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Neuroimaging and Other Biomarkers

MRI for Diagnosis, Prognosis and Treatment Decisions in MS

Eric Klawiter, MD MScMassachusetts General Hospital

May 30, 2014

Disclosures and Funding

• Disclosures: Consulting fees from Biogen Idec, Teva Neurosciences, Genzyme Corporation. Clinical trial funding from Roche.

• Funding: NIH (K23 NS078044-03)

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Outline

• Imaging in Diagnosis of MS

• Imaging for Prognosis in MS

• Imaging to Make Initial Treatment Decisions in MS

Case Study

• 25 y/o RH AAF who is 2 months postpartum and presents with one week of numbness and tingling involving her hands and feet

• She admits to left LE weakness and balance difficulties

• PMH of unilateral right eye vision loss 6 years ago lasting 2 weeks with complete resolution

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Case Study MRI Results

What imaging feature in MS correlates to the greatest extent

with clinical disability?

A. T2 Lesions Volume

B. Gray Matter Volume

C. Number of Gad Enhancing Lesions

D. White Matter Volume

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2010 McDonald Diagnostic Criteria

Polman CH. Ann Neurol. 2011.

Dissemination in Space

≥1 T2 hyperintensity in 2 or 4 areas:

•Periventricular

•Juxtacortical

•Infratentorial

•Spinal cord

Dissemination in Time

T2 lesions

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Corpus Callosum

Pelletier et al. Arch Neurol. 1993. 50: 1077-1082.

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Corpus Callosum Area

Klawiter et al. J Neuroimaging. 2014. Epub.

Posterior Fossa

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Gad enhancing lesions

Cotton et al. Neurology. 2003. 60: 640-646.

Enhancement patterns

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T1 hypointensities “Black Holes”

van Walderveen. Neurology. 1998.

Persistent Black Holes

Characteristics that predict persistent BHs

• 1) Gad enhancement on two months MRIs

• 2) Ring enhancing pattern of enhancement

• 3) Enhancement >6 mm in diameter

Bagnato et al. Brain. 2003. 126: 1782-1789.

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Predictors of Cognitive Impairment

• Baseline MRI features in CIS were predictive of cognitive impairment at 7 years follow-up– T1 hypointensity metrics at baseline predicted

executive dysfunction

– A new T2 lesion predicted slowed information processing

Summers et al. JNNP. 2008. 79: 955-958.

Atrophy

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Gray Matter Atrophy as Predictor of Future Disability

• GMV correlated in MSFC but not EDSS1

• At 13 years follow up, only baseline GMV predicted accumulation of disability2

• T2 lesion volume may complement atrophy measures in predicting disability3

• BL EDSS and GMV predict conversion to SPMS4

1Rudick et al. J Neurol Sci. 2013. 282: 106-111.2Filippi et al. Neurology. 2013. 81: 1759-1767.

3Lavorgna et al. Mult Scler. 2013. 4Popescu et al. JNNP. 2013. 84: 1082-1091.

Thalamic Atrophy

Rocca et al. Radiology. 2010. 257: 463-469 Calabrese et al. Neurology. 2011. 77(3): 257-263.

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• Can occur very early in MS

• Present in RIS

• Correlates with fatigue, cognitive dysfunction

Thalamic Atrophy

Case Study

• 31 year old female, presents with right arm numbness.

• A brain MRI is obtained that demonstrates one periventricular lesion and 2 juxtacortical lesions. No corpus callosum or posterior fossa involvement. No enhancement.

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What should be the next step?

A. Start treatment immediately for MS

B. Obtain a repeat brain MRI in 3 months

C. Obtain spinal cord MRI

D. Obtain CSF oligoclonal bands

E. Obtain VEPs

Spinal cord MRI

• Asymmetry

• Postero-lateral location

• Spanning one segment

• Patchy involvement

• Margins non-discrete

Bot et al. Neurology. 2004.

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Spinal cord atrophy

Losseff NA et al. Brain. 1996.Rocca et al. Neurology. 2011.Cohen-Adad et al. Muscle Nerve. 2013.Figure used with permission.

• Spinal cord atrophy correlates with EDSS (R=-0.7)

• More prominent in progressive subtypes

Case Study

• 29 y/o male presents with ascending numbness in BLE

• No prior history of neurological symptoms

• Enhancing lesion at T8

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What spinal cord features predict a worse prognosis?

A. Presence of enhancement

B. Number of spinal cord lesions

C. Dorsal column involvement

D. Thoracic cord involvement

Lukas et al. Radiology. 2013.

80

36

0

10

20

30

40

50

60

70

80

90

> 10 lesions <= 10 lesions

Percent Patients with EDSS >3after 14 years

Percent Patients with EDSS >6after 14 years

60

18

0

10

20

30

40

50

60

70

80

90

> 10 lesions <= 10 lesions

Modified from Brex et al, N Eng J Med. 2002:346;158-164.

Natural History of CISBaseline MRI and Disease Evolution

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2010 McDonald Diagnostic Criteria

O’Riordan et al. Brain. 1998. 121: 495-503.

In CIS and a normal brain MRI, the likelihood of MS at 10 follow up is:

A. 1%

B. 11%

C. 21%

D. 51%

2010 McDonald Diagnostic Criteria

Polman CH. Ann Neurol. 2011.

In CIS and an MRI with 1 or more lesions, the likelihood of MS at 10 follow up is:

A. 11%

B. 51%

C. 83%

D. 98%

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T2LV accumulation over time

Modified from Fisniku et al. Brain. 2008.

Early Changes in CIS

• Baseline gad-enhancing lesion number is predictive of EDSS and MSFC at 6 years

• Brain atrophy and lesion load over one year relate to clinical status after 6 years.

Di Filippo et al. JNNP. 2010. 81:204-208.

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RIS – What is the #1 predictor of a future clinical event

A. More than 1 gad enhancing lesion

B. Corpus callosum involvement

C. Spinal cord involvement

D. At least one T1 hypointensity

Okuda et al. PLoSOne. 2014.

RIS –predictors of a future clinical event

Okuda et al. PLoSOne. 2014.HR = 3.08

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Case Study

• 25 year old male

• Previous history of right groin numbness 4 years ago lasting one month

• New bilateral arm and leg numbness

Baseline MRI

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Based on this initial presentation on baseline MRI, what treatment would

you start?

A. Glatiramer acetate

B. Fingolimod

C. Dimethyl fumarate

D. Natalizumab

E. High dose Beta-interferon

Summary

• MRI essential in MS diagnosis– Characteristic features on brain MRI

– Spinal cord MRI can help confirm diagnsosis

• At baseline, atrophy and large disease burden may predict future disability

• MRI can help with initial disease modifying treatment selection