The Neuro-ophthalmology of Multiple Sclerosis

Ryan D Walsh; Collin M McClelland; Steven L Galetta


Future Neurology. 2012;7(6):679-700. 

In This Article

Efferent Sequelae

Eye movement abnormalities are common in MS, occurring in 40–76% of patients.[6–8] Most eye movement abnormalities associated with MS are due to brainstem or cerebellar lesions and result in symptoms of visual fatigue, blurred vision, diplopia and oscillopsia.[98] MS patients with eye movement abnormalities are more disabled than those with normal movements and are also more likely to have posterior fossa lesions present on MRI.[8,99] Patients with CIS and infratentorial lesions on MRI have been found to have a higher risk of conversion to MS and of developing disability.[100] The predominant abnormalities of efferent ocular function encountered in MS include internuclear ophthalmoplegia (INO), saccadic abnormalities, nystagmus, abnormalities of the vestibulo-ocular reflex (VOR) and smooth pursuit abnormalities.

Internuclear Ophthalmoplegia

INO is a horizontal gaze abnormality characterized by impaired adduction of the involved eye, often associated with nystagmus of the contralateral abducting eye (Figure 2).[101] Adduction with convergence may or may not be preserved, but typically is;[102] of 34 patients with INO in one series, convergence was maintained in all but two cases.[6] INO results from damage to interneurons within the medial longitudinal fasciculus (MLF) coursing from the cranial nerve (CN) VI nucleus in the dorsomedial pons to the contralateral medial rectus subnucleus of CN III in the upper midbrain.[103,104] The MLF lesion occurs ipsilaterally to the side of ocular adduction impairment.[102] The dissociated nystagmus of the abducting eye is most likely the result of an adaptive mechanism attempting to overcome the adduction weakness of the opposite eye.[105] The lateral rectus muscle and the medial rectus muscle of the opposite eye are a yoke pair; thus, in accordance with Herring's law of equal innervation, any attempt to increase the innervations to a weak muscle (i.e., the medial rectus) in one eye must be accompanied by a commensurate increase in innervations to the yoke muscle (i.e., the lateral rectus) in the other eye.[105] This produces an exaggerated abduction saccade followed by a postsaccadic backward drift characteristic of abduction nystagmus.[105]

Figure 2.

Bilateral internuclear ophthalmoplegia in a patient with multiple sclerosis.
(A) In primary gaze, the patient has an exotropia. (B) On attempted gaze to the right, adduction of the left eye is decreased consistent with a left internuclear ophthalmoplegia; there was an associated abducting nystagmus of the right eye. (C) On attempted gaze to the left, adduction of the right eye is decreased consistent with a right internuclear ophthalmoplegia; there was an associated abducting nystagmus of the left eye.

INO is detectable clinically in 15–38% of patients with MS.[6,106,107] MS is a common cause of INO, second only to infarction, accounting for 34% of cases in one large series.[108] While infarction typically results in unilateral INO, MS often causes bilateral INO.[6,108,109] If the lesion is sufficiently rostral within the brainstem and involves the convergence pathways or the medial rectus subnuclei, then convergence will be compromised and the eyes may appear divergent in primary gaze producing the so-called 'wall-eyed' bilateral INO.[104] It should be noted that MS is not an exclusive cause of wall-eyed bilateral INO, which can occasionally be seen in other conditions including stroke,[110] NMO[111] and neurodegenerative conditions such as progressive supranuclear palsy.[110] In most cases of INO, the eyes are orthotropic in primary position although there may be a mild exophoria detectable on alternate cover testing.[112] Patients may be asymptomatic or may have transient blurred vision or diplopia with head turning or gaze-direction changes, which result from dysconjugate saccades and breaks in binocular fusion.[112,113]

The presence of an INO may be obvious in cases with a clear adduction limitation; however, most often INO is subtle with either a normal or slightly limited adduction amplitude.[6] The most sensitive sign is disjunction of horizontal saccades, characterized as a slight lag in adduction speed, which in some cases may be the only demonstrable sign of INO.[6,8,114] One study showed that mild cases of INO are not detected on exam by the majority (71%) of physicians.[115] Electro-oculographic techniques may be used to detect subtle cases of INO.[106,107,115–117]

Most patients (61.9%) with INO secondary to a demyelinating lesion will have complete recovery, in contrast to INO from vascular or neoplastic causes which often persist.[109] Unlike in cases of INO caused by stroke or tumor, in which a lesion affecting the MLF is typically demonstrable on MRI, a compatible lesion is not always evident on MRI in patients with MS (only 57.1% in one study).[109] Evidence suggests that proton density imaging is more sensitive than T2-weighted or FLAIR sequences for detecting lesions of the MLF on MRI.[118]

'One-&-a-Half' Syndrome

A lesion affecting the paramedian pontine reticular formation (PPRF) and/or the CN VI nucleus in the pons and the ipsilateral MLF produces the 'one-and-a-half syndrome'.[104] The syndrome is characterized by a conjugate horizontal gaze palsy in the direction of the lesion (as a result of damage to the PPRF or CN VI nucleus) and an INO of the eye ipsilateral to the lesion (as a result of damage to the MLF).[104,119,120] Thus, the ipsilateral eye will neither abduct nor adduct appropriately, and the contralateral eye will not adduct appropriately. The syndrome may occasionally be seen in MS patients.[120,121] In a study of patients with INO from various causes, two out of 21 cases (9.5%) caused by MS followed a one-and-a-half syndrome pattern.[109] A lesion affecting the MLF and ipsilateral CN VI fascicle within the pontine tegmentum may cause a monocular horizontal gaze paralysis (i.e., defective adduction and abduction of the eye ipsilateral to the lesion).[122]

Saccadic Abnormalities

Saccadic abnormalities occur commonly in MS including saccadic intrusions, saccadic dysmetria, increased latency and decreased velocity.[106,123,124] Burst neurons, located in the PPRF in the pons for horizontal saccades and in the rostral interstitial nucleus of the MLF in the midbrain for vertical saccades, are important in the generation of saccadic eye movements.[16] Pause-cell neurons, located in the paramedian pontine region, tonically inhibit burst neurons; thus, dysfunction of pause-cell neurons may result in inappropriate firing of burst neurons and unwanted saccades.[104] These 'saccadic intrusions' may cause visual dysfunction through retinal slip, a shift of an object of fixation of the macular fovea.[112] Square wave jerks (<5 degrees) and larger amplitude macro-square wave jerks are conjugate horizontal saccadic intrusions that interrupt fixation.[16] The presence of an intersaccadic interval (approximately 200 ms) differentiates square wave jerks from ocular flutter, which is characterized by intrusive back-to-back horizontal saccades without an intersaccadic interval.[16,125] Opsoclonus is characterized by random conjugate multidirectional saccades, which, like ocular flutter, lack an intersaccadic interval.[112] Ocular flutter[126] and opsoclonus[121] have been reported in patients with MS; however, they are more commonly due to a postinfectious syndrome, medication/drug effect, paraneoplastic syndrome (particularly in association with neuroblastoma in children) or encephalitis.[16]

Saccadic dysmetria occurs when the eyes undershoot (hypometria) or overshoot (hypermetria) the target of fixation and is a sign of cerebellar dysfunction. The dorsal vermis and the caudal fastigial oculomotor region to which it projects, play an important role in making saccades accurate.[127] Saccadic dysmetria, particularly saccadic hypermetria, occurs frequently in MS affecting approximately 32–40% of all MS patients.[8,98] Contrapulsion is a unique type of saccadic dysmetria caused by a lesion of the uncinate fasciculus within the superior cerebellar peduncle and has been reported in patients with MS; it is characterized by the triad of hypermetric saccades in the direction contralateral to the lesion; hypometric saccades towards the side of the lesion; and oblique saccades directed away from the side of the lesion with attempted vertical saccades.[128] Ipsipulsion, in which hypermetric saccades are directed toward the side of the lesion, is most commonly observed with lateral medullary lesions.


Nystagmus is common in MS, occurring in approximately 30% of patients.[8] In general, failure of visual fixation, imbalance of the vestibular system or impairment of gaze-holding mechanisms are the most common causes of nystagmus.[16] Mechanisms for visual fixation suppress unwanted saccades and maintain the eye fixed on the visual target.[129] The vestibular system, through the VOR, generates eye movements to stabilize gaze during head movements.[129] Gaze-holding mechanisms convert eye velocity signals to position-holding signals necessary for counteracting the orbital viscoelastic forces that pull the eyes back toward primary position.[16]

The neural integrator is the network of cells responsible for maintaining the eyes in eccentric gaze.[104] The medial vestibular nucleus, nucleus prepositus hypoglossi and cerebellar flocculus serve as the neural integrator for horizontal gaze.[16] The interstitial nucleus of Cajal and paramedian tracts serve as the neural integrator for vertical eye movements.[16] Demyelinating lesions in the brainstem or cerebellum can affect key structures involved in eccentric gaze-holding. This may result in pathologic gaze-evoked nystagmus, a jerk nystagmus that occurs on eccentric gaze, characterized by a slow drift of the eyes away from the direction of fixation and a corrective saccade back in the direction of eccentric gaze; this usually indicates a lesion of the neural integrators.[104] This type of nystagmus is common in MS occurring in 26% of patients in one study.[8]

Pendular nystagmus is also commonly seen in MS and can be quite visually disabling.[8,16,98] It is characterized by a back and forth slow phase without a fast corrective saccade or 'jerk' phase.[16] In a study of MS patients with visual complaints, five out of 24 (21%) were found to have pendular nystagmus.[98] This type of nystagmus likely occurs as a result of injury to critical feedback circuits within the brainstem and cerebellum controlling the neural integrators.[130,131] The pons (medial vestibular nuclei and central tegmental tract) is the most frequently involved region on MRI; lesions in the medulla (reticular formation, dorsal accessory olivary nucleus, central tegmental tract, inferior olivary nucleus and olivo-cerebellar fibres) and midbrain (lateral aspect of the red nucleus) may also result in pendular nystagmus.[132] Optic neuropathy may also play a role in the development of pendular nystagmus; in a study of 37 MS patients with pendular nystagmus, all had signs of cerebellar dysfunction and optic neuropathy, and in cases where the nystagmus was dissociated (i.e., asymmetric between the two eyes), the nystagmus was more prominent on the side of worse optic neuropathy.[133]

Several medications, particularly memantine and gabapentin, appear to be effective in treating pendular nystagmus associated with MS.[129,134,135] A masked, crossover, therapeutic trial of ten patients with acquired nystagmus compared gabapentin 1200 mg/day with memantine 40 mg/day and demonstrated decreased median eye speed (gabapentin by 32.8% and memantine by 27.8%; p < 0.001) and improved visual acuity (p < 0.05) for both medications.[135] This was a somewhat heterogeneous group with six patients having pendular nystagmus and only three patients having MS. Both drugs were reportedly well-tolerated with gabapentin most likely to cause unsteadiness and memantine most likely to cause lethargy and drowsiness. No exacerbation of symptoms was reported in MS patients treated with memantine and eight out of ten patients chose to continue taking their preferred drug following the trial, though some preferred a reduced dose to minimize side effects. Another study, a prospective examiner-blind cross-over study comparing the efficacy of memantine (40 or 60 mg/day) and gabapentin (1200 mg/day) for the treatment of acquired pendular nystagmus in 11 patients with MS reported an at least 50% reduction in the amplitude and frequency of nystagmus in 17 out of 20 eyes with memantine and in 11 out of 16 eyes with gabapentin.[134] Complete cessation of nystagmus was reported in 12 eyes with memantine (eight eyes at a dose of 40 mg/day and four additional eyes at 60 mg/day) and five eyes with gabapentin. Side effects were reported by two out of 11 patients treated with memantine 40 mg/day (heavy arms, fatigue, nausea, dizziness), four out of five patients treated with memantine 60 mg/day (dizziness, restlessness, slurred speech, fatigue, increased spasticity) and eight out of ten patients treated with gabapentin (muscular weakness, increase of ataxia, fatigue, increased spasticity, dizziness, restlessness) with one patient not completing the protocol due to side effects (muscle weakness with a dose of gabapentin 200 mg). Although the medications were reported to be generally well-tolerated and associated side effects mild, the frequency of the reported side effects seems quite high, especially considering the short duration of treatment (1 week of each medication with an interval 5-day washout period). Indeed, beyond demonstrating efficacy, for a pharmacologic agent to be broadly useful in the symptomatic treatment of nystagmus, tolerability is of paramount importance. This is of particular concern in the setting of MS where patients often have other neurologic deficits (whether overt or subclinical) at baseline that may be susceptible to marked worsening as an unintended result of systemic medications given to provide symptomatic benefit. For example, a pilot trial evaluating the use of memantine (30 mg/day) in the setting of cognitive impairment in MS was halted early due to reported worsening neurologic symptoms in patients.[136] Although 19 patients had been included, nine patients in the memantine treatment group reported worsening neurologic symptoms causing deterioration in their quality of life (only two patients in the placebo group reported such symptoms and in both cases these were felt to be related to changes in disease-modifying therapy); common symptoms included blurred vision, fatigue, headache, worsening weakness and gait dysfunction. These symptoms only occurred at the maximum dose studied of 30 mg/day and resolved several days after stopping the medication. Thus, an analysis of a particular symptomatic agent's efficacy must be tempered by an evaluation of that agent's tolerability with respect to the patient's general MS symptomatology. Although specific agents (such as memantine and gabapentin) may be quite useful in individual cases of pendular nystagmus in MS, the potential adverse systemic effects of currently available agents limit routine use. In the future, efforts aimed at developing symptomatic agents for nystagmus with even fewer systemic side effects will be needed.

A variety of other types of nystagmus and nystagmoid eye movements have been reported in patients with MS including see-saw nystagmus,[137] head-shaking nystagmus,[138] periodic alternating nystagmus,[139] convergence-evoked pendular nystagmus,[140] monocular gaze-evoked pendular nystagmus,[141] central vestibular nystagmus,[98] upbeat nystagmus[142] and downbeat nystagmus.[7]

CN III, IV & VI Palsies

Isolated CN palsies are rare signs of MS.[143] Lesions within the brainstem may cause injury to the CN III, CN IV or CN VI nuclei or fascicles resulting in oculomotor, trochlear or abducens nerve palsies respectively. CN VI palsies occur more commonly in MS than CN III or IV palsies.

CN III Palsy

The most frequent causes of CN III palsy include stroke, trauma, tumor, diabetes, arterial aneurysm, surgery and infection.[144] Although MS is a frequent cause of INO (see above), it is an infrequent cause of CN III palsy. Several landmark studies evaluating the etiologies of CN III, IV and VI palsies found very low rates of CN III palsies attributable to MS; however, these studies antedated both the use of computed tomography[145,146] and widespread use of MRI[147,148] and approximately one-fifth of cases of CN III palsy were attributed to unknown causes. In another large study performed prior to the use of MRI, only three out of 172 (1.74%) cases of CN III palsy were attributed to MS.[149] Despite the improved diagnostic accuracy of MRI, MS remains an infrequent cause of CN III palsy. In a more recently published study of 1400 patients with CN III palsy (which included MRI examination on many of the patients), only 1 case (0.07%) was attributed to MS.[144] In a study that included 483 patients with demyelinating disease (120 with CIS and 363 with MS), only two patients (0.4%) were found to have CN III palsy.[150] An isolated CN III palsy as the presenting sign of MS is very unusual.[151–153] Painful pupil-involving[154] and pupil-sparing[152] CN III palsies have been reported in association with MS. Other unusual patterns, such as bilateral pupil-sparing CN III palsy,[121] unilateral partial CN III palsy with bilateral INO[155] and an inferior rectus palsy associated with a nuclear CN III lesion[153] have been documented in patients with MS.

CN IV Palsy

Trauma is the most common cause of CN IV palsies.[156] Similar to CN III palsies, CN IV palsies are rarely caused by MS. In one series, 0 of 172 CN IV palsies were attributed to MS.[147] In a study of 438 patients with CIS and MS, 50 patients had CN abnormalities, but none had CN IV involvement.[150] In another series of 1489 MS patients, an isolated CN IV palsy was diagnosed in just one patient.[143] Jacobson et al. reported five patients with MS and isolated CN IV palsy; in two, the CN IV palsy was the presenting feature.[157] The authors postulate that isolated CN IV palsy occurs so rarely in MS because the short course of the CN IV fascicles exposes these fibers to little myelin (thereby reducing the likelihood of their being affected by a demyelinating process) and isolated CN IV palsies can be difficult to detect on clinical exam without specialized techniques and equipment.[157]

CN VI Palsy

Major causes of CN VI palsy in adults include microvascular disease, neoplasms and trauma.[147] MS is a more common cause of CN VI palsies than of CN III or IV palsies. Of 419 patients with CN VI palsy in one series, 18 (4.3%) were attributed to MS.[147] A population-based series identified 137 cases of CN VI palsy over a 15-year period, 7% of which were attributed to MS.[158]

The proportion of CN VI palsies attributable to MS is higher in younger adults. A pre-MRI era series of 49 young adults (aged 15–50 years) with isolated acquired CN VI palsy found that six cases (12%) were caused by MS; moreover, the CN VI palsy was the presenting sign of MS in all 6 patients.[159] In a more recent study of young adults aged 15–50 years, MS accounted for 11 out of 45 cases (24%) of nontraumatic CN VI palsy.[160] In eight out of the 11 patients, the CN VI palsy was reported to be the only presenting sign of MS.[160] The routine use of MRI in this study may have accounted for the higher rate of CN VI palsies attributed to MS than in prior series.

Although MS is not a rare cause of CN VI palsy, isolated CN VI palsy remains a rare presentation of MS.[150,161–163] In one series, five out of 483 patients (1%) with CIS or MS were found to have an isolated CN VI palsy at presentation or as a sign of exacerbation.[150] Another study of 600 patients with MS identified just 3 (0.5%) with isolated CN VI palsy.[161]

In children, neoplasms and trauma are the predominant etiologies of CN VI palsy, and MS appears to be an unusual cause.[164–167] In a series of 75 pediatric patients with sixth nerve palsy, only one case (1.3%) was caused by MS.[167] In another series of patients younger than 14 years of age, 0 of 15 cases of CN VI palsy were attributed to MS.[168]

Other Efferent Sequelae

A variety of other eye movement abnormalities may occur in patients with MS. For instance, MS patients often have smooth pursuit abnormalities. One study demonstrated abnormal smooth pursuit eye movements on clinical exam in 15 of 60 MS patients (25%); with electro-oculographic techniques, 76.7% of patients were noted to have abnormal smooth pursuit as characterized by decreased gain (i.e., the ratio of eye velocity to target velocity).[169] Meienberg et al. found abnormal smooth pursuits in 25 out of 31 (80%) patients with definite MS and ten out of 17 (58%) patients with probable MS.[106] Despite the frequency of smooth pursuit abnormalities seen in MS, there is marked interindividual and intraindividual variability in MS patients and in healthy subjects (likely due to factors such as cooperation level and fatigue) often preventing reliable distinction of physiologic variation from pathology.[106]

Damage to the MLF resulting in INO (see above) may be accompanied by various other eye movement abnormalities. Fibers arising from the medial vestibular nucleus, with additional contributions mainly from the superior vestibular nucleus, ascend in the MLF to connect the vestibular nuclei to the oculomotor, trochlear and abducens nuclei.[103] As such, the MLF is an important brainstem conduit, serving as the final common pathway for the coordination of conjugate eye movements including saccades, smooth pursuit, VOR and semicircular and otolith-mediated reflex eye movements.[170] Efferent abnormalities that may accompany INO include vertical gaze abnormalities such as diminished vertical gaze-holding, abnormal optokinetic and pursuit responses, impaired VOR, vertical gaze-evoked nystagmus, convergent-retraction nystagmus, impaired vertical smooth pursuit and skew deviation.[92,170]

Skew deviation is a vertical misalignment of the eyes caused by damage to supranuclear vestibular input to ocular motor nuclei.[171] It may occur with or without INO, depending on where the damage occurs to the vestibular supranuclear inputs.[171] Skew deviation is often accompanied by a head tilt and bilateral ocular torsion in the direction of the lower eye; these features, in conjunction with a skew deviation, constitute the ocular tilt reaction.[104] When skew deviation occurs with INO, the hypertropic eye is typically on the same side as the INO.[92]

Abnormalities of the VOR are common in MS, seen in 16–22% of MS patients.[7,8,99] The VOR functions to maintain foveation on an object during head movements. The integrity of the VOR can be assessed at the bedside using short, rapid head thrusts while the patient fixates on a stationary target;[172] if there is an abnormality of the VOR, fixation will not be maintained through the movement and a compensatory saccade (in the direction opposite to the head movement) will be required to recapture fixation. Oscillopsia without nystagmus has been reported in the setting of impaired VOR and head tremor due to MS.[173,174]

Dysfunction of normal suppression of the VOR (SVOR) is also common in MS, seen in up to 83% of patients.[106] The ability to suppress the VOR is necessary for combined smooth eye and head movements.[104] When there is a deficit in the SVOR, a series of 'catch-up' saccades will characteristically be required to maintain fixation on the object moving with the head.[104] Deficient SVOR is typically a sign of cerebellar (particularly floccular) pathway dysfunction and often occurs concomitantly with smooth pursuit abnormalities.[16,104]

Other unusual efferent eye abnormalities in MS include dorsal midbrain syndrome (Parinaud syndrome),[175–177] Horner syndrome,[121] and alternating Horner syndrome.[178]