The Neuro-ophthalmology of Multiple Sclerosis

Ryan D Walsh; Collin M McClelland; Steven L Galetta

Future Neurology. 2012;7(6):679-700.

Uveitis in MS

Several types of ocular inflammation may occur in association with MS including anterior uveitis, intermediate uveitis, posterior uveitis and periphlebitis.^[92] Uveitis is ten-times more common in patients with MS than in the general population.^[93] Reports of the incidence of uveitis in patients with MS vary, but larger well-designed studies found uveitis in 1–2% of MS patients.^[94,95] The diagnosis of uveitis may precede or follow the diagnosis of MS.^[96] Idiopathic intermediate uveitis, also referred to as pars planitis, is the most common form of uveitis associated with MS and usually manifests bilaterally.^[96] Pars planitis is characterized by inflammatory cellular infiltration over the pars plana or peripheral retina and into the vitreous body.^[97] Complications of pars planitis include epiretinal membrane, cataracts and cystoid ME. The visual prognosis is generally good with one-third of patients maintaining normal vision without treatment, and 75% of patients maintaining a visual acuity of 20/40 or better after 10 years.^[97] The association of MS and uveitis suggests that these two entities may share a common environmental trigger, genetic susceptibility or alteration of autoimmune homeostasis.^[95]

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Table 1. Red flags in acute vision loss: mimickers of demyelinating optic neuritis.
Sign, symptom, historical element or radiologic finding	Alternative diagnosis
Lack of pain	Ischemic optic neuropathy, NMO-associated optic neuritis, LHON, Susac syndrome, various maculopathies
Disc hemorrhages	Ischemic optic neuropathy, inflammatory optic neuritis, (lupus-, Sjogren syndrome-, inflammatory bowel disease- or sarcoid-associated) or infectious optic neuritis (Lyme disease-, Varicella virus-, HIV- or syphilis-associated)
Macular exudates	Neuroretinitis, ischemic optic neuropathy, hypertensive retinopathy, severe papilledema
Progression >2 weeks or lack of some recovery by 1 month	NMO-associated optic neuritis, ischemic optic neuropathy, malignant optic nerve glioma or other malignancy, various maculopathies
Uveitis	Various inflammatory and infectious causes of optic neuritis (sarcoid-, inflammatory bowel disease-, Lyme disease-, Behçet disease- or syphilis-associated), intraocular lymphoma, intraocular TB
Optic nerve sheath enhancement 'optic perineuritis'	Orbital inflammatory syndrome, sarcoid, inflammatory bowel disease, Lyme disease, syphilis, Wegener disease, TB, optic nerve sheath meningioma (vision loss rarely acute)
Lack of an afferent pupillary defect	Various maculopathies, bilateral optic neuropathy (including bilateral DON), Susac syndrome, media opacities (e.g., posterior subcapsular cataract, corneal edema, vitreous hemorrhage among others)
Metamorphopsia	Maculopathies: choroidal neovascularization, central serous chorioretinopathy, macular hole, macular edema
Positive visual phenomena as predominant symptom	Retinal detachment, white dot syndromes (e.g., multiple evanescent white dot syndrome, acute zonal occult outer retinopathy among others), cancer-associated retinopathy, melanoma-associated retinopathy, various optic neuropathies
Family history of unexplained vision loss	LHON
Fixed unreactive pupil with corneal clouding	Angle closure glaucoma
Immunocompromised patient	Infectious optic neuritis (Aspergillus-, mucormycosis-, Lyme disease-, varicella zoster virus-, HIV- or syphilis-associated), cytomegalovirus retinitis, lymphoma-associated optic neuropathy
Lumpy elevation of optic nerve	Leukemic optic nerve infiltration, ischemic optic neuropathy or peripapillary choroidal neovascularization associated with optic nerve head drusen
Bilateral at onset or shortly after	LHON, NMO-associated optic neuritis, paraneoplastic optic neuropathy or retinopathy, autoimmune associated optic neuropathy
Treatment with TNF-antagonist (e.g., infliximab, adalimumab and etanercept)	TNF antagonist-associated optic neuritis
Corticosteroid use	Central serous chorioretinopathy, (also see 'Immunocompromised patient' above)

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Executive Summary

Optic neuritis

Demyelinating optic neuritis (DON) is a hallmark feature of multiple sclerosis (MS) and often occurrs as the heralding event of the disease.
Optical coherence tomography has revolutionized the evaluation of vision in MS and has shown to be a structural correlate for visual function in DON and MS.
Intravenous steroids hasten visual recovery but do not change visual outcomes at 1 year or beyond; intravenous steroids for DON may impart a short-term protective effect against developing MS, though this protective effect seems to be lost after 2 years.
The risk of developing MS following DON can be stratified based on MRI findings with a long-term risk of 25% in patients with a normal MRI and 72% with an abnormal MRI.

Mimickers of demyelinating optic neuritis

In atypical cases of DON alternative causes must be considered, including nonarteritic anterior ischemic optic neuropathy, neuromyelitis optica, inflammatory optic neuropathies (sarcoid, lupus and giant cell arteritis), infectious optic neuropathies (Lyme disease, syphilis and neuroretinitis) and neoplastic optic neuropathies.
Fingolimod is associated with a 0.5–0.6% of macular edema, usually presenting within the first 3–4 months; diagnosis usually requires optical coherence tomography and/or fluorescein angiography.
Central serous chorioretinopathy is marked by painless neurosensory detachment of the macula from fluid leakage in the subretinal space; symptoms may be similar to DON with sudden-onset blurred vision and decreased color vision, but no pain.

Retrochiasmatic demyelination

MS demyelinating lesions involving the retrochiasmal visual pathways are most often asymptomatic. Homonymous field defects are associated with large lesions.
New-onset homonymous hemianopia or cortical visual impairment in MS patients on natalizumab should prompt an urgent evaluation for progressive multifocal leukoencephalopathy.

Uveitis in MS

Uveitis affects 1–2% of MS patients and usually occurs as a bilateral intermediate uveitis.
The association of MS and uveitis suggests that they may share a common environmental exposure, genetic susceptibility or abnormality of autoimmune homeostasis.

Internuclear ophthalmoplegia

Internuclear ophthalmoplegia is common in MS and results from damage to interneurons travelling from the cranial nerve (CN) VI nucleus in the pons to the contralateral medial rectus subnucleus of CN III in the upper midbrain via the medial longitudinal fasciculus.

Saccadic abnormalities

Saccadic abnormalities encountered in MS include intrusions (square wave jerks, macro square wave jerks, ocular flutter and opsoclonus), saccadic dysmetria (most commonly hypermetria), increased latency and decreased velocity.
Saccadic dysmetria, particularly hypermetria, occurs frequently in MS.

Nystagmus

Gaze-evoked nystagmus typically results from damage to the neural integrator (the medial vestibular nucleus, nucleus prepositus hypoglossi and cerebellar flocculus for horizontal gaze; the interstitial nucleus of Cajal and paramedian tracts for vertical gaze).
Pendular nystagmus likely occurs as a result of injury to critical feedback circuits within the brainstem and cerebellum controlling the neural integrators and can be quite visually disabling. It may respond to treatment with memantine or gabapentin.

CN III, IV & VI palsies

Isolated CN VI palsies (from fascicular damage in the brainstem) occur occasionally in MS, while CN III and CN IV palsies are seen very rarely in MS.
Other eye movement abnormalities which may occur in MS include impaired smooth pursuit, skew deviation, impaired vestibulo-ocular reflex and an inability to suppress the vestibulo-ocular reflex.

Conclusion

Afferent and efferent neuro-ophthalmologic abnormalities are common in MS and may occur as a result of the disease itself or from treatments given to manage the disease.
Eye movement abnormalities in MS are associated with brainstem/cerebellar lesions and increased disability.
Research focused on identifying novel targets for therapeutic intervention has offered the prospect of neuro-protection and/or remyelination and a likely shift in how treatment success in MS is measured.

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The Neuro-ophthalmology of Multiple Sclerosis

Uveitis in MS

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Authors and Disclosures

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