Eye movement disorders and update of disease-modifying therapies

Multiple sclerosis: review of eye movement disorders and update of disease-modifying therapies

Lilyana Amezcua, Mark J. Morrow and Guy V. Jirawuthiworavong

Current Opinion in Ophthalmology

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Purpose of review

To review important eye movement disorders in multiple sclerosis (MS) and update the ophthalmologist on disease-modifying therapies in MS, from the perspective of expert neurologists.

 

Recent findings

A large study confirmed that eye movement abnormalities in MS can be commonly identified by bedside examination. Identifying such ocular motility disturbances can assist in the diagnosis and prognosis for patients with MS. Articles published on such agents as oral teriflunomide and the biologics, natalizumab and alemtuzumab, have defined emerging roles of these treatments in the management of MS.

Summary

Many patients with MS suffer from isolated or a combination of eye movement disorders. Understanding their ocular motility disturbance patterns can help diagnose MS and correlate with the progression of MS. Exciting advances in MS disease-modifying treatments have been developed. Patients have more options than ever before of injectable, infusion and oral therapies. The therapeutic efficacy in lowering relapse rates is counterbalanced by these drugs’ side-effects.

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INTRODUCTION

Since the last two reviews in Current Opinion in Ophthalmology in 2009 and 2012, there has been continuous advancement in research and the understanding of multiple sclerosis (MS) and its protean manifestations. Eye movement disorders are common to patients with MS. New disease-modifying treatments have been discovered and have helped many patients minimize their morbidity. However, many of these medications have undesirable sideeffects that patients often want to avoid. In the history of MS reviews in this journal, it has literally been a ‘Who’s Who’ in the world of neuro-ophthalmology, ophthalmology and neurology. This review gathers expert neurologists specializing in eye movements and therapies for MS. The goal is to provide ophthalmologists a brief, updated reference source for the understanding of some common eye movement disorders in MS and the latest management of this demyelinating condition.

Eye movements in multiple sclerosis

Many patients with MS suffer the effects of disordered eye movement at some point in their illness [1–3]. Their most common symptoms are oscillopsia from nystagmus and diplopia from ocular misalignment. As with any MS symptom, complaints may appear for days or weeks during a relapse, or for minutes to hours with increases in body temperature. Symptoms may also persist continuously after a relapse or in progressive disease. MS can cause virtually any pattern of abnormal motility that can arise from focal brain lesions, although some patterns like internuclear ophthalmoplegia (INO) are more common by virtue of the typical locations of demyelinating plaques. Many patients manifest combinations of two or more patterns of dysfunction. Careful bedside or laboratory examination of eye movements may tease out subtle evidence pointing to the diagnosis [4,5&&,6]. In turn, eye movement abnormalities correlate with the progression of MS [7].

 

Internuclear ophthalmoplegia

The syndrome of INO follows from the disruption of signal transmission through the medial longitudinal fasciculus (MLF), affecting interneurons that send horizontal gaze signals from the abducens (sixth) nucleus in the caudal pons to the contralateral medial rectus subnucleus of the oculomotor (third) nuclear complex (Fig. 1). These interneurons cross the midline almost immediately after leaving the abducens nucleus, so that unilateral dorsal pontine lesions impair adduction in the ipsilateral eye. As signals to the MLFs on each side cross in the midline, small MS lesions often cause bilateral INO, with impaired adduction in both eyes. With complete INO, the eye on the affected side cannot adduct past the midline, and exotropia is present on contralateral gaze. In mild cases, adduction range may be full, and the most obvious sign is slowing of adducting saccades. Regardless of the degree of adduction defect, INO is usually characterized by a few beats of nystagmus in the abducting eye immediately after contralateral saccades. This is an adaptive saccadic phenomenon and changes with persistent monocular viewing. INO does not usually cause primary position diplopia; even when it is bilateral, convergence movements are typically spared. The exception is ‘wall-eyed bilateral INO’ syndrome, in which complete or near-complete bilateral INO is associated with primary position exotropia. As vertical gaze signals also travel in the MLF, patients with bilateral INO often demonstrate upward or downward gaze-evoked nystagmus and impaired vertical vestibulo-ocular reflexes (VOR). 

Other patterns of ocular misalignment

Nonparetic vertical ocular misalignment (skew deviation) is another common sequela of brainstem MS plaques. Skew is usually, but not always, associated with other central findings such as INO and nystagmus. It arises from imbalance in otolith ocular pathways that may produce a full-blown ocular tilt phenomenon with static binocular roll around the visual axis (conjugate torsional rotation) and skew deviation with the intorted eye higher. With midbrain lesions, the eye on the side of the lesion is generally hypertropic. The opposite is true with medullary lesions, and either eye may be higher with lateralized pontine damage.

 

Occasionally, an MS plaque may interrupt the intra-axial (brainstem) portion of the third, fourth or sixth cranial nerves, producing a characteristic deficit [8]. These central cranial neuropathies are usually associated with other findings (e.g. contralateral hemiparesis and ipsilateral third nerve palsy in midbrain Weber syndrome), but they may rarely present in isolation. Patients with midbrain lesions may also demonstrate defective convergence or divergence, producing exotropia at near or esotropia at distance. 

 

Gaze paresis

Conjugate gaze paresis results from damage to pathways that drive both eyes in the same direction. It may be horizontal or vertical according to plaque location. Pontine lesions that affect the paramedian pontine reticular formation (PPRF) or abducens nucleus prevent the eyes from turning normally to the side of the lesion. The PPRF is the origin of ipsiversive horizontal saccadic burst signals; damage to this structure may cause an isolated deficit of saccades, which spares smooth pursuit and VOR. In contrast, the abducens nucleus serves as the final common pathway for all ipsilateral conjugate gaze signals. It is the origin of all fibers to the ipsilateral lateral rectus muscle and of interneurons that transmit gaze signals to the contralateral medial rectus muscle through the MLF. Lesions here will affect saccades, pursuit and VOR.

 

Conjugate upward or downward gaze paresis results from midbrain lesions that affect the rostral interstitial nucleus of the MLF, the site of vertical saccadic burst neurons or the interstitial nucleus of Cajal, which is a way station for vestibular and smooth pursuit signals. As with horizontal gaze paresis, vertical eye movement dysfunction may be complete, with failure of all movements above or below fixation, or it may be partial, with conjugate saccadic slowing as its only manifestation. In cases of pure horizontal or vertical gaze dysfunction, the eyes remain aligned, and there is no diplopia. However, these deficits are often combined with INO, skew deviation or intra-axial cranial neuropathy. The best-known example of such a combined deficit is the ‘one and a half syndrome’ in which a unilateral pontine lesion affects either the abducens nucleus or PPRF and the MLF on the same side. In such cases, the patient cannot gaze to the side of the lesion or adduct the ipsilateral eye normally. The only intact horizontal movement is abduction of the contralateral eye, but vertical movements are usually normal.

 

Nystagmus

MS has been associated with virtually every form of jerk nystagmus, including isolated left- or rightbeating, torsional, upbeating and downbeating (DBN) patterns, as well as oblique nystagmus that beats in two or three planes [9]. MS also frequently causes acquired pendular (APN) nystagmus in which the eyes move to and fro in a quasisinusoidal fashion with no fast phases. As with jerk nystagmus, MS-associated pendular nystagmus may be the same in both eyes, greater in one eye, or purely unilateral. It may also be disjunctive, with oppositely directed movements, as in seesaw nystagmus. The localization of jerk nystagmus in MS is similar to other types of focal brain lesions such as stroke and neoplasm. Most causative plaques affect medullary, pontine or midbrain regions that transmit vestibular or smooth pursuit signals. In contrast, pendular nystagmus seldom localizes to a single lesion and is more often seen with multifocal or diffuse dysfunction of brainstem and cerebellar eye movement circuits. Visual loss may contribute to pendular nystagmus by reducing inputs needed for steady fixation. Conversely, any form of nystagmus can degrade vision by inducing slippage of visual images across the retina. Visual acuity loss is proportional to the velocity of retinal image motion, which also causes the often-distressing symptom of oscillopsia.

 

Of the types of nystagmus associated with MS, DBN and APN are the most amenable to pharmacological therapy. DBN often responds to 4-aminopyridine, a potassium channel inhibitor, at similar doses to those used for MS-associated gait disturbance. APN can respond well to memantine in similar doses to those used for dementia [10]. Other drugs shown to have occasional benefit in central nystagmus include gabapentin, baclofen and clonazepam. Therapeutic goals include the improvement of visual acuity and the reduction of subjective oscillopsia and nausea.

 

Impaired smooth pursuit

Finally, we should mention the most common (albeit usually asymptomatic) eye movement finding in MS: smooth pursuit impairment. The smooth pursuit system is needed to follow slowly moving objects and to augment or suppress the VOR when the head is moving, depending on visual demands. Driving an automobile invokes all of these functions. As the pursuit system employs a large neural network for visual motion processing in the cerebrum and for precise motor control in the brainstem and cerebellum, it is impaired in a broad range of neurological disorders. Depending on the site(s) of lesions, pursuit may be impaired in one or more directions.

 

MANAGEMENT OF OPTIC NEURITIS AND MULTIPLE SCLEROSIS

Acute treatment

The common approach to the treatment of acute optic neuritis derives from the results of the Optic Neuritis Treatment Trial, which was a multicenter randomized trial to placebo, oral prednisone and high dose intravenous (i.v.) methylprednisolone [11]. The group treated with i.v. methylprednisolone recovered visual function faster compared with those treated with oral or no treatment at all. Age and baseline visual acuity were significantly associated with visual outcomes at 6 months [12]. However, at 1 year, there was no significant difference between treated and untreated patients in any functional outcomes. Interestingly, the administration of moderate-dose oral prednisone (60 mg/d) to patients with acute optic neuritis increased the risk of recurrence by two-fold. Despite the observation that many patients do recover on their own, i.v. methylprednisolone is commonly used. Results from the Optic Neuritis Treatment Trial also showed that the treatment with steroids can also delay the onset of clinical definite MS.

 

Disease-modifying therapies in multiple sclerosis

Evidence for the efficacy of disease-modifying treatment to treat relapsing forms of MS is well established by the pivotal, placebo-controlled clinical trials (Table 1) [13**]. The effect of treatment on relapse rate is the accepted assessment of therapeutic efficacy even though the most important therapeutic aim is to prevent long-term disability. For each drug, an accurate evaluation of the benefits and risks provided by the different treatment options is critical.

 

Injectables

Interferon b and glatiramer acetate are the most common treatments used in MS and are generally used as first-line treatment [14]. Reductions in relapse rates ranging from 18–34% were observed in these pivotal trials (Table 1). Despite not fully understanding their mechanisms of action, both classes of drugs have excellent safety profiles but require frequent intramuscular or subcutaneous injections.

The interferons were the first approved category of medications for the relapsing forms of MS. Differing in their routes of delivery and duration of action, interferons have a complex mechanism of action that is not entirely understood but are thought to prevent inflammatory cells from crossing the blood–brain barrier. Common side-effects to interferon b are flu-like symptoms, including myalgia, fever, fatigue, headache, chills, nausea, vomiting, pain, and injection side reactions. The formation of neutralizing antibodies is also a possibility with interferon b treatment [15].

 

Glatiramer acetate is also commonly used as a first-line treatment in MS. Studies have shown this be effective in decreasing the number of clinical exacerbations. Its mechanism of action is not completely understood but is thought to enhance specific anti-inflammatory T helper cell type 2 cytokines. Although glatiramer acetate may not have the flu-like symptoms associated with the interferons, the most common adverse events associated with glatiramer acetate are injection-site reactions and vasodilation, which can present as shortness of breath, palpitations and chest tightness [16]. Head-to-head comparisons between interferon b-1a or-1b and glatiramer acetate have shown comparable clinical efficacy [17,18**]. To date, no ocularrelated side-effects have been reported.

 

Oral therapy

Several oral disease-modifying medications for MS have been approved, which include teriflunomide, tecfidera and fingolimod. All three have shown efficacy profiles comparable or greater than injectables [19* ,20,21]. Despite their contemporary nature of enrolling patients earlier in the disease and with lesser activity compared with pivotal trials (i.e. injectable), the reduction in relapses is a key to the assessment of therapeutic success.

 

Fingolimod was the first approved oral treatment. It resembles a natural extracellular lipid mediator, sphingosine 1-phosphate (S1P), and induces internalization and degradation of S1P receptors. The most frequent reported adverse event after the first dose is transient bradycardia and conduction abnormalities (first- or second-degree atrioventricular block) that are usually asymptomatic and resolve within 24 h [22,23]. Rare cases of opportunistic central nervous system (CNS) infections by generalized herpes simplex or varicella zoster virus have been reported, and immunity to varicella is required before starting. Macular edema is also a potential complication of fingolimod, which seems to be dose dependent with an incidence of approximately 0.5% with 0.5-mg oral dose, which is the currently approved dose. The mechanism underlying fingolimod-associated macular edema is not entirely clear but is presumed that the S1P receptor has a role in regulating vascular permeability. Patients on fingolimod should be advised of the possible adverse visual symptoms and ophthalmologic evaluation prior to treatment and at 3 to 4 months after initiation of the first dose [peripheral and central nervous system drugs advisory committee meeting: fingolimod [new drug application 22-527] background package; 2010 [24]]. Although considered more efficacious than conventional treatment, short- and long-term risks associated with immunosuppression and systemic effects need careful consideration.

 

Teriflunomide is also approved for relapsing forms of MS. Teriflunomide is the active metabolite of leflunomide, used in rheumatoid arthritis [25] and in some cases has been used as a platform therapy for uveitis [26]. The proposed mechanism of action of teriflunomide is that it inhibits dihydroorotate dehydrogenase, an enzyme responsible for pyrimidine synthesis of nucleic acids. Through inhibition of this enzyme, teriflunomide halts the production of nucleic acids needed in the proliferation of activated lymphocytes and B cells involved in the inflammatory cascade responsible for myelin destruction [27* ]. The safety profile and tolerability were recently updated with most common adverse effects of concern being increase in liver enzymes, diarrhea and alopecia. Monitoring of liver function tests is recommended both at baseline, then monthly for the first 6 months, then every 6 months. In addition, teriflunomide possesses teratogenic potential [pregnancy category X rating by the United States Food and Drug Administration], which requires that effective birth control before initiation be on board.

 

Dimethyl fumarate (DMF) is a twice daily oral pill that is also approved for the treatment of relapsing MS. It is thought to possess anti-inflammatory and cytoprotective properties. The approval of DMF was based on two large, placebo-controlled, phase 3 studies [Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis trial (CONFIRM) and Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis trial (DEFINE)] [21,28]. DMF significantly reduced annual relapse rates in both studies. However, the rate of disability progression, as measured by the Expanded Disability Status Scale, significantly improved only in DEFINE. Gastrointestinal symptoms and flushing are common side-effects for DMF.

 

Infusions

Several infusion options are available for the treatment of MS. Natalizumab is thought to block the transmigration of lymphocytes across the blood– brain barrier and is a monotherapeutic i.v. infusion required every 4 weeks at a registered facility for the treatment of relapsing MS [29]. Although it has been shown to reduce the risk of sustained progression of disability and the rate of clinical relapse, natalizumab therapy can be associated with the progressive multifocal leukoencephalopathy, a potentially fatal viral infection of the CNS. The risk of progressive multifocal leukoencephalopathy is determined partly by the treatment duration, previous exposure to immunosuppressive therapies and the presence of serum antibodies to the causative agent, JC virus [30* ]. Other common side-effects include headache, fatigue and urinary tract infections. The formation of neutralizing antibodies to natalizumab is also a possibility.

 

Alemtuzumab is a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes [31]. It readily depletes monocytes and B and T lymphocytes, leading to long-lasting changes in adaptive immunity and reduces the pathogenesis of inflammatory response in MS. When administered, alemtuzumab remains within the blood and interstitial space. The approval of alemtuzumab was also based on two randomized-controlled trials [Comparision of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) and CARE-MS II]. Both phase 3 studies were randomized, raterblinded, controlled trials that evaluated alemtuzumab versus subcutaneous interferon b-1a 44mg given every 3 days. It is associated with infusionrelated reactions and increased frequency of generally mild-to-moderate infections [32& ]. The safety profile of alemtuzumab led to the delayed approval in the USA. Reported adverse events include idiopathic thrombocytopenia, autoimmune thyroid disease, neoplasm, and opportunistic infections. It is recommended that patients are pretreated with corticosteroids before the first 3 days of each treatment course; in addition, antihistamines and antipyretics may be considered. Antiviral prophylaxis with acyclovir 200 mg twice daily should be provided during treatment and for at least 2 months after completion of alemtuzumab and until the CD4þ lymphocyte count is 200/mL.

 

CONCLUSION

MS can be a very debilitating disease. The ophthalmologist remains at the forefront with the team of neurologists and neuro-ophthalmologists at their side in managing this common demyelinating condition. The understanding of eye movement disorders in patients with MS can assist in expedient diagnoses of these patients. With the advent of numerous disease-modifying treatments in the past years, patients have more options than ever before to minimize relapse rates. These medications are not without risk with their plethora of undesirable sideeffects.

 

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Conflicts of interest

L.A. has served as a consultant to Biogen, Novartis, Genzyme and Mallinckrodt, and has received research support from Biogen, Novartis and Acorda. M.J.M. has received research support from Novartis. G.V.J. has no conflicts of interest.

 

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest

** of outstanding interest

1. Leigh RJ, Zee DS. The neurology of eye movements. 4th ed. New York, NY: Oxford University Press; 2006.

2. Frohman EM, Frohman TC, Zee DS, et al. The neuro-ophthalmology of multiple sclerosis. Lancet Neurol 2005; 4:111–121.

3. Prasad S, Galetta SL. Eye movement abnormalities in multiple sclerosis. Neurol Clin 2010; 28:641–655.

4. Serra A, Derwenskus J, Downey DL, Leigh RJ. Role of eye movement examination and subjective visual vertical in clinical evaluation of multiple sclerosis. J Neurol 2003; 250:569–575.

5. ** Servillo G, Renard D, Taieb G, et al. Bedside tested ocular motor disorders in multiple sclerosis patients. Mult Scler Int 2014; 732329. A recent study of more than 150 patients with MS showing a majority (70%) had some form of eye movement disorder diagnosed by the bedside examination.

6. Niestroy A, Rucker JC, Leigh RJ. Neuro-ophthalmologic aspects of multiple sclerosis: using eye movements as a clinical and experimental tool. J Clin Ophthalmol 2007; 1:267–272.

7. Derwenskus J, Rucker JC, Serra A, et al. Abnormal eye movements predict disability in MS: two-year follow-up. Ann NY Acad Sci 2005; 1039:521–523.

8. de Seze J, Vukusic S, Viallet-Marcel M, et al. Unusual ocular motor findings in multiple sclerosis. J Neurol Sci 2006; 243:91–95.

9. Frohman EM, Solomon D, Zee DS. Vestibular dysfunction and nystagmus in multiple sclerosis. Int J Mult Scler 1997; 3:13–26.

10. Starck M, Albrecht H, Straube D, Dieterich M. Drug therapy for acquired pendular nystagmus in multiple sclerosis. J Neurol 1997; 244:9–16.

11. Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 1992; 326:581–588.

12. Beck RW, Cleary PA, Backlund JC. The course of visual recovery after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Ophthalmology 1994; 101:1771–1778.

13. ** English C, Aloi JJ. New FDA-approved disease-modifying therapies for multiple sclerosis. Clin Therapeut 2015; 37:691–715. An excellent review and critical analysis of pivotal MS trials since 2010.

14. Scott LJ. Glatiramer acetate: a review of its use in patients with relapsingremitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. CNS Drugs 2013; 27:971–988.

15. Fox E, Green B, Markowitz C, et al. The effect of scheduled antibody testing on treatment patterns in interferon-treated patients with multiple sclerosis. BMC Neurol 2014; 14:73.

16. Ford C, Goodman AD, Johnson K, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler 2010; 16:342–350.

17. O’Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 2009; 8:889–897.

18. ** La Mantia L, Di Pietrantonj C, Rovaris M, et al. Comparative efficacy of interferon beta versus glatiramer acetate for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatr 2015; 86:1016–1020. This article is a meta-analysis of five randomized-controlled trials comparing interferon b versus glatiramer acetate.

19. * Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler 2014; 20:705–716. This is the phase 3 trial of oral teriflunomide versus an injectable b-1a in relapsingremitting MS.

20. Agius M, Meng X, Chin P, et al. Fingolimod therapy in early multiple sclerosis: an efficacy analysis of the TRANSFORMS and FREEDOMS studies by time since first symptom. CNS Neurosci Therapeut 2014; 20:446–451.

21. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367:1087– 1097.

22. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362:387– 401.

23. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362:402–415.

24. Novatis NDA 22-527 Risk analysis and mitigation strategy (REMS) 2015 http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm227965.pdf

25. Meier FM, Frerix M, Hermann W, Muller-Ladner U. Current immunotherapy in rheumatoid arthritis. Immunotherapy 2013; 5:955–974.

26. Molina C, Modesto C, Martin-Begue N, Arnal C. Leflunomide, a valid and safe drug for the treatment of chronic anterior uveitis associated with juvenile idiopathic arthritis. Clin Rheumatol 2013; 32:1673–1675.

27.* Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs 2014; 74:659–674. This article explains the pathophysiology of how oral teriflunomide works in MS by selectively inhibiting a mitochondrial enzyme that leads to a reduction in of T and B lymphocytes.

28. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367:1098–1107.

29. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899–910.

30. * Kornek B. An update on the use of natalizumab in the treatment of multiple sclerosis: appropriate patient selection and special considerations. Patient Prefer Adherence 2015; 9:675–684. This is a useful update about natalizumab and it use in MS over the past 10 years.

31. Jones DE, Goldman MD. Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety. Expert Rev Clin Immunol 2014; 10:1281–1291.

32. * Havrdova E, Horakova D, Kovarova I. Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use. Ther Adv Neurol Disord 2015; 8:31–45. Experts comment on benefits and risks about alemtuzumab for the treatment of MS. Ocular manifestations of systemic disease 6 www.co-ophthalmology.com Volume 26
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