1. Challenges in Diagnosing MS

2. 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 ARS Polling

3. McDonald WI, et al. Ann Neurol. 2001;50:121-127. 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

4. 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

5. 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

6. 1. Polman CH, et al. Ann Neurol. 2005;58:840-846. 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

7. Time Preclinical MRI Activity Relapses/Disability MRI T2 Burden of Disease Axonal Loss Disability CIS * Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications. Relapsing-Remitting MS Secondary Progressive MS Natural History of MS Clinical and MRI Measures

8. 8 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. 11% 79% 87% 85% 19% 89%87%88% 6% 54% 92% 80% Natural History of CIS (Queen Square) Risk of Conversion Based on Lesion Count at Presentation

9. Polman CH, et al. Ann Neurol. 2005;58:840-846. 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

10. 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

11. A and B: Courtesy of Tracy M. DeAngelis, MD. Gd-enhancing Corpus Callosum Typical MRI Lesions in MS

12. Infratentorial Juxtacortical C and D: Courtesy of Daniel Pelletier, MD. Typical MRI Lesions in MS

13. Spinal Cord Periventricular E: Courtesy of Daniel Pelletier, MD. F: Courtesy of Tracy M. DeAngelis, MD. Typical MRI Lesions in MS

14. Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf 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

15. Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf RequiredOptional Brain MRISagittal 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 MRICervical 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 RequirementsSlice thickness <3 mm except <4 mm for axial spinal cord; no gaps Adequate signal to noise ratio and resolution CMSC Standardized MRI Protocol 2009

16. 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. 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

17. 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

18. Emerging MRI Technologies Measures of CNS atrophy Magnetization transfer imaging Proton magnetic resonance spectroscopy Diffusion tensor imaging Susceptibility weighted imaging

19. 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

20. 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

21. EDSS 1 0 1.0 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 Normal neurologic exam Minimal disability Some limitation in walking ability Need for walking assistance Restricted to wheelchair Bedridden Death 1. Kurtzke JF. Neurology. 1983;33:1444-1452. 2. Confavreux C, et al. Brain. 2003;126:770-782. Time to EDSS score of 4.0 strongly influenced by relapses in the first 5 years and time to CDMS. 2 21

22. Residual Disability Sustained After a Relapse a a In 224 placebo patients from the NMSS task force on clinical outcome assessment. Lublin FD, et al. Neurology. 2003;61:1528-1532. Patients with Residual Disability (%) Days Since Exacerbation 30−59 Days60−89 Days90+ Days ≥0.5 EDSS points42%44%41% ≥1 EDSS points27%29%30%

23. 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. 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 1 –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 NMO 3 –Blood testing is available at Mayo Medical Laboratories 4

24. NMO Distinguishing NMO from MS Courtesy of Bruce A.C. Cree, MD, PhD, MCRCourtesy of Tracy M. DeAngelis, MD MS

25. 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

26. 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