1. Neuro-ophthalmic
Complications in
Multiple Sclerosis
Dwight Thibodeaux, OD

2. 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

3. 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

4. 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

5. 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

6. 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

7. Additional Tests
CSF – 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

8. Classification
RRMS Relapsing/Remitting – 75%+
SPMS Secondary Progressive
PPMS Primary Progressive
PRMS Progressive Relapsing
Subgroups: CIS, “Benign”, RIS

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. PML
Progressive 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

16. Ophthalmic Manifestations
Other than optic neuritis, what are they?

17. Ophthalmic manifestations
Demyelinating Optic Neuritis - DON
EOM palsy
Internuclear ophthalmoplegia
Nystagmus
Saccadic abnormalities
Uveitis

18. 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

19. Internuclear
Ophthalmoplegia
Adduction deficit in ipsilateral eye combined
with a pendular nystagmus in abducting
contralateral eye
Lesion in medial longitudinal fasciculus

20. Nystagmus
Newly acquired pendular most common
Other forms can also be found
Depends on lesion location

21. 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

22. 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

23. DON
Demyelinating Optic Neuritis
Acute, inflammatory
Young adults
Monophasic (CIS) or polyphasic
(recurs)
MS vs. neuromyelitis optica (NMO)

24. Neuromyleitis Optica
Devic’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.

25. 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

26. 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

27. 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

28. DON
APD
Dyschromatopsia and reduced vision in
bright light
Phosphenes during, before or after
onset
Reduced contrast sensitivity,
stereovision
1/3rd have mild nerve head swelling

29. 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

30. Red Flags for Differentials
Lack of pain
Onset age>50
Lack of recovery
Worsening > 2 wks
Temple pain
Other acute symp.
Hemes/exudates/m
arked swelling
Bilateral

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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?