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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
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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
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*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
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Examples: Multilobar
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Frontal Lobe and BG Contiguous Lobes
Examples: Widespread
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Bilateral or Noncontiguous Lobes
PML Disease Progression
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Asymptomatic
Symptoms:scalp dysasthesias, fatigue,
unclear headache
Dec 2008
Dec 2009
Visual symptoms
Feb 2010
Feb 2010
PML Disease Progression
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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
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FLAIR=Fluid Attenuated Inversion Recovery; DWI=diffusion weighted imaging; T2W=T2-weighted; T1W=T1-weighted; Gd=gadolinium.
PML Detection:FLAIR Superior to T2W Scans
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FLAIR More Sensitive Than T2W ScansEven in Posterior Fossa
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In contrast to MS lesions
In Contrast: FLAIR Is Insensitive toMS Lesions in the Posterior Fossa
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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
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Location of PML: Peripheral and SubcorticalLocation of MS: Periventricular
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Example: Peripheral Location
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Lesion Borders:MS: Well Circumscribed/PML: Ill Defined
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MS
PML
Unilobar PML:Frontal Lobe most common location
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As of September 2011, 34 (54%) of 63 unilobar cases. No mass effect
PML Progression: Rapid Increase in Lesion Volume
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July Sept.2.1 cc vol 125 cc vol
B.PML.25
Patient Asymptomatic
MS: Subcortical U Fiber
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PML: Subcortical U Fiber
PML: Fills the Gyrus and Extends to the Cortex
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• 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
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DWI for Detection of PML in Confluent WM Disease
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Month 0WM=white matter.
DWI for Progression of PML
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Month 1
DWI for Progression of PML
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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
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Appearance: Large Confluent Can Appear Microcystic on T2W
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Moth-Eaten Appearance On T1W
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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
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*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
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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
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REL=ring-enhancing lesion.
Enhancement: Subtle in Acute PML
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PML:Gd enhancement only in some not all PML lesions
PML: Patchy or Linear Enhancement
40
Quiz: Is This MS or PML?
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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
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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?
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*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?
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Beware: Punctate Clusters of T2 Lesions
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1 year
Particularly If Gd+/DWI+
54
Progression 1 Month Later
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T2W DWI Gd-T1W
Early PML: Gyral Thickening withHyperintensity on FLAIR
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PML: Mimics an MS Lesion
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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
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Thank You for Your Attention!
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