Multiple Sclerosis and the Eye

Multiple sclerosis is a chronic immune mediated demyelinating disease of the central nervous system. The visual pathway is among the most common sites of involvement: optic neuritis is the presenting event in about 20 percent and occurs at some point in 50 percent of patients, and eye movement abnormalities are present in most patients with established disease.

• A first episode of acute demyelinating optic neuritis carries a 15-year risk of developing multiple sclerosis of about 25 percent when brain MRI is normal and about 70 to 75 percent when one or more typical white matter lesions are present.
• Neuromyelitis optica spectrum disorder (aquaporin-4 antibody) and myelin oligodendrocyte glycoprotein antibody disease can mimic multiple sclerosis in the optic nerve but need different treatment, so antibody status matters before long term therapy is chosen.
• Intermediate uveitis (pars planitis pattern with peripheral periphlebitis) occurs in about 1 to 2 percent of multiple sclerosis patients, and the risk of multiple sclerosis in a patient with intermediate uveitis is increased.

• Optic neuritis: subacute unilateral loss of vision over hours to days, pain on eye movement (in over 90 percent, may precede the visual loss), dyschromatopsia (red desaturation), central or arcuate field defects, relative afferent pupillary defect, normal disc appearance in about two thirds (retrobulbar neuritis) or mild disc swelling. Vision reaches its nadir by 1 to 2 weeks and then recovers over 4 to 12 weeks, with 90 percent regaining 6/12 or better, but contrast sensitivity, colour vision and stereopsis often stay abnormal.
• Uhthoff phenomenon: transient worsening of vision with heat, exercise or fever. Pulfrich phenomenon: distorted perception of moving objects due to asymmetric conduction.
• Internuclear ophthalmoplegia: failure of adduction (or slowed adducting saccades) on the affected side with abducting nystagmus of the contralateral eye, convergence preserved. Bilateral in multiple sclerosis in a young patient. One-and-a-half syndrome, skew deviation and gaze evoked or downbeat nystagmus. Pendular nystagmus with oscillopsia. Sixth nerve palsy is less common.
• Optic atrophy (temporal pallor) after attacks, retinal nerve fibre layer thinning, and subtle chiasmal or retrochiasmal field defects.
• Atypical features pointing away from classic demyelinating optic neuritis: severe persistent pain, absent recovery by 4 weeks, marked disc swelling with haemorrhage, bilateral simultaneous involvement, retinal exudates, long segment or chiasmal enhancement, and age over 50 or under 12 years.

• Clinical: visual acuity, colour vision (Ishihara plates), contrast sensitivity, pupils, visual fields (central scotoma), fundus, eye movements.
• MRI brain and orbits with gadolinium, with fat suppression: optic nerve enhancement and typical periventricular, juxtacortical, infratentorial and spinal cord lesions (dissemination in space and time).
• Optical coherence tomography: retinal nerve fibre layer thinning (under 75 micrometres suggests prior optic neuritis) and ganglion cell layer loss, useful for monitoring progression.
• Visual evoked potentials: delayed P100 latency with preserved amplitude.
• Antibody testing in serum: aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG (cell based assays), mandatory in severe, bilateral, recurrent or atypical cases.
• Lumbar puncture: oligoclonal IgG bands in CSF not in serum (positive in over 90 percent of multiple sclerosis), raised IgG index, CSF cell count, protein.
• Exclude mimics: syphilis serology, tuberculosis, sarcoid (ACE, chest imaging), vitamin B12 and folate, thyroid function, ANA and ANCA, Leber hereditary optic neuropathy gene testing in a young male with painless sequential loss, and infiltrative or compressive lesions on MRI.

• Acute optic neuritis: intravenous methylprednisolone 1 g once daily for 3 days (500 mg daily for 5 days is an alternative), within 2 weeks of onset, with or without a short oral taper. Intravenous steroids speed visual recovery and reduce the risk of new MRI lesions in the first 2 years, but do not change final visual acuity. Low dose oral prednisolone alone (1 mg/kg/day) is avoided because it is associated with more relapses. Oral methylprednisolone 1250 mg daily for 3 days is equivalent where intravenous access is a problem. Cover with a proton pump inhibitor, monitor glucose, blood pressure, mood and sleep.
• Severe, steroid unresponsive visual loss (no improvement after about 5 to 7 days) or aquaporin-4 positive disease: plasma exchange, 5 to 7 exchanges on alternate days, started as early as possible.
• Neuromyelitis optica spectrum disorder maintenance (aquaporin-4 positive): rituximab 1000 mg intravenously on days 1 and 15, repeated every 6 months guided by B-cell counts; inebilizumab 300 mg intravenously on days 1 and 15 then every 6 months; satralizumab 120 mg subcutaneously at weeks 0, 2 and 4 then every 4 weeks; eculizumab 900 mg weekly for 4 weeks then 1200 mg every 2 weeks; or azathioprine 2 to 3 mg/kg/day with prednisolone, or mycophenolate mofetil 1 to 1.5 g twice daily. Interferon beta, natalizumab and fingolimod can worsen this disease and are avoided.
• Myelin oligodendrocyte glycoprotein antibody disease: acute treatment with intravenous methylprednisolone 1 g daily for 3 days (plasma exchange if there is no response), then maintenance with an oral prednisolone taper over at least 3 to 6 months (relapses occur on rapid withdrawal), with intravenous immunoglobulin 1 to 2 g/kg every 4 to 8 weeks, rituximab, azathioprine or mycophenolate when relapsing.
• Multiple sclerosis disease modifying therapy (decided with the neurology team after MRI shows dissemination): interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, ocrelizumab, natalizumab, ofatumumab or cladribine as indicated by disease activity. Fingolimod and siponimod cause macular oedema in about 0.5 percent, so macular OCT is done at baseline and again at 3 to 4 months, and earlier with any visual symptom, particularly in diabetes or past uveitis.
• Internuclear ophthalmoplegia: no treatment needed for most; diplopia managed by prisms or occlusion, and botulinum toxin or surgery in stable cases.
• Nystagmus and oscillopsia: gabapentin 300 mg three times daily increasing to 600 mg four times daily, or memantine 10 mg twice daily (start 5 mg daily and increase weekly), or baclofen 5 to 10 mg three times daily for downbeat nystagmus, and 4-aminopyridine (fampridine) 10 mg twice daily when appropriate.
• Intermediate uveitis: periocular triamcinolone 40 mg, or oral prednisolone 1 mg/kg/day tapered, with steroid sparing agents (methotrexate 15 to 25 mg weekly) when needed.
• Heat avoidance counselling (cooling vests), smoking cessation, vitamin D supplementation where deficient, and low vision rehabilitation for permanent loss.
• Review at 4 to 6 weeks, repeat colour vision, fields and OCT, and refer to neurology early because the best window for disease modifying treatment is soon after the first attack.