Keywords

Overview

  • Definition

    • A chronic demyelinating disease primarily affecting the CNS

    • Episodic reversible neurologic dysfunction

    • 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

    • 72% patients with magnetic resonance imaging (MRI) abnormalities convert to multiple sclerosis within 15 years

  • Age of onset

    • 30–50 years, but can range from childhood to 60s

  • Gender/race

    • F:M = 2:1

    • No racial predilection

  • Systemic association

    • Demyelination of the nerves lead to neurological defects affecting the central nervous system

    • Episodic focal neurological defects, paresis and paresthesia may occur

    • Cranial nerve dysfunction is common

    • Difficulty in walking, coordination, and fine motor activity

    • Slurring of speech and difficulty in movements of tongue are common

Optic Neuritis in MS

  • Epidemiology

    • In 15–20% of patients, optic neuritis is the presenting feature of their disease

    • 50–75% of patients with MS will develop optic neuritis during their lifetime (usually in relapsing-remitting stage)

  • Laterality

    • Usually unilateral, with bilateral cases in 10% of the cases

    • Sequential involvement of both eyes is common

  • Symptoms

    • Periorbital or ocular pain that is increased with extraocular movements and usually lasts several days

    • Acute monocular vision loss with great variability

    • Visual field defects such as diffuse loss, central scotoma, arcuate and nasal-step scotomas, and altitudinal defects occur

    • Impaired color vision and contrast sensitivity (>75%)

    • Phosphenes: bright fleeting , flashes of light that tend to be connected to eye movement

    • Uhthoff’s phenomenon: worsening of vision provoked by small increases in body temperature attributed to exercise, hot baths or showers, or hot weather conditions

    • Pulfrich’s phenomenon: anomalous stereoscopic perception of objects in motion due to asymmetrical conduction between the optic nerves

  • Exam findings

    • Relative afferent pupillary defect

    • Optic nerve head may be swollen with peripapillary flame-shaped hemorrhages , and loss of spontaneous pulsations

    • Optic nerve head may appear normal in retrobulbar optic neuritis

Uveitis in MS

  • Epidemiology

    • Occurs in 1–3% of MS patients

    • 80–90% of the time presents as intermediate uveitis (anterior uveitis may occur)

    • Third most common cause of intermediate uveitis (after pars planitis and sarcoidosis)

    • No clear pattern in onset between uveitis and MS: one may precede the other and can be separated by many years

    • Incidence is higher in individuals with HLA-DR15 allele

  • Laterality

    • Typically bilateral

  • Course

    • May be recurrent or chronic

  • Symptoms

    • Floaters

    • Decreased vision due to macular edema

  • Exam findings

    • AC inflammation (may be granulomatous or non-granulomatous)

    • Vitritis (+/− snowbanking)

    • Retinal periphlebitis (>50%)

    • CME more common in patients with prior optic neuritis

    • Other complications: cataract, glaucoma, ERM, retinal neovascularization, VH, tractional RD

Neuro-ophthalmological Disease in MS

  • Oculomotor palsies are common in MS, frequently involving the sixth cranial nerve

  • Deficits in pursuit, saccades, and vestibular eye movement

  • Ocular flutter, opsoclonus, and saccadic oscillations

  • Various types of nystagmus including vertical, vestibular, pendular. Periodic alternating, or convergence-retraction with pupillary light-near dissociation

  • 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

  • Miscellaneous: oscillopsia, skew deviation, Charles Bonnet syndrome

Imaging

  • FA

    • Optic nerve leakage (except retrobulbar optic neuritis)

    • Peripheral retinal vascular leakage

    • Macular leakage

  • OCT

    • ERM

    • CME

    • Optic nerve atrophy from prior optic neuritis

  • Visual evoked potential (VEP)

    • Well-preserved wave form but delayed response in 75% of patients

Laboratory and Radiographic Testing

  • MRI brain and spine with gadolinium: 3 of the 4 below meet the revised McDonald diagnostic criteria

    • 1 gadolinium-enhancing lesion or 9 T2 hyperintense lesions if enhancing lesions are not present

    • ≥1 infratentorial lesion

    • ≥1 juxtacortical lesion

    • ≥3 periventricular lesions

  • Cerebrospinal fluid analysis

    • Elevated IgG index (comparison of IgG levels in CSF and in serum)

    • ≥2 oligocolonal bands via electrophoresis

    • Lymphocyte cell count should be <50/mm3 and protein should be <100 mg/dL; otherwise seek alternate Dx

  • 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

  • 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)

  • Other causes of intermediate uveitis with retinal vasculitis

    • Autoimmune: idiopathic (pars planitis), sarcoidosis, inflammatory bowel diseases

    • Infectious: TB, Lyme, syphilis, Whipple’s disease, toxocariasis

    • Masquerade: lymphoma

Treatment

  • Acute disease exacerbation

    • Intravenous corticosteroids

      • Usually first line in cases with acute optic neuritis, uveitis, and neuro-ophthalmological defects

      • Accelerates visual recovery in cases with optic neuritis but has no effect on long-term visual outcome

    • Plasmapheresis

      • May be indicated in patients with exacerbation of severe, rapidly progressive form of MS and optic neuritis unresponsive to corticosteroids

    • Intravenous immunoglobulins

      • Conflicting evidence in cases of optic neuritis

  • Treatment algorithm for long-term control

    • In patients with intermediate uveitis, but no neurological symptoms:

      • 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

      • 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)

    • In patients who present with uveitis, and subsequent confirmed diagnosis of MS:

      • Refer to neurology for disease-modifying agents (DMAs), including

        • Injectables : interferon beta-1a/1b, glatiramer acetate

        • Infusions: alemtuzumab, mitoxantrone, ocrelizumab, natalizumab

        • Oral: fingolimod (beware of CME risk), teriflunomide, dimethyl fumarate

        • Off-label: methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide, rituximab

    • In patients with established MS diagnosis but present with a uveitis flare-up:

      • Manage the flare-up with a brief course of corticosteroids – topical or regional depending on location of inflammation

      • 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

      • Avoid TNF-alpha inhibitors , and possibly IL-6 inhibitor (tocilizumab) as well

Referral/Co-management

  • Neurology

  • Physical medicine and rehabilitation