Neuro-ophthalmic Complications in Multiple Sclerosis

Dwight Thibodeaux, OD

MS

Immune mediated, inflammatory disorder

Focal demyelinating plaques on axons

Episodes separated in time and space

Affects sensory and motor functions through neuronal injury within the CNS

MS Histology

Inflammation involves neutrophils, plasma cells and macrophages

Cellular responses cause the breakdown of myelin into fat globules

Macrophages ingest the fat, stimulate astrocytes and they form glial tissue (scars)visualized as plaques on MRI

Axonal damage and neuron loss follows

MS

Historically, 30% have had physical disability within 25 yrs of Dx

Wide range of disease severity

Incidence 12/10,000 per confirmed dx

Significant geographic variability

Dx by clinical signs and ancillary tests

McDonald criteria for formal dx

McDonald Criteria

Developed in 2001, last revised in 2010

Uses MRI to document dissemination of lesions in time and space

DIS – more than one T2 lesion in at least 2 of 4 specific areas of the brain or sp. cord

DIT – new T2 or gadolinium enhancing lesions on F/U MRI at a later date

MRI for MS

Optic nerve – Thin, 2-3 mm, fat suppressed, T-2 weighted images

Brain – T2 weighted images demonstrate inflammation, breakdown of b/b barrier and fluid presence in ovoid shapes in para-ventricular white matter (Dawson’s bars or claws), brainstem, cerebellum and spinal cord, Gadolinium enhancement helpful in some cases

Additional TestsCSF – oligoclonal banding and increased IgG levels

VEP’s – increased latency/reduced amplitude

OCT – Thinning of RNFL/GCL/IPL (GCC) independent of optic neuritis

PET - measuring myelin reduction (damage) in brain - independent of inflammation

Classification

RRMS Relapsing/Remitting – 75%+

SPMS Secondary Progressive

PPMS Primary Progressive

PRMS Progressive Relapsing

Subgroups: CIS, “Benign”, RIS

MS

More common in women, greater gender bias more recently points to environmental vs. sex-linked genetic factors

Family history – shared Human Leucocyte Antigen profiles

Childhood in northern latitudes

Vitamin D deficiency, increased incidence and decreased response to therapies

Questionable viral trigger, Epstein-Barr virus antibodies

Males of African decent generally have most aggressive disease

Smoking (cumulative dose), moderate/high salt diet and obesity all assoc. with both incidence and progression

Signs and Symptoms

Paresthesia, peripheral neuralgia and anesthesia, trigeminal neuralgia, L’Hermitte’s- shock or buzz on bending the neck

Ophthalmic manifestations

Muscle cramping/spasticity/myokymia/tremor/ataxia/dysarthria/”MS hug”

Urinary/sexual dysfunction

Fatigue/heat intolerance/Uhthoff phenomenon

Depression/bipolar disorder/dementia/pseudobulbar affect

Cognitive difficulties

Vertigo, balance issues

Management Immunosuppression- steroids for acute phase

Immunomodulation therapy (IMT)

Symptomatic therapies for inflammation, pain, fatigue, depression, cognition, etc

Avoidance of high salt and sugar intake, and cessation of smoking, vitamin D supplements

Re-myelination therapy in future through reduction in endogenous hyaluronidase-enzyme depresses myelin repair activities

Plasmapheresis – auto-antibody removal

Promising new therapy?

Transdermal application of Myelin Peptides – antigen specific therapy

Small referral center study - 30 patients reduced relapses, reduced Gd+ lesions in 2/3rds vs placebo

Safe, only local skin reactions in 20%

RRMS patients studied

JAMA neurology 2013

Immunomodulation Therapy

Reduced conversion from a CIS to MS in high risk patients (w/one or more brain lesions on MRI)

Improved motor function over time

Reduces relapse frequency and also the loss of function with each relapse

IMT options Interferon Beta 1a, 2a – Avonex q1wk IM, Betaseron, Rebif q2-3d SQ, interferes with immune response, blood-brain barrier protection, flu-like symptoms, hepatotoxic, blood work needed

Glatiramer – Copaxone, daily SQ, lipo-atrophy, occasional acute mild reactions, otherwise safe

Orals – 3 recently approved, some with rare heart risk, flu- like symptoms, hepatotoxic, uveitis, renal dysfunction, peripheral neuropathy, rarely PML (progressive multifocal leukoencephalpathy)

Tysabri (natalizumab) monthly infusion, monoclonal antibody blocks receptors on WBC’s that allow infiltration into axon, PML, HZO

PMLProgressive Multifocal Leukoencephalopathy

Debilitating, often deadly viral encephalopathy

Caused by JC (John Cunningham) virus, genus Polyoma

Common non-pathologic incidence (50%)

Antibodies detected in blood work prior to tx allowing virus to propagate in brain

Ophthalmic Manifestations

Other than optic neuritis, what are they?

Ophthalmic manifestations

Demyelinating Optic Neuritis - DON

EOM palsy

Internuclear ophthalmoplegia

Nystagmus

Saccadic abnormalities

Uveitis

EOM Palsy

Abducens (6th nerve) most commonly affected

Loss of abduction in ipsilateral eye

DDx: post viral in younger patients and ischemic vasculopathy in older population

Internuclear Ophthalmoplegia

Adduction deficit in ipsilateral eye combined with a pendular nystagmus in abducting contralateral eye

Lesion in medial longitudinal fasciculus

Nystagmus

Newly acquired pendular most common

Other forms can also be found

Depends on lesion location

Saccadic Abnormalities

Common in MS

Retinal slip – shift of an object off the macula

Square wave jerks – conjugate horizontal saccadic intrusions that interrupt fixation

Ocular flutter – shorter jerks

Opsoclonus - random multidirectional saccades

Uveitis

Ten times more common in MS patients

Found in 1-2% of MS population

May precede or follow Dx of MS – 12% assoc.

Pars planitis most common form, CME

Can also see anterior, posterior uveitis and periphlebitis

DONDemyelinating Optic Neuritis

Acute, inflammatory

Young adults

Monophasic (CIS) or polyphasic (recurs)

MS vs. neuromyelitis optica (NMO)

Neuromyleitis OpticaDevic’s disease

Demyelinating disease of optic nerves, spinal cord and occasionally, the brainstem

Bouts of DOM and transverse myelitis - loss of limb, bladder and bowel control separated by months to years

Female, African and Asian most common pts.

Biomarker NML-IgG in 70%, not in MS

Treated with steroids, IMT and plasma exch.

DON

Initial presenting event of MS in 20%

Occurs in 50% during course of disease

Typically unilateral, subacute vision loss

Retrobulbar pain first in most (90%)

No assoc. systemic or neuro symptoms

DON

VA from 20/20 to NLP

Progression of loss over 1-2 weeks

79% see improvement in 3 wks

93% by 5 wks

5-10% fail to recover significant function

DON

ONTT -- VA’s, Contrast Sensitivity, VF’s

Typically VA worse w/previous dx of MS

Altitudinal/centrocecal/central VF defects most common

Also spectrum of diffuse and focal defects

DONAPD

Dyschromatopsia and reduced vision in bright light

Phosphenes during, before or after onset

Reduced contrast sensitivity, stereovision

1/3rd have mild nerve head swelling

Other Optic Neuropathies

Inflammatory - sarcoid, SLE, Wegener’s

Infectious – bacterial, viral, fungal

Infiltrative – leukemia, lymphoma

Toxic – antimetabolites, Plaquenil, methanol

Nutritional - B-12, folate

Compressive – tumor, aneurysm, thyroid

Ischemic – AION, PION

Leber’s herid. optic neuropathy

NMO

Red Flags for Differentials

Lack of pain

Onset age>50

Lack of recovery

Worsening > 2 wks

Temple pain

Other acute symp.

Hemes/exudates/marked swelling

Bilateral

Treatment

ONTT –multicenter, randomized, 15yr

IV steriods followed by oral taper vs no treatment - no difference in final visual outcome, just more rapid recovery

Oral steroids alone showed 2X increased recurrence in same or fellow eye

ONTT

IV steroids for DON decreased risk of developing MS at two years, but effect not sustained after 3 yrs..

Over the short-term:

8% w/IV steroids converted to MS

18% of placebo group converted

16% of oral steroid group converted

Other Predictive Factors for Conversion to MS

Prior episode of optic neuritis

White matter lesions in spinal cord on MRI

Early recurrence

Family Hx of MS

Early age of onset

HLA DR2

DON

Although IV steroids are often recommended, no consensus on dosage or duration of treatment has been developed

ONTT - IV infusion of methylprednisolone, 250 mg every 6 hrs x 3 days with oral taper of 1mg/kg/day x 11days

Neuro consult, discussion with patient on logistics of infusion, cost/ benefit ratio

Other Treatments for DON

If steroids contraindicated or not effective

IVIG controversial, conflicting data, possible remyelination effect

Plasma exchange – recent studies show some improvement in endpoint visual function compared to placebo

DON work-up

MRI brain and orbits

OCT and VF studies

DON wo brain lesions: 25% MS in 15 yr.

75% risk w/one or more brain lesions

Spinal cord lesions very predictive of MS

DON without MRI lesions

With only one-fourth of patients converting to MS after first episode, management remains a challenge

Follow with OCT vs MRI?

Frequency? No established guidelines.

MRI if progression of NFL loss on OCT?