can brain atrophy measurement help us in monitoring ms progression in routine clinical practice?

Department of Neurology and Centre of Clinical Neuroscience Charles University in Prague

1st Medical Faculty and General University Hospital

Can brain atrophy measurement help us

in monitoring MS progression in routine clinical practice?

Dana Horáková

MS center – Prague

New center opened

March 2007

Comprehensive care

for > 4000 patients

ASA - 10 yrs evolution of disability on IFN

1999-2003, 181 pts, age 31 yrs, disease duration 3.7 yrs

100 confirmed 12 M progression

73 stable

173 RR MS

„MS world has changed“

1993 2010 2006 2013 20XX 2015 ?

Molecules in clinical

studies,

not registered yet

Department of Neurology and Centre of Clinical Neuroscience Charles University in Prague, 1st Medical Faculty and General University Hospital

MRI is the only window

we can use to look directly

at patological processes

in MS

Focal inflammatory disease of white matter

Conventional MRI

Advanced MRI

Diffuse disease

Remyelination

Regeneration and repair

CONVE NT I ON A L

M

R

I

T

E

C

H

N

I

Q

U

E

S

T1W T2W

FLAIR T1W+Gd

Typical lesions

Peri

Ventricular

Posterior

Fossa

Juxta

Cortical

Spinal

cord

„Clinico-radiological paradox“

• Lack of pathologic specificity (de-, remyelination, edema, gliosis, axonal loss)

• Location – strategic areas

• Underestimation of spinal cord lesions

• Insensitivity to pathology in NAWM and NAGM

• Plasticity of the CNS

• Interaction between brain atrophy and lesion burden

• Limitations of current scales (EDSS)

Barkhof, Curr Opin in Neurology, 2002;

Zivadinov, J Neurol, 2008


Advanced technique

New MRI Methods for Detecting Demyelination and Axonal Loss

• Brain and spinal cord atrophy

• Magnetisation transfer imaging

• Diffusion weighted and diffusion tensor imaging

• Magnetic resonance spectroscopy

• Functional MRI

• PET

• …….

Why should we measure brain atrophy? Significant brain volume loss is observed from

the earliest stage of MS and proceeds throughout

the disease course

Healthy controls 0.1-0.3 % per yr

MS 0.5-1.35 % per yr

Nicola De Stefano, CNS Drugs, 2014

How do we measure atrophy?

Cross-sectional

Global or regional brain volume

Brain parenchymal fraction

Longitudinal

Changes in particular volumes

% changes

• Proprietary software

• SIENAX

• FreeSurfer

• Scanview.cz

• SIENA

• Proprietary softwares

– Scanview.cz

Miller D, Brain, 2002

Anderson, Journal of Magnetic Resonance Imaging, 2006

De Stefano, CNS drugs, 2014

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic

The results are good at a group level but

difficult to apply at an individual level

Technique independent

• ‘Ageing’ –

HC 0.1–0.3%/yr

MS 0.7–1.5%/yr

• Physiological variability

(de/hydration) Dunning, Neurology, 2005

• Other pathology

(smoking, diet, ApoE...)

• Rx effect, pseudoatrophy Zivadinov, Neurology, 2008

Technique dependent

• Scanner !!!

• Protocol !!!

• Software (measurement

accuracy – around 0.2%

• Stability of technical parameters

• Repositioning

Confounding factors

ApoE, apolipoprotein E; HC, healthy control; MS, multiple sclerosis; Rx, prescription.

Technique independent

• ‘Ageing’ –

HC 0.1–0.3%/yr

MS 0.7–1.5%/yr

• Physiological variability

(de/hydration) Dunning, Neurology, 2005

• Other pathology

(smoking, diet, ApoE...)

• Rx effect, pseudoatrophy Zivadinov, Neurology, 2008

Technique dependent

• Scanner

• Protocol

• Software (measurement accuracy

– around 0.2%

• Stability of technical parameters

• Repositioning

Confounding factors

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic

Are we able to overcome these problems?

CIS, clinically isolated syndrome; IFN β, beta-interferon; MRI, magnetic resonance imaging; RRMS, relapsing–remitting MS.

April 1999

Avonex-Steroid-Azathioprine (ASA) study 181 patients with RRMS, mean disease duration 5.1 years,

positive for oligoclonal bands

Dec

2003

Dec

2009

Dec

2005

Dec

2013

4,050

MRI

scans

1,500

MRI

scans

Jul

2009

Oct

2005

Observational study of early IFN β-1a treatment in

high-risk subjects after CIS (SET study)

220 CIS patients, mean disease duration 4 months, positive for oligoclonal bands

Jul

2011

Jul

2013

• Since 1999

– 1.5 mm FLAIR

– 1 mm T1W 3D

• 25 min without Gd

• Same scanner –1.5 T Philips

Proprietary sofware, developed by

Dr J Krásenský

• T2, T1 lesion volume

• BPF with % whole brain volume change

• Regional atrophy – corpus callosum, thalamus

www.scanview.cz

ScanView QMRI protocol – Prague

FLAIR, fluid-attenuated inversion recovery; Gd, gadolinium; QMRI, quantitative magnetic resonance imaging; T1W, T1-weighted.

ASA

181 patients

10 years of

follow-up

> 4,050 MRI

scans

SET 220 patients

4 years of

follow-up

> 1,500 MRI

scans

QMRI > 2,700 patients

1–4 years of

follow-up

> 9,000 MRI

scans

> 3,000 patients with MS

> 16,500 volumetric scans using the same protocol

ASA - 10 yrs evolution on 1 line therapy 1999-2003, 181 pts, mean age 31 yrs, DD 3.7 yrs

0,5

MS patients:

0,5-1,35% per year

0,5

ASA - 10 yrs evolution on 1 line therapy 1999-2003, 181 pts, mean age 31 yrs, DD 3.7 yrs

Healthy controls:

0,1-0,3% per year

MS patients:

0,5-1,35% per year

0,5

≈5x higher

Time (years)

88

90

92

94

96

98

100

102

104

0 2 8 4 6 10 12 14 16

9-Year ASA (181 Patients and 44 Healthy Controls)

% Change in

Corpus Callosum

Volume

Whole Brain

Volume (%)

Absolute Grey

Matter Volume

(mL)

Absolute White

Matter Volume

(mL)

Healthy Controls (n=44)

Stable Patients (n=71)

Patients with1-point Increase in EDSS at

12 Months (n=110)

16

400

450

500

550

600

650

700

750

800

350

Time (years)

0 2 8 4 6 10 12 14 0

0

−10

−20

10

−30

Time (years)

2 8 4 6 10 12 14 16 16

650

700

800

400

450

500

550

600

350

750

0 2 8 4 6 10 12 14

Time (years)

ASA=Avonex-Steroid-Azathioprine study.

Horáková D Unpublished results.


Data we receive in

a real clinical practice

Patient 1: F, 1984 , onset 2006, (22y) malignant course

CC (%), corpus callosum % change; Load, T2 lesion load; NMR, nuclear magnetic resonance.

Dept Ć.n. Date Code of

purpose Research Effects Anatomy Pathology Load BPF Atrophy CC (%)

Patient 1: last examination, 22 October 2013

Patient 1: co-registration of all available scans

22 Oct

2013

11 Aug

2008

30 Sep

2012

12 Jan

2012

16 Aug

2006

24 Sep

2009

Patient 1: colour-coding system

Red = new lesion since last scan; green = reduction in lesion since last scan; yellow = new lesions since first scan.


Patient 2: F, 1975, onset 92 (17y) Stable

Patient 2: Stable, F, 1975, onset 92 (17y)

-1,88:11 yrs= 0,17 %

Healthy controls 0,1-0,3 %


9/02

9/13

9/11

9/12

2. M,

1972,

onset

2003

(31)

1. M,

1970,

onset

1998

(28)

1

2. M, 1972, onset 2003 (31) 1. M, 1970, onset 1998 (28)

2. M, 1972, onset 2003 (31) 1. M, 1970, onset 1998 (28)

1.55 cm3

BPF 86.7

−2.2%/13 yrs = −0.17%/yr

+1.1% CC

1.52 cm3

BPF 89.47

−5.9%/11 yrs = −0.54%/yr

−21.2% CC

2. M,

1972,

onset

2003

(31)

1. M,

1970,

onset

1998

(28)

1

Patient 5: F, 1985, onset 2007, (22y) Early escalation

Patient 5: Early escalation

-3%:3 yrs= 1,0 %

3% of CC/yr


-1,7%:4 yrs= 0,4 %

1,25% of CC/yr


.

Disease free concept

NEDA 4

Without relapses

Without Disability

progression

Without T2 + Gd lesions

Atrophy within a range

of healthy controls

Without

clinical activity

„Disease free Concept“

Without MRI activity

EDSS Gait

Cognition

Havrdová a kol., Roztroušená skleróza, Triton, 2013

Scanview Q-MRI System in Prague

Scanner

Protocol

Volumetric

software

Clinical

implementation

MS Centre

Interpretation

Database

Personalised

medicine

Research

Validation

Acknowledgements:

To all patients who have participated in clinical research

MS Center, Dpt of Neurology Charles University, Prague Prof E Havrdová, MD, PhD

MRI Dpt, Dpt of Radiology Charles University, Prague Prof Z Seidl, Dr M Vaněčková and RNDr J Krásenský

can brain atrophy measurement help us in monitoring ms progression in routine clinical practice?

Health & Medicine

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axonal loss brain

significant brain volume

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siena proprietary softwares

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atrophy measurement

monitoring ms progression