Early Detection of PML in Natalizumab treated MS patientsskisse.newelement.no/cegedim/biogen_idec_0712/pdf/Nancy...Date of Preparation: March 2012 MU‐GBR‐0161f Early Detection

Date of Preparation: March 2012  MU‐GBR‐0161f

Early Detection of PML in Natalizumab treated MS patientsNancy D. Richert, MD, PhDBiogen IdecCambridge, MA, United States

• Share our experience of PML cases – Various MRI presentations– Distinguishing from MS lesions– IRIS – Useful imaging sequences– Goal: improve PML outcome by ensuring early recognition

Objectives

2

MRI=magnetic resonance imaging; MS=multiple sclerosis; IRIS=immune reconstitution inflammatory syndrome.

• MRI review of 212 PML cases*

– 112 cases with DICOM images 22 cases (68 scans) reviewed by Advisory Board

– 100 cases reviewed from MedWatch radiology reports

Cases Reviewed

3

*As of March 1, 2012.DICOM=Digital Imaging and Communications in Medicine.

Localized Disease on MRI at Time of DiagnosisIs Associated with Improved Survival

4

PML Extensionat Diagnosis

AllPML Cases*

(n=173)

Nonfatal PML Cases

(n=137)

FatalPML Cases

(n=36)Percentage of Survival

Unilobar, n (%)† 75 (43) 65 (47) 10 (28) 87

Multilobar, n (%) 32 (19) 27 (20) 5 (14) 84

Widespread, n (%) 66 (38) 45 (33) 21 (58) 68

Based on confirmed PML cases as of December 1, 2011.*MRI results were available for only 173 of 193 cases as of December 1, 2011; 17 of 20 patients without available MRI results are alive and 3 patients died; †of 75 patients with unilobar PML lesions, 40 (53%) had frontal lobe, 21 (28%) had occipital or parietal lobe, 4 (5%) had BG/thalamus, 6 (8%) had temporal lobe, and 3 (4%) had cerebellar lesions; the remaining unilobar case had unknown location per report.Unilobar=confined to 1 lobe; multilobar=involving 2 or more contiguous lobes; widespread=involving 2 or more noncontiguous lobesand/or present in both hemispheres; BG=basal ganglia.

Examples: Unilobar

5

Examples: Multilobar

6

Frontal Lobe and BG Contiguous Lobes

Examples: Widespread

7

Bilateral or Noncontiguous Lobes

PML Disease Progression

8

Asymptomatic

Symptoms:scalp dysasthesias, fatigue,

unclear headache

Dec 2008

Dec 2009

Visual symptoms

Feb 2010

Feb 2010

PML Disease Progression

9

WidespreadUnilobar

Sep 2008

Symptoms:scalp dysasthesias, fatigue,

unclear headache

Dec 2008

Asymptomatic

Feb 2009

Visual symptoms

• FLAIR: most sensitive MRI sequence fordetecting PML

• Location: peripheral/MRI with full brain coverage• DWI: is the lesion new?• T2W: is its appearance ground glass/microcystic?• T1W: pre and post contrast (Gd)

Early Recognition:Stepwise Approach to Natalizumab-AssociatedPML

10

FLAIR=Fluid Attenuated Inversion Recovery; DWI=diffusion weighted imaging; T2W=T2-weighted; T1W=T1-weighted; Gd=gadolinium.

PML Detection:FLAIR Superior to T2W Scans

11

FLAIR More Sensitive Than T2W ScansEven in Posterior Fossa

12

In contrast to MS lesions

In Contrast: FLAIR Is Insensitive toMS Lesions in the Posterior Fossa

13

1. Left frontal lobe2. Right frontal lobe3. Left parietal lobe4. Right parietal lobe5. No abnormality seen

PML Quiz:Where Is the Abnormality?

14

L

• FLAIR: first sequence you should examine• Location: peripheral/MRI with full brain coverage• DWI: is the lesion new?• T2W: is its appearance ground glass/microcystic?• T1W: pre and post contrast (Gd)

Stepwise Approachto Natalizumab-Associated PML

15

Location of PML: Peripheral and SubcorticalLocation of MS: Periventricular

16

Example: Peripheral Location

17

Lesion Borders:MS: Well Circumscribed/PML: Ill Defined

18

MS

PML

Unilobar PML:Frontal Lobe most common location

19

As of September 2011, 34 (54%) of 63 unilobar cases. No mass effect

PML Progression: Rapid Increase in Lesion Volume

20

July Sept.2.1 cc vol 125 cc vol

B.PML.25

Patient Asymptomatic

MS: Subcortical U Fiber

21

PML: Subcortical U Fiber

PML: Fills the Gyrus and Extends to the Cortex

23

• FLAIR: first sequence you should examine• Location: peripheral/MRI with full brain coverage• DWI: is the lesion new?• T2W: is its appearance ground glass/microcystic?• T1W: pre and post contrast (Gd)

Stepwise Approachto Natalizumab-Associated PML

24

DWI for Detection of PML in Confluent WM Disease

25

Month 0WM=white matter.

DWI for Progression of PML

26

Month 1

DWI for Progression of PML

27

Rim

Month 2

DWI for detection of PML

DWI

Flair T1Gd

T2W

Confidential. For internal use only. Not to be copied, modified, or distributed.

• ADC

DWI for detection of PML

Flair DWI ADC

• FLAIR: first sequence you should examine• Location: peripheral/MRI with full brain coverage• DWI: is the lesion new?• T2W: is its appearance ground glass or microcystic?• T1W: pre and post contrast (Gd)

Stepwise Approachto Natalizumab-Associated PML

30

Appearance: Large Confluent Can Appear Microcystic on T2W

31

Moth-Eaten Appearance On T1W

32

Demyelination in PML

• FLAIR: first sequence you should examine• Location: peripheral/MRI with full brain coverage• DWI: is the lesion new?• T2W: is its appearance ground glass/microcystic• T1W + Gd: <50% of PML lesions enhance

Stepwise Approachto Natalizumab-Associated PML

34

*116 of 159 patients had MRI scans/reports at the time of PML diagnosis that mentioned the presence or absence ofGd enhancement. (Of the remaining 43 patients, 6 patients died and 37 were alive.)

Gd Enhancement on MRI at DiagnosisNot Diagnostic for PML

35

Gd Enhancementon MRI at Diagnosis

AllPML Cases

(n=116)*

NonfatalPML Cases

(n=93)

FatalPML Cases

(n=23)Percentage of Survival

Yes, n (%) 40 (34) 32 (34) 8 (35) 80

No, n (%) 76 (66) 61 (66) 15 (65) 80

*116 of 159 patients had MRI scans/reports at the time of PML diagnosis that mentioned the presence or absence ofGd enhancement. Of the remaining 43 patients, 6 patients died and 37 were alive.

Gd Enhancement on MRI at DiagnosisDoes Not Predict Survival

36

Gd Enhancementon MRI at Diagnosis

AllPML Cases

(n=116)*

NonfatalPML Cases

(n=93)

FatalPML Cases

(n=23)Percentage of Survival

Yes, n (%) 40 (34) 32 (34) 8 (35) 80

No, n (%) 76 (66) 61 (66) 15 (65) 80

Gd Enhancement in MS Lesions:Nodular or REL

37

REL=ring-enhancing lesion.

Enhancement: Subtle in Acute PML

38

PML:Gd enhancement only in some not all PML lesions

PML: Patchy or Linear Enhancement

40

Quiz: Is This MS or PML?

41

FLAIR T1W Gd

Additional Images

42

FLAIR T1W Gd

Additional Images

43

FLAIR T1W Gd

Additional Images

44

FLAIR T1W Gd

PML: 2 Months Later

45

FLAIR T1W Gd

PML: 3 Months Later

46

FLAIR T1W Gd

Unnecessary• 22 imaging sequences• Spinal cord imaging• GRE• High-field imaging• Spectroscopy• MTR• DTI-tractography• PET scanning

Summary: Diagnosis of PML

Useful• Comparison to prior MRI • FLAIR: sag/axial• DWI• T2W• T1W pre and post Gd

47

GRE=gradient echo; MTR=magnetization transfer ratio; DTI=diffusion tensor imaging; PET=positron emission tomography.

2011BIO46027.

2011BIO46027.

MS or PML ?

48

49

MRI 8 months prior Current MRI

2011BIO46027.

Stable Compared to Prior MRI Scans

When Does PML Develop?

50

*PML diagnosis: date defined in Wiki database from MedWatch.Date of CSF sample=JCV+, or brain biopsy or MRI identified as PML.CSF=cerebrospinal fluid

Early PML Lesion Seen on MRI

No lesion seen on MRI

12 11 10 9 8 7 6 5 4 3 2 1 0Months

MRI atPML diagnosis*

PML Lesions Detected by MRI Prior to Diagnostic Workup

51

22 cases with MRI scans within 1–4 months prior to diagnosis: 19 positive (86%) and 3 negative (14%).Richert data on file (unpublished).

–12 –11 –10 –9 –8 –7 –6 –5 –4 –3 –2 –1Months Prior to Diagnosis

0

1

2

3

4

5

6

7

8

Num

ber o

f Cas

es

No PML (n=15)PML (n=26)

• A cluster of small punctate lesions• A thickened gyrus• Mimics an MS lesion • Occult–because of confluent MS• An extension of MS lesion toward cortex

What Does PML Look Like in Earliest Stages?

52

Beware: Punctate Clusters of T2 Lesions

53

1 year

Particularly If Gd+/DWI+

54

Progression 1 Month Later

55

T2W DWI Gd-T1W

Early PML: Gyral Thickening withHyperintensity on FLAIR

56

PML: Mimics an MS Lesion

57

Final Words

1. Every MRI requisition should request :on Tysabri r/o PML.

2. Any lesion that develops on Tysabri :Suspect PML

3. If a radiology report states: “New T2 lesion but no pathological enhancement”

Suspect PML4. If radiology report states “ significant progression of

white matter disease”Suspect PML

• Who to scan?– All TYSABRI patients treated with natalizumab?– All who are JCV Ab+?– All who are triple risk (JCV Ab+, prior IS, >24 months)?

• How frequently to scan? 4–6 months?• Can limited MRI be used?

– FLAIR +/– DWI?– Is Gd contrast necessary?

Frequent MRI Scanning

59

• What criteria should be used for flagging “early PML” or atypical MS?

– Lesion size >1cm2

– Location• What to do if the radiological images look like PML, but

the patient is asymptomatic and/or has JCV– CSF or a low viral copy number?

• False negative and false positive rates of early PML remain crucial questions

Frequent MRI Scanning (cont.)

60

Acknowledgements

We would like to thank the neurologists, and their patients, for allowing us to share their cases to educate all of us about PML

Ongoing educational tools: Frederik Barkhof (VUMC), in collaboration with Biogen Idec, is developing an interactive e-learning PML module that will be available to health care professionals.

• All the neurologists who provided MRI scans• Biogen team

– Diego Cadavid– Barry Ticho– Sandra Richman– Thorsten Eikenhorst

• Advisory board– Tarek Yousry– Dan Pelletier– Massimo Filippi– Achim Gass– Ernst-Wilhelm Radue

• NeuroRX (Doug Arnold)

Thank You

62

Thank You for Your Attention!

63