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CIS and MS; A Case Based Assessment
Anastas F. Pass OD, MS, JD, FAAO
Rosa A. Tang MD, MPH, MBA
James Walters OD, PhD
Course Description:
A case-based approach to assessing Clinically Isolated Syndrome (CIS) and Multiple
Sclerosis (MS) in an optometric setting. An extensive review of CIS and MS for the
optometrist and current methods of assessment.
I. General Multiple Sclerosis (MS) Information
A. Approximately 400,000 Americans have MS, and every week about 200 people are
diagnosed
B. The cost of treatment varies from $12,000 to $18,000 for the medication alone
1. Estimates for overall average cost of managing MS is $50,000 to $87,000 per year
C. What’s happening?
1. Chronic inflammatory demyelinating disorder of CNS white matter
2. Widespread demyelination followed by gliosis of brain, spinal cord and optic nerves
3. Compromise in the BBB causes increase in vascular permeability
4. Plasma proteins leak into extracellular space
5. Lymphocytes, macrophages and other immunocompetent cells accumulate and exit
into the brain attacking and destroying the myelin and forming multiple sclerotic
plaques ... hence the name.
II. CIS
A. General description and definition
1. Clinically isolated syndrome (CIS) is a single monosymptomatic attack compatible
with multiple sclerosis
2. Elements of CIS
a) First neurologic episode
b) That episode lasts at least 24 hours
c) That episode is caused by inflammation-demyelination
d) That episode is in one or more sites in the central nervous system (CNS).
3. Over 80% of patients with a CIS and magnetic resonance imaging (MRI) lesions go
on to develop MS
B. Presentation of CIS
1. CIS is the first acute clinical demyelinating event with evidence of prior subclinical
demyelination on the brain or spinal cord
2. Characteristic syndrome presentaitons
a) Optic neuritis
b) Brainstem/cerebellar dysfunction
c) Transverse myelitis (incomplete)
III. CIS and the risk of developing MS
A. The challenge is to determine the likelihood that a person experiencing this type of
demyelinating event will ultimately meet the criteria for a definite diagnosis of MS
B. Basically, these criteria state that in the case of only one attack (CIS), MS can be
confirmed by:
1. Dissemination in space by two or more MRI lesions consistent with MS and
2. Dissemination in time by MRI or 2nd attack
IV. Diagnosis MS
A. In order to make a diagnosis of MS, the physician must:
1. Find evidence of damage in at least two separate areas of the central nervous system
(CNS)
a) Which includes the brain, spinal cord and optic nerves AND
2. Find evidence that the damage occurred at least one month apart AND
3. Rule out all other possible diagnoses
B. These criteria were revised in 2005 (now referred to as The Revised McDonald
Criteria) to make the process even easier and more efficient.
1. Two or more attacks; objective clinical evidence of two or more lesions with no
additional data needed
2. If there is only objective clinical evidence of 1 lesion then the MRI data can be used
to make the MS diagnosis (CIS: see III (B))
V. Who gets MS?
A. Anyone may develop MS but there are some patterns.
B. More common in women than men have MS (5:1)
1. When males get MS, it can present with a more severe course
C. Studies suggest that genetic factors make certain individuals more susceptible than
others, but there is no evidence that MS is directly inherited.
D. It occurs more commonly among people with northern European ancestry
E. People of African, Asian, and Hispanic backgrounds are also diagnosed with MS,
however, the incidence is much lower
VI. What is the risk in having MS?
A. Risk to general population ≈ 0.1%
B. Risk to children and siblings of patients ≈ 1% to 4%
C. Risk to a non-identical twin ≈ 16%
D. Risk to an identical twin ≈ 25% to 30%
VII.
Etiology…?
A. Identified genetic markers
1. Immuno-regulatory genes identified
2. CNS Structural genes identified
B. Epigentics (modifications of gene expression/function)
1. Histone acetylation
2. DNA methylation
C. Environment
1. Geographical location and climate
2. Migration of populations
3. Incidence
a) Sex
b) Birth month
4. Viral infection
a) EBV
5. Smoking
6. Vitamin D status
VIII. Presentation of MS
A. Relapsing Remitting MS (RRMS)
1. Relapsing-remitting MS (RRMS) is the most common form of Multiple Sclerosis
(approximately 40% to 50% of all MS cases)
2. People with relapsing-remitting MS have unpredictable relapses
(attacks) or symptoms, but generally return to normal (the state of 'remission')
between attacks
3. During this time, the person will either fully or partially recover from the symptoms
experienced during the relapse
B. Secondary Progressive MS (SPMS)
1. Following an initial period of RRMS, many people develop a secondary-progressive
disease course in which the disease worsens more steadily, with or without occasional
flare-ups, minor recoveries (remissions), or plateaus
2. Without treatment, secondary-progressive MS, formerly called chronic progressive
MS, develops within 10 years in about 50% of people who have RRMS
C. Primary Progressive (PPMS)
1. People with Primary-Progressive MS have steadily worsening symptoms from the
outset of their diagnosis, and do not have distinct relapses
2. The disability associated with Primary-Progressive MS gradually worsens, and it may
level off at some point or continue over months or years
3. Primary-Progressive MS is a progressive form of the disease and does not display any
definitive periods of relapse or remission
B. Progressive Relapsing (PRMS)
1. In this relatively rare course of MS (5%), people experience steadily worsening
disease from the beginning, but with clear attacks of worsening neurologic function
along the way
2. They may or may not experience some recovery following these relapses, but the
disease continues to progress without remissions
IX. Assessing CIS and MS
A. The optometrist is very likely the first doctor to assess and evaluate a patient presenting
with optic neuritis (CIS)
1. General vision and optic nerve assessment
2. Vision field testing
3. OCT assessment
a) Nerve fiber layer thickness to determine NFL axon loss
b) Macular volume to determine retinal ganglion cell loss
c) Potential assessment of OCT predicting brain atrophy
4. Electrodiagnositic assessment
a) VEP
b) mVEP
c) mERG
B. Obtain baseline data to better determine the risks for developing MS
C. Collaboration with neurology over the clinical presentation of the disease course to
provide ideal management for the patient
X. Management of CIS and RRMS
A. Interferon beta-1a (Avonex®)
1. Intramuscular injection once per week and has been shown to reduce exacerbations,
2. Reduction in physical disability and a reduction in number and size of active lesions
in the brain (as shown on MRI)
B. Interferon beta-1b (Betaseron®)
1. Subcutaneous injection, every other day and has been shown to reduce the frequency
and severity of exacerbations
C. Glatiramer acetate (Copaxone®)
1. Subcutaneous injection every day and has been shown to reduce the frequency of
exacerbations and the level of disability
D. Natalizumab (TYSABRI®)
1. TYSABRI® is designed to hamper movement of potentially damaging immune cells
from the bloodstream, across the "blood-brain barrier" into the brain and spinal cord
2. Studies have verified that those taking the medication had a reduced risk of disability
progression and experienced fewer exacerbations (relapses) compared with the group
taking a placebo
3. TYSABRI® is given once every four weeks by intravenous infusion
E. FDA approved Ampyra, formally called Fampridine SR
1. Ampyra, an oral potassium-channel blocker, is a newly developed medication that
addreses gait difficulties in MS patients regardless of the disease course type or
concomitant treatment
2. Results of a phase 3 trial show Fampridine (4-aminopyridine) improves the quality of
life in multiple sclerosis (MS) patients through increasing their walking speed
F. Teriflunomide (Phase III Clinical Trials)
1. Oral Teriflunomide is a dihydro-orotate dehydrogenase inhibitor, has
immunomodulatory effects, including the ability to suppress experimental allergic
encephalomyelitis
2. Teriflunomide-treated patients had significantly fewer T1 enhancing lesions per scan,
new or enlarging T2 lesions per scan, and new T2 lesions
3. Patients receiving oral Teriflunomide 14 mg/day had significantly reduced T2 disease
burden. Teriflunomide treatment resulted in trends toward a lower annualized relapse
rate and fewer relapsing patients (14 mg/day only) v. placebo
XI. Case Discussions
A. CIS with optic neuritis
B. CIS without optic neuritis
C. Relapsing Remitting Multiple Sclerosis
D. Secondary Progressive Multiple Sclerosis
E. Primary Progressive Multiple Sclerosis
F. MS in childhood
G. MS with transverse myelitis (incomplete)
H. Complete transverse myelitis – a case of neuromyelitis