplegia, all had an Internuclear ophthalmoplegia can also be associated
abnormality within the region of the MLF on proton with slowing of abduction of the same eye.78,79 In the
density weighted imaging. 51 (88%) had MLF lesions on context of adduction weakness, a small degree of
T2-weighted imaging, and 28 (48%) had lesions on abduction slowing might be expected because of the loss
FLAIR imaging.54 of the contribution of the off-pulse of innervation when
the medial rectus is acting as an antagonist (ie, defective
Abduction nystagmus in internuclear ophthalmoplegia relaxation).80 The more prominent the ophthalmoplegia,
The discrepant movement of the two eyes in internuclear and the larger the lesion as seen on MRI, the more likely
ophthalmoplegia during saccades results in a break in there will be slowing of abduction in the same eye.81
binocular fusion that can lead to visual confusion,
transient oscillopsia, diplopia, reading fatigue, and loss of Vertical eye movements in internuclear ophthalmoplegia
stereopsis. There is also a horizontal dissociated The white-matter myelinated pathways involved in the
nystagmus that is most prominent in the abducting eye. regulation of vertical pursuit, vertical vestibular, and
The most likely mechanisms for abducting nystagmus otolithic mediated eye movements or vertical alignment

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 Review

are contained within the MLF. Many patients with suppression in the assessment of eye-movement
bilateral internuclear ophthalmoplegia consequently abnormalities has been supported by Sharpe and co-
show characteristic patterns of disorganised vertical eye workers88 who found impaired suppression in 15 of 20
movements such as diminished vertical-gaze holding, patients with MS. Abnormal vestibulo-ocular-reflex
inadequate vertical vestibulo-ocular reflex, and abnormal suppression typically parallels abnormalities in smooth
optokinetic and pursuit responses.82,83 Vertical and pursuit tracking.
torsional types of nystagmus can occur on the basis of
disruption of the semicircular canal pathways. Many Vertical saccadic abnormalities
patients with MS and internuclear ophthalmoplegia When demyelinating lesions occur in the dorsal
have a skew deviation, which is characterised by a midbrain, Parinaud’s syndrome may occur and is
supranuclear vertical misalignment and changes in characterised by diminished upward saccades,
ocular torsion of the two eyes. convergent retraction nystagmus on attempted upward
saccades (often best elicited when viewing a downward-
The one-and-a-half syndrome moving optokinetic-nystagmus tape), and near-light
A gaze palsy in one direction and internuclear dissociation.89 Other features can include skew deviation,
ophthalmoplegia on attempted gaze contralaterally is fixation instability (square-wave jerks), convergence
referred to as the one-and-a-half syndrome.84 This spasm or divergence paralysis, irregular pupils
syndrome is produced by a lesion that damages either (correctopia), pseudoabducens palsy (a slower moving
the paramedian reticular formation of the pons or abducting eye during horizontal saccades perhaps
abducens nucleus (or both) together with the MLF on related to convergence excess), downward gaze
the same side. An ipsilateral internuclear preference (setting sun sign), downbeat nystagmus, and
ophthalmoplegia and cranial-nerve-VI fascicle lesion can abnormalities of vertical smooth pursuit and the vertical
produce paralysis of both adduction and abduction in vestibul-ocular reflex. We recently reported a variant of
one eye (monocular horizontal gaze paralysis).85 the dorsal midbrain syndrome in MS that produced an
unusual convergent monocular retraction nystagmus in
Skew deviation and vestibular abnormalities one eye and a severe internuclear ophthalmoplegia in
Skew deviation is a supranuclear vertical ocular the contralateral eye (figure 5).89
misalignment with the higher eye most commonly on
the side of the lesion in midpontine and midbrain Nuclear and fascicular lesions
lesions, and the lower eye on the side of the lesion in Nuclear and fascicular cranial nerve syndromes have
medullary lesions. It can occur in isolation or in been described in MS. Sixth nerve paresis is the most
conjunction with internuclear ophthalmoplegia. In common.90–92 In one study, six of 49 people with isolated
addition to change in alignment, the higher eye is usually lateral rectus palsies had demyelination.93
intorted while the lower eye extorted, though not Involvement of the abducens nucleus produces a gaze
necessarily by the same amounts. Many patients have a palsy to the side of the lesion; involvement of the
head tilt away from the high eye and may also perceive a abducens nerve produces only an ipsilateral lateral
deviation of the subjective visual vertical. Taken together, rectus palsy. Bilateral horizontal gaze palsy secondary to
these features are referred to as the ocular tilt reaction. a midline pontine lesion has been reported in MS.94
On occasion, MS patients will present with positional Isolated oculomotor (cranial nerve III) palsies can
vertigo. The most common cause of vertigo (and its occur in MS and partial fascicular (upper and lower
corresponding nystagmus) in MS is benign paroxysmal division) and nuclear lesions have also been reported.95,96
positioning vertigo.86,87 Demyelinating plaques within the Trochlear nucleus and nerve lesions are rare.97 A unique
eighth cranial nerve entry zone at the pontomedullary ocular motor syndrome combines an internuclear
junction and in the medullary tegmentum can also ophthalmoplegia with a contralateral hyperdeviation
produce vertigo that can mimic an acute peripheral secondary to superior oblique weakness. Neuro-
vestibulopathy.86 anatomically, the lesion is localised to the caudal
midbrain involving the MLF and trochlear nucleus and
Abnormal suppression of the vestibulo-ocular reflex and may also be associated with Horner’s syndrome.98
impaired smooth pursuit Ptosis from a brainstem lesion can be unilateral or
Suppression of the vestibulo-ocular reflex is the ability bilateral. When caused by oculomotor dysfunction,
to cancel the reflex during combined smooth eye and fascicular lesions give rise to unilateral ptosis, whereas
head movements. When abnormal, the characteristic nuclear lesions produce bilateral ptosis owing to
feature is “catch up” saccades that are needed to involvement of the central caudal subnucleus of cranial
maintain fixation of the target moving with the head nerve III. This nucleus is unpaired and contains cells
because the reflex normally drives the eyes in a that project to both levator palpebre superioris muscles.
direction opposite from head movement. The An unusual eyelid abnormality—blepharoclonus—
diagnostic and localising value of vestibulo-ocular-reflex has been reported in MS and is characterised by

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 Review

RN

nMLF Ocn
MLF
INC
Aqu
PC
SupCol

Figure 5: Dorsal midbrain syndrome

Left: several features consistent with the dorsal midbrain syndrome are shown. In the primary position we observe a left hyperdeviation consistent with skew deviation in
addition to anisocoria (left > right). On attempted upgaze there is rapid convergence of the right eye and a corresponding mild divergence of the left eye (note the displacement
of the pupils away from the white marker). Attempted left gaze is relatively preserved. During attempted right gaze there is severe limitation of the left eye and slowing of the
abducting right eye was observed clinically (pseudoabducens palsy). Middle: a proton-density-weighted MRI reveals a large hyperintensity within the left rostral midbrain at the
level of the red nucleus. The lesion is extensive and involves the entire left tegmentum, the red nucleus, and a portion of the cerebral peduncle. There also appears to be some
extension of the lesion into the contralateral right-midbrain tegmentum. Right: the anatomic circuitry of the rostral midbrain ocular motor system superimposed on the MRI, at
the level of the patient’s lesion. This schematic shows several structures that were likely affected by the demyelinating plaque and contributed to the patient’s ocular motor
syndrome. Reproduced with permission from Hodder Arnold.89

paroxysms of forced eye closure that can be triggered by whereas the latter group may require reconstitution of
eccentric eye movements or spontaneously while axonal circuitry before myelin repair can be useful.
looking straight ahead.99 Ultimately, quantitative analysis of the MLF syndrome
with sophisticated imaging techniques may represent a
Future directions in eye-movement research in MS useful proof of principle model of CNS damage from
The ability to quantitatively characterise the association which to launch therapeutic initiatives that focus on the
between the degree of disability of a specific MS-related repair of MS-related tissue damage. In a similar fashion,
clinical syndrome to neuroradiological measures of the development of sophisticated optic nerve assessment
brain-tissue injury would provide an opportunity to link techniques, such as optical coherence tomography and
MS-related pathophysiology with radiographic measures Heidelberg retinal tomography, provide quantitative
of disruption in tissue architecture. Internuclear methods with the capability of longitudinally measuring
ophthalmoplegia and optic neuritis represent two such changes within the optic nerve and the retinal nerve-fibre
syndromes that can now be objectively characterised with layer. These very exciting techniques may also be able to
precise neurophysiological methods. In internuclear detect responses to both neuroprotective as well as
ophthalmoplegia, the small size of the MLF within the restoration treatment strategies for the optic nerve.
brainstem makes definition of the neuroradiological Authors’ contributions
abnormalities of this white-matter tract system difficult. EMF organised the framework of the manuscript and contributed to the
To overcome this challenge, we have constructed sections on ocular motor syndromes in MS. TCF contributed to the
section on internuclear ophthalmoplegia. DSZ contributed to the
computer graphic vector images derived from myelin sections on mechanisms of eye movement control and nystagmus. SG
stained brainstem atlas sections in the axial plane. contributed the section on optic neuritis and uveitis. RM contributed to
Computer vector imaging allowed us to superimpose the section on future directions. All authors have made editorial
and co-register these graphic images onto conventional, changes to the manuscript and have approved the final version.
diffusion tensor, and magnetisation transfer images for
further analysis. As an example, the application of this
technique may enable differentiation of patients with MS Search strategy and selection criteria
and internuclear ophthalmoplegia characterised Data used in the development of this review was derived
principally by slow eye-movement velocity (presumably from searches in MEDLINE, PubMed (without restriction to
with axons preserved) and those with MS and the year of publication), and through the authors’ extensive
ophthalmoplegia characterised by both slowing and files. The search terms were “Multiple sclerosis” combined
limitation of ocular movements (presumably with axons with: “Optic neuritis”, “uveitis”, “nystagmus”, and “eye
involved). Myelin restoration strategies may be applicable movements”. The search was completed in June, 2004.
to the former group given the preservation of axons,

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 Review

Conflicts of interest magnetization transfer ratio histogram analysis. Am J Neuroradiol

EMF has received speaker honoraria from BiogenIdec and TEVA 2003; 24: 1935–40.
Neuroscience and SG has received speaker honoraria from BiogenIdec. TCF, 23 McDonald WI, Compston A, Edan G, et al. Recommended
DSZ, and RM have no conflicts. diagnostic criteria for multiple sclerosis: guidelines from the
International Panel on the diagnosis of multiple sclerosis.
Role of the funding source Ann Neurol 2001; 50: 121–27.
This work was supported by the National Multiple Sclerosis Society. No 24 Frohman EM, Goodin D, Calabresi P, et al. The utility of MRI in
funding source had a role in the preparation of this paper or the decision to suspected MS. The Therapeutics and Technology Assessment
submit it for publication. Committee of the American Academy of Neurology. Neurology
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