Abstract
Multiple sclerosis is a chronic demyelinating disease primarily affecting the CNS. There is episodic reversible neurologic dysfunction. It has a variable clinical course and unpredictable course with four major categories: relapsing-remitting (85%), secondary progressive, primary progressive (10%), and progressive-relapsing (5%). Ocular disease presents as optic neuritis, uveitis, or neuro-ophthalmological disease. The majority of patients may show excellent recovery; permanent visual disability is possible if not treated adequately. Seventy-two percent of patients with MRI abnormalities convert to multiple sclerosis within 15 years.
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Keywords
Overview
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Definition
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A chronic demyelinating disease primarily affecting the CNS
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Episodic reversible neurologic dysfunction
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Variable clinical course and unpredictable course with four major categories: relapsing-remitting (85%), secondary progressive, primary progressive (10%), and progressive-relapsing (5%)
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Ocular disease presents as optic neuritis, uveitis, or neuro-ophthalmological disease
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The majority of patients may show excellent recovery; permanent visual disability is possible if not treated adequately
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72% patients with magnetic resonance imaging (MRI) abnormalities convert to multiple sclerosis within 15 years
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Age of onset
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30–50 years, but can range from childhood to 60s
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Gender/race
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F:M = 2:1
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No racial predilection
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Systemic association
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Demyelination of the nerves lead to neurological defects affecting the central nervous system
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Episodic focal neurological defects, paresis and paresthesia may occur
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Cranial nerve dysfunction is common
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Difficulty in walking, coordination, and fine motor activity
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Slurring of speech and difficulty in movements of tongue are common
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Optic Neuritis in MS
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Epidemiology
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In 15–20% of patients, optic neuritis is the presenting feature of their disease
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50–75% of patients with MS will develop optic neuritis during their lifetime (usually in relapsing-remitting stage)
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Laterality
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Usually unilateral, with bilateral cases in 10% of the cases
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Sequential involvement of both eyes is common
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Symptoms
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Periorbital or ocular pain that is increased with extraocular movements and usually lasts several days
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Acute monocular vision loss with great variability
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Visual field defects such as diffuse loss, central scotoma, arcuate and nasal-step scotomas, and altitudinal defects occur
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Impaired color vision and contrast sensitivity (>75%)
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Phosphenes: bright fleeting , flashes of light that tend to be connected to eye movement
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Uhthoff’s phenomenon: worsening of vision provoked by small increases in body temperature attributed to exercise, hot baths or showers, or hot weather conditions
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Pulfrich’s phenomenon: anomalous stereoscopic perception of objects in motion due to asymmetrical conduction between the optic nerves
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Exam findings
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Relative afferent pupillary defect
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Optic nerve head may be swollen with peripapillary flame-shaped hemorrhages , and loss of spontaneous pulsations
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Optic nerve head may appear normal in retrobulbar optic neuritis
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Uveitis in MS
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Epidemiology
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Occurs in 1–3% of MS patients
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80–90% of the time presents as intermediate uveitis (anterior uveitis may occur)
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Third most common cause of intermediate uveitis (after pars planitis and sarcoidosis)
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No clear pattern in onset between uveitis and MS: one may precede the other and can be separated by many years
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Incidence is higher in individuals with HLA-DR15 allele
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Laterality
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Typically bilateral
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Course
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May be recurrent or chronic
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Symptoms
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Floaters
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Decreased vision due to macular edema
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Exam findings
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AC inflammation (may be granulomatous or non-granulomatous)
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Vitritis (+/− snowbanking)
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Retinal periphlebitis (>50%)
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CME more common in patients with prior optic neuritis
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Other complications: cataract, glaucoma, ERM, retinal neovascularization, VH, tractional RD
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Neuro-ophthalmological Disease in MS
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Oculomotor palsies are common in MS, frequently involving the sixth cranial nerve
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Deficits in pursuit, saccades, and vestibular eye movement
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Ocular flutter, opsoclonus, and saccadic oscillations
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Various types of nystagmus including vertical, vestibular, pendular. Periodic alternating, or convergence-retraction with pupillary light-near dissociation
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Internuclear ophthalmoplegia (INO): limitation of adduction of the ipsilateral eye and rapid nystagmus during abduction of the contralateral eye due to lesions in the medial longitudinal fasciculus
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Miscellaneous: oscillopsia, skew deviation, Charles Bonnet syndrome
Imaging
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FA
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Optic nerve leakage (except retrobulbar optic neuritis)
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Peripheral retinal vascular leakage
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Macular leakage
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OCT
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ERM
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CME
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Optic nerve atrophy from prior optic neuritis
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Visual evoked potential (VEP)
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Well-preserved wave form but delayed response in 75% of patients
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Laboratory and Radiographic Testing
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MRI brain and spine with gadolinium: 3 of the 4 below meet the revised McDonald diagnostic criteria
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1 gadolinium-enhancing lesion or 9 T2 hyperintense lesions if enhancing lesions are not present
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≥1 infratentorial lesion
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≥1 juxtacortical lesion
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≥3 periventricular lesions
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Cerebrospinal fluid analysis
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Elevated IgG index (comparison of IgG levels in CSF and in serum)
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≥2 oligocolonal bands via electrophoresis
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Lymphocyte cell count should be <50/mm3 and protein should be <100 mg/dL; otherwise seek alternate Dx
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HLA-DR15 can be obtained in patients presenting with intermediate uveitis to assess the risk of MS development (and thus avoiding use of TNF-alpha inhibitors)
Differential Diagnosis
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For neurological manifestations, MS has a board DDx, ranging from ischemic/inflammatory (neurosarcoidosis, disseminated SLE), infectious (Lyme disease, syphilis, PML), toxins (ethambutol), to demyelination (acute transverse myelitis, neuromyelitis optica)
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Other causes of intermediate uveitis with retinal vasculitis
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Autoimmune: idiopathic (pars planitis), sarcoidosis, inflammatory bowel diseases
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Infectious: TB, Lyme, syphilis, Whipple’s disease, toxocariasis
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Masquerade: lymphoma
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Treatment
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Acute disease exacerbation
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Intravenous corticosteroids
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Usually first line in cases with acute optic neuritis, uveitis, and neuro-ophthalmological defects
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Accelerates visual recovery in cases with optic neuritis but has no effect on long-term visual outcome
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Plasmapheresis
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May be indicated in patients with exacerbation of severe, rapidly progressive form of MS and optic neuritis unresponsive to corticosteroids
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Intravenous immunoglobulins
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Conflicting evidence in cases of optic neuritis
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Treatment algorithm for long-term control
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In patients with intermediate uveitis, but no neurological symptoms:
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If HLA-DR15 positive, significant retinal periphlebitis on FA, or has a strong family history of demyelinating diseases ➔ refer to neurology for further workup; be cautious with TNF-alpha inhibitors
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If HLA-DR15 negative, no significant retinal periphlebitis on FA, and no strong family history of demyelinating disease ➔ approach as usual (see above for DDx and see corresponding chapters)
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In patients who present with uveitis, and subsequent confirmed diagnosis of MS:
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Refer to neurology for disease-modifying agents (DMAs), including
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Injectables : interferon beta-1a/1b, glatiramer acetate
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Infusions: alemtuzumab, mitoxantrone, ocrelizumab, natalizumab
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Oral: fingolimod (beware of CME risk), teriflunomide, dimethyl fumarate
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Off-label: methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, rituximab
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In patients with established MS diagnosis but present with a uveitis flare-up:
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Manage the flare-up with a brief course of corticosteroids – topical or regional depending on location of inflammation
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If uveitis remains steroid-dependent or recurs frequently, then coordinate with neurology on choosing a DMA that may be more effective for both CNS and eye (i.e., interferon beta-1a/1b and glatiramer acetate; ocrelizumab should in theory be effective as it is similar to rituximab), or any of the off-label meds as they all are effective in ocular inflammatory diseases
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Avoid TNF-alpha inhibitors , and possibly IL-6 inhibitor (tocilizumab) as well
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Referral/Co-management
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Neurology
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Physical medicine and rehabilitation
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Nguyen, Q.D., Hassan, M., Agarwal, A. (2021). Multiple Sclerosis. In: Foster, C.S., Anesi, S.D., Chang, P.Y. (eds) Uveitis. Springer, Cham. https://doi.org/10.1007/978-3-030-52974-1_12
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DOI: https://doi.org/10.1007/978-3-030-52974-1_12
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