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 for 1 – 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 MRI T2 Burden of Disease Axonal Loss Secondary Progressive MS Preclinical

*

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

54% 92% 80% 79% 87% 85% 89% 87% 88% 19% 11% 6% 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 Gd enhancing – ≥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

Brain MRI Spinal Cord MRI Gadolinium (Gd)

CMSC Standardized MRI Protocol 2009

Required Optional

Sagittal FLAIR Axial FLAIR Axial T2 Axial T2 pre/post Gd Cervical cord coverage Sagittal T2 Sagittal PD or STIR Sagittal T1 Axial PD 3D IR prepared T1 gradient echo (1.0-1.5 mm thick) Post-Gd T1 3D IR prepared T1 gradient echo Thoracic cord and conus coverage 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

EDSS

1 Bedridden Restricted to wheelchair Death Need for walking assistance Normal neurologic exam

0

disability

1.0 1.5

Minimal

2.0

Some limitation in walking ability

2.5

3.0

3.5

4.0

4.5

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

5.0

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 Relapse

a

≥0.5 EDSS points

Patients with Residual Disability (%)

Days Since Exacerbation

30−59 Days

42%

60−89 Days

44%

90+ Days

41% ≥1 EDSS points 27% 29% 30% a In 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 cord 1 , often associated with severe disability • Associated with infections and collagen vascular diseases 1 – Idiopathic form is considered a variant of MS • Modern case series indicate that NMO is characterized by – Multisegmental spinal cord lesion >3 vertebral segments 1 – Recurrent attacks of optic neuritis and acute transverse myelitis – Initial brain MRI that is often (but not always) normal • The NMO-IgG antibody recognizes aquaporin-4 (AQP4), 2 water channel expressed on astrocytes a – Anti-AQP4 antibody is 73% sensitive and 91% specific for NMO 3 – Blood testing is available at Mayo Medical Laboratories 4 1. Cree B.

Curr Neurol Neurosci Rep.

2008;8:427-433. 2. Lennon VA, et al.

J Exp Med

. 2005;202:473 477. 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