Challenges in Diagnosing MS
ARS Polling
An MS diagnosis requires evidence of dissemination in
both space and time. Which of the following would not
constitute evidence of dissemination in time?
a) A second clinical episode 2 months after the first
one
b) Three new Gd-enhancing lesions 1.5 months after
the initial clinical episode
c) A new T2 lesion found 5 months after a reference
scan that was performed 2 months after the initial
episode
d) A single new Gd-enhancing lesion 4 months after
the initial clinical episode
What Is an MS “Attack”?
• Neurologic symptoms lasting ≥24 hours but
generally longer
– Not explained by other conditions
– Do not represent recurrent symptoms in
association with increased body temperature or
infection (pseudoexacerbations)
• To be considered separate attacks, the
interval between episodes must be ≥30 days
McDonald WI, et al. Ann Neurol. 2001;50:121-127.
Clinical Presentation
• MS symptoms vary widely among individual patients
• Numbness, tingling, or weakness in the limbs
– Usually unilateral or only lower half of body
• Tremor, spasticity, incoordination, unsteady gait,
imbalance
• Vision loss (usually unilateral), pain with eye
movement, double vision
• Fatigue, dizziness, cognitive impairment, unstable
mood
• Urinary and bowel incontinence or frequency
• Increased body temperature may trigger or worsen
symptoms
Disease Course
• After initial episode, MS patients typically follow a
chronic pattern of acute neurologic symptoms
(relapses) followed by periods of stability (remission)
• Timing, progression, duration, severity, and specific
symptoms are variable and unpredictable
• Typically 2 to 3 relapses per year in untreated
patients; treated patients have significantly fewer
relapses
• Some symptoms may be ongoing/chronic; these do
not represent relapse
• Long-term deficits range from mild to severe
Diagnosis of MS
• Clinically definite MS must meet criteria for1
– Dissemination in space
– Dissemination in time
• A single episode of MS-like symptoms (clinically
isolated syndrome [CIS]) will not meet these criteria
– But if MS is likely based on MRI, it still should be treated like
MS
• Delaying treatment may be missing an important window of
opportunity to delay the onset of irreversible disability
– Requires close monitoring over time to confirm diagnosis
1. Polman CH, et al. Ann Neurol. 2005;58:840-846.
Natural History of MS
Clinical and MRI Measures
Relapses/Disability
MRI Activity
Disability
MRI T2 Burden of Disease
Axonal Loss
Preclinical
*
Secondary Progressive
MS
Relapsing-Remitting
MS
CIS
Time
Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications.
Natural History of CIS (Queen Square)
Risk of Conversion Based on Lesion
Count at Presentation
92%
87%
80%
89%
85%
87%
88%
79%
54%
19%
6%
11%
Morrissey S, et al. Brain. 1993;116:135-146. O’Riordan J, et al. Brain. 1998;121:495-503. Brex PA, et al. N
Engl J Med. 2002;346:158-164.
8
Revised McDonald Criteria for
Dissemination in Space
• At least 3 of the following:
– ≥1 Gd-enhancing brain or spinal cord lesion or ≥9
T2 hyperintense brain and/or spinal cord lesions of
≥3 mm in size if none of the lesions are Gdenhancing
– ≥1 brain infratentorial lesion or spinal cord lesion
≥3 mm in size
– ≥1 juxtacortical lesion ≥3 mm in size
– ≥3 periventricular lesions ≥3 mm in size
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria for
Dissemination in Time
• At least 1 of the following
– A 2nd clinical episode
– A Gd-enhancing lesion detected ≥3 months after onset of
initial clinical event
• Located at a site different from the one corresponding to the
initial event
– A new T2 lesion detected any time after a reference scan
that was performed at least 30 days after the onset of an
initial clinical event
• Thus, it is not always necessary to wait for 2 attacks
to diagnose MS. A first attack plus changes on MRI
may be enough
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Typical MRI Lesions in MS
Gd-enhancing
A and B: Courtesy of Tracy M. DeAngelis, MD.
Corpus Callosum
Typical MRI Lesions in MS
Infratentorial
C and D: Courtesy of Daniel Pelletier, MD.
Juxtacortical
Typical MRI Lesions in MS
Periventricular
E: Courtesy of Daniel Pelletier, MD.
F: Courtesy of Tracy M. DeAngelis, MD.
Spinal Cord
CMSC MRI Protocol 2009
• Obtain brain MRI at baseline, with contrast
• Obtain spinal cord MRI if symptoms pertaining to
spinal cord lesions or no evidence of disease activity
in brain
• Repeat scan if:
– Unexpected clinical worsening
– Need to re-evaluate diagnosis
– Starting or modifying treatment
• Consider serial MRI every 1-2 years to evaluate
subclinical activity
Consortium of Multiple Sclerosis Centers.
http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf
CMSC Standardized
MRI Protocol 2009
Required
Optional
Brain MRI
Sagittal FLAIR
Axial FLAIR
Axial T2
Axial T2 pre/post Gd
Axial PD
3D IR prepared T1 gradient
echo (1.0-1.5 mm thick)
Spinal Cord MRI
Cervical cord coverage
Sagittal T2
Sagittal PD or STIR
Sagittal T1
Post-Gd T1
3D IR prepared T1 gradient
echo
Thoracic cord and conus
coverage
Gadolinium (Gd)
0.1 mmol/kg given over 30 sec with ≥5
min delay before scanning
Other Requirements
Slice thickness <3 mm except <4 mm
for axial spinal cord; no gaps
Adequate signal to noise ratio and
resolution
Consortium of Multiple Sclerosis Centers.
http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf
MRI Correlates Poorly With
Clinical Outcomes
• T2 lesion volume at a single point in time correlates
weakly with clinical disability and is a measure of past
attack frequency1
– Change in lesion volume over time may be a better
correlate2
• T1-weighted black holes are a better but still
imperfect correlate of disability3
• Brain atrophy is a measure of neurodegeneration that
may predict disability4
1. Bar-Zohar D, et al. Mult Scler. 2008;14:719-727. 2. Brex PA, et al. N Engl J Med.
2002;346:158-164. 3. Truyen L, et al. Neurology. 1996;47:1469-1476. 4. Miller DH, et al.
Brain. 2002;125:1676-1695.
Why MRI Correlates Poorly
with MS Disability
• MRI cannot determine extent/nature of tissue
damage
• Location of lesion influences its clinical manifestation
• MRI cannot distinguish between demyelinated and
remyelinated lesions
• MRI cannot detect gray matter lesions or diffuse
damage in normal-appearing white matter
• Plasticity of CNS may lead to compensatory use of
alternative neural circuit to circumvent damaged
areas
Emerging MRI Technologies
•
•
•
•
•
Measures of CNS atrophy
Magnetization transfer imaging
Proton magnetic resonance spectroscopy
Diffusion tensor imaging
Susceptibility weighted imaging
Other Diagnostic Tools for MS
CSF Analysis
• Positive if oligoclonal IgG bands present but absent
from corresponding serum sample or IgG index is
elevated
– Sensitive but not specific: other causes of CNS inflammation
can yield similar findings
• Lymphocytic pleocytosis is rarely >50/mm3
• Protein levels rarely exceed 100 mg/dL
• Elevated myelin basic protein is not pathognomonic
for MS
Other Diagnostic Tools for MS
Visual Evoked Potentials (VEPs)
• Provides evidence of a lesion associated with
visual pathways
• Positive if shows delayed but well-preserved
wave forms
– Abnormal VEP is not specific for MS
• Can help establish dissemination in space
EDSS1
Bedridden
Death
Restricted to
wheelchair
Need for walking
assistance
Normal
neurologic
exam
Some limitation
in walking ability
Minimal
disability
3.5 4.0
3.0
2.0 2.5
1.5
0 1.0
10.0
9.0
4.5 5.0
5.5
6.0
6.5
7.0
7.5
8.0
9.5
8.5
Time to EDSS score of 4.0 strongly influenced
by relapses in the first 5 years and time to
CDMS.2
1. Kurtzke JF. Neurology. 1983;33:1444-1452. 2. Confavreux C, et al. Brain. 2003;126:770-782.
21
Residual Disability Sustained
After a Relapsea
Patients with Residual Disability (%)
Days Since Exacerbation
30−59 Days
60−89 Days
90+
Days
≥0.5 EDSS points
42%
44%
41%
≥1 EDSS points
27%
29%
30%
aIn
224 placebo patients from the NMSS task force on clinical outcome assessment.
Lublin FD, et al. Neurology. 2003;61:1528-1532.
Neuromyelitis Optica (NMO)
• Syndrome of aggressive inflammatory demyelination afflicting
the optic nerves and spinal cord1, often associated with severe
disability
• Associated with infections and collagen vascular diseases1
– Idiopathic form is considered a variant of MS
• Modern case series indicate that NMO is characterized by1
– Recurrent attacks of optic neuritis and acute transverse myelitis
– Multisegmental spinal cord lesion >3 vertebral segments
– Initial brain MRI that is often (but not always) normal
• The NMO-IgG antibody recognizes aquaporin-4 (AQP4),2 a
water channel expressed on astrocytes
– Anti-AQP4 antibody is 73% sensitive and 91% specific for NMO3
– Blood testing is available at Mayo Medical Laboratories4
1. Cree B. Curr Neurol Neurosci Rep. 2008;8:427-433. 2. Lennon VA, et al. J Exp Med. 2005;202:473477. 3. Lennon V, et al. Lancet. 2004;364:2106-2112. 4. Mayo Medical Laboratories.
http://www.mayomedicallaboratories.com/test-catalog/Overview/83185.
Distinguishing NMO from MS
NMO
Courtesy of Bruce A.C. Cree, MD, PhD, MCR
MS
Courtesy of Tracy M. DeAngelis, MD
ARS Polling
An MS diagnosis requires evidence of dissemination in
both space and time. Which of the following would not
constitute evidence of dissemination in time?
a) A second clinical episode 2 months after the first
one
b) Three new Gd-enhancing lesions 1.5 months after
the initial clinical episode
c) A new T2 lesion found 5 months after a reference
scan that was performed 2 months after the initial
episode
d) A single new Gd-enhancing lesion 4 months after
the initial clinical episode
Conclusions
• Diagnosis of MS is based on a combination of clinical
and radiologic factors
– MRI should be performed according to CMSC standardized
protocol
• Revised McDonald criteria are the gold standard for
diagnosis
• High-risk CIS should be treated the same as clinically
definite MS
• Clinical variants and red flags should be taken into
account in formulating differential diagnosis