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Àlex Rovira Secció de Neurorradiologia. Servei de Radiologia
Hospital Universitari Vall d’Hebron Barcelona
‘‘MRI in the diagnosis of MS ”
• Highly sensitive for detecting MS plaques (white matter)
• Provide quantitative assessment of disease activity and severity
• Characterize disease course over time
• Monitor and predict treatment response
• Early detection of treatment-related adverse effects
Most important paraclinical tool for diagnosing and monitoring MS
T2-weighted (FLAIR)
Post-contrast T1-weighted
MR imaging in MS
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Incidental finding aging (80-100%) normal young adult population (5-10%) migraine (x4) Virchow-Robin spaces Hipoxic-ischemic vasculopathies
Lipohyalinotic small-vessel disease Cerebral amyloid angiopathy Genetic vascular disorders: CADASIL…
Primary demyelinating diseases multiple sclerosis and variants ADEM neuromyelitis optica
Vasculitis primary systemic: lupus, Behçet, APLAS
Multifocal WM signal abnormalities: “white spots”
Sánchez Aliaga E, Barkhof F. Handb Clin Neurol 2014;122:291-316; Charil et al. Lancet Neurol 2006;5:841-52
Miscellaneous neurosarcoidosis Lyme disease PML metabolic: Leber, xantomatosis, adult forms of leukodystrophy effects of radiation therapy or drugs lymphoma metastasic disease
Comprehensive checklist for evaluation of focal lesions
Brief and precise diagnostic impression that must consider:
Demographics Family history Vascular risk factors Clinical information and question Lab findings
Diagnosis of MS Identify typical lesions
Systematic reading
•Lesion distribution / involvement subcortical/periventricular U-fibers cortical grey matter deep grey matter corpus callosum brainstem spinal cord
•Lesion shape •Central vein sign, hypointense rims (SWI) •Enhancement pattern
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Rovira et al. Nat Rev Neurol 2015; Wattjes et al. Nat Rev Neurol 2015; Traboulsee et al. Am J Neuroradiol 2016
0.1 mmol/kg Minimum delay 5 minutes
Gadolinium injection
3D T1 2D proton density-T2 3D T1-Gadolinium
3 mm. slice thickness (no gap) for 2D sequences Isotropic 1x1x1 mm for 3D sequences
3D FLAIR
Standardised MRI acquisition protocol
0.1 mmol/kg Minimum delay 5 minutes
Gadolinium injection (low risk GBCA)
T2 sequences: spinal cord
Single echo heavily T2 weighted1-2 : – limited sensitivity in depicting signal abnormalities1-2.
Combination of at least two T2w sequences: T2 and STIR, T2 and PD
1. Philpott et al. Eur J Radiol 2011; 80:780-5; 2. Bot et al. Eur Radiol 2000; 10:753-8; 3.Rovira et al. Nat Rev Neurol 2015;11:471-82.
T2 STIR
Do not use a single echo T2w sequence as a stand-alone sequence3 !!!!
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•MRI focal white matter lesions (incidental, vascular?): Prevalence 5-10% (20-40 years)
Focal WMLs involving the subcortical frontal white matter Small and non confluent Stable over time Weak association with vascular risk factors More prevalent in migraine headaches
•Multiple sclerosis: Prevalence <0.1% (20-40 years)
Charil et al. Lancet Neurol 2006
Multifocal White matter lesions in young adults
Solomon et al. Neurology 2012;78:1986-91
•Survey: 122 Neurologist (90% from Academic Hospitals) •95% reported having evaluated 1 or more patients who had been diagnosed with MS, but who they strongly felt did not have MS (within the last year) •Mainly due to overuse and improper interpretation of MRI (non specific findings) •>25% under treatment (difficult to take away)
Increase specificity of MRI findings is highly required
Misdiagnosis of Multiple Sclerosis
2013
2015
55 year old female with a diagnosis of multiple sclerosis. Treated with DMDs since 2009
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Fazekas et al. Eur Neurol. 1989; Solomon et al. Neurology 2016; Solomon et al. Curr Neurol Neurosci Rep 2013; Charil et al. Lancet Neurol 2006; Solomon et al. Neurology 2012; Rudick et al. Neurology 2013; Kim et al. Mult Scler. 2013
•Frequent contemporary reason for misdiagnosis •MRI features not considered in the context of appropiate clinical findings •Overdiagnosis of RIS
Misdiagnosis of MS: overreliance on MRI interpretation, wrong application of DX criteria
•Incidental multifocal WM brain lesions on MRI
normal population aged 18-50 (5-10%) migraine (x4)
Misdiagnosis has significant consequences: • Clinical, psychosocial and scientific • Health care system cost (overtreatment with DMTs)
Solomon et al. Neurology 2016
Misdiagnosis of Multiple Sclerosis
•Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. •110 misdiagnosed patients:
51 (46%) “definite” misdiagnoses 59 (54%) “probable ” misdiagnoses
70% received ≥ 1 DMD
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Solomon et al. Neurology 2016
Misdiagnosis of Multiple Sclerosis
Diagnosis and syndromes mistaken for MS
Contributors to MS misdiagnosis
Typical imaging findings in MS
Periventricular /ovoid Juxtacortical Cortical Pons (periphery) Middle cerebellar peduncles Inferior margin CC
Spinal cord Short segment <50% cord transverse area Lateral/posterior
Open-ring enhancement Central vein sign Hipointense rims (iron)
Susceptibility-weighted imaging
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MS diagnosis: McDonald 2017 criteria
Clinical Attacksa Clinical Evidence of Lesions Additional Requirements for MS Diagnosis
≥2 Objective clinical evidence of ≥2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack
None
≥2
Objective clinical evidence of 1 lesion
Dissemination in space, defined as:
● ≥1 T2 lesion in ≥2 MS-typical CNS regions; or
● Await further clinical attack implicating a different CNS site
1 Objective clinical evidence of ≥2 lesions
Dissemination in time, defined as:
● Simultaneous Gd-enhancing and non-enhancing lesions at any time; or
● New T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of its timing; or
● Await a second clinical attack
1 Objective clinical evidence of 1 lesion (clinically isolated syndrome)
Dissemination in space AND time (as defined above)
● Requirements can be met by a single MRI scan
Thompson AJ et al. Lancet Neurol 2017
Only apply them if clinical and MRI findings are suggestive of MS!!!!! Exclude alternative diagnosis
Kutzelnigg et al. Brain 2005
RRMS SPMS PPMS
focal demyelinated plaques in the white matter
cortical demyelination
demyelinated lesions in the deep grey matter
Cortical gray matter involvement in MS
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• Characterised by: – demyelination1
– microglial activation1
– often meningeal inflammation2,3
• Less often associated with4
– immune cell influx
– complement activation
– BBB leakage
• Difficult to detect by MRI5
• Three types of cortical lesion*6
*Based on post-mortem tissue samples taken from 22 patients with MS. Leukocortical Type I lesions involve neocortex and subcortical white matter; intracortical Type II lesions are confined to the neocortex and often located around a vessel; subpial Type III lesions extend from the pial surface into the neocortex. 1. Peterson JW et al. Ann Neurol 2001; 2. Lucchinetti CF et
al. N Engl J Med 2011; 3. Magliozzi R et al. Ann Neurol 2010; 4. Klaver R et al. Prion 2013; 5. Filippi M et al. Neurology 2010; 6. Wegner C et al. Neurology 2006
38% are Type I (leukocortical)
18% are Type II (intracortical)
44% are Type III (subpial)
Focal lesions in grey matter 90% of MS autopsy cases show cortical demyelination
Type I Type II Type III
Courtesy of Dr. García-Merino
T2-FLAIR
leukocortical lesion Lucchinetti et al. NEJM 2011;365:2188-97
Juxtacortical lesions (type I)
9T MRI (T2) Schmierer et al. Brain 2010
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MRI sensitivity depends on lesion type and sequence
Geurts et al. J Neurol 2008; Wattjes et al. Am J Neuroradiol 2006; Geurts et al. Radiology 2005; Roosendaal et al. Mult Scler 2009
• cMRI detects <10% of pure intracortical lesions • Higher detection of mixed lesions • Improved sensitivity by using DIR or heavily 3D T1-weighted sequences
mixed lesion intracortical lesion
Cortical lesions (type II-III)
T2-FLAIR DIR
Double inversion recovery
T GM GM/WM Subpial
FLAIR 4% 65% 0%
DIR 9% 83% 7%
Seewan et al. Neurology 2012
GM GM/WM Subpial
FLAIR 9% 91% 6%
DIR 29% 96% 33%
Prospective
Retrospective
3D FLAIR and 3D DIR 1.1 x 1.1 x 1.3 mm
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Phase sensitive inversion recovery (PSIR)
DIR PSIR
Courtesy Juan Linera (Madrid)
Phase sensitive inversion recovery (PSIR)
Lesion type Mean lesion counts
DIR PSIR GM 6 18 GM/WM 7 13
(60 MS; 30 controls)
DIR 83% MS ≥l purely GML All controls 0 GML PSIR 100% MS ≥l purely GML 3% controls ≥l purely GML
Sethi et al. JNNP 2012
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Leukocortical lesions
Present in 44% of CIS and in 70% of MS patients
Absent in NMO, migraine…
Calabrese et al. Neurology 2012; 79:1671-6; Absinta et al. J Neurol 2012; 259:2695-8; Pareto et al. Am J Neuroradiol 2016
Perivenular topography of MS plaques “Dawson‘s fingers“
Post-mortem pathology studies show central vein in > 90% white matter lesions
Dawson J. Trans Roy Soc Edinb 1916; 50:517-740 Horowitz et al. Am J Neuroradiol 1989;10:303-5
venule plaque
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Perivenular topography of MS plaques “Dawson‘s fingers“
Multiple sclerosis Kuijf et al. Eur Radiol 2017
Susceptibility-weighted MRI (7T)
FLAIR=fluid-attenuated inversion recovery. Kilsdonk ID et al. Eur Radiol. 2014;24:841–849
Axial 7-T FLAIR images of an MS patient and a patient with non-MS brain lesions
Dawson J. Trans Roy Soc Edinb 1916; 50:517-740 Horowitz et al. Am J Neuroradiol 1989;10:303-5
venule plaque
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Central vein sign
Absinta et al. Nat Rev Neurol 2016
Courtesy Pascal Sati. NIH (ECTRIMS teaching course 2017)
SWI + FLAIR
Central vein sign
Magi et al. Ann Neurol 2018
The “central vein sign” differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths.
31 patients with inflammatory CNS vasculopathies and 52 with RRMS 3D T2*-w EPI acquired during or after iv injection of a single dose (0.1 mmol/kg)
of GBCA
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Central vein sign (3 T) MS vs NMO
Cortese et al. Neurology 2018
•The clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD is now extended to clinical 3T scanners •Step towards the use of CVS in clinical practice. •Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD.
•Cutoff value of 54% of lesions with CVS was optimal in differentiating MS from NMOSD in the groups with high lesion numbers (sensitivity 94%; specificity 100%; accuracy 94%). •In patients with low lesion numbers, the cutoff point rose to 80% of lesions with CVS and produced less convincing results (sensitivity 50%; specificity 93%; accuracy 88%).
Intralesional susceptibility signal (ISS) in MS (3T)
SWI FLAIR
Intralesional susceptibility signal (ISS) 48% of non-enhancing MS lesions 58% of enhancing MS lesions
Susceptibility-weighted MR imaging
Likely represents iron-rich macrophages / microglia Myelin loss also contributes
Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209
Hagemeier et al. J Magn Reson Imaging 2012;36:73-83; Bian et al. Mult Scler 2013;19:69-75
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Susceptibility-weighted MR imaging Determinants in image contrast
Myelin, iron, deoxyhemoglobin, and free radicals—all relevant in MS pathogenesis—influence susceptibility signal
• T2*/phase contrast in acute MS lesions appear to be influenced by the presence of free radicals
• T2*/phase contrast in chronic MS lesions appear to be influenced by the topography of iron-laden macrophages / activated microglia within lesions
Absinta et al. Ann Neurol 2013
T2-FLAIR
Migraine-related WMLs vs Multiple Sclerosis (3T)
Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209
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SWI
Migraine-related WMLs vs Multiple Sclerosis (3T)
Areas of intralesional signal loss on SWI increases
diagnostic specificity and accuracy
MS
Migraine
Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209
T2-FLAIR
Phase imaging in the diagnosis of MS
6 RR, 6 PP and 4 SP MS patients
Ten MS lesions (2.3 %) were surrounded by a hypointense rim on FLAIR*, and 24 MS lesions (5.5 %) were hypointense on T2*. No lesions in vascular patients showed any rim or hypointensity.
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1. Early active
2. Center, chronic-active
Large, myelin-laden macrophages without iron
Small myelin-laden macrophages and occasional iron-containing macrophages
Macrophages with large amounts of iron, but without myelin
Perls’ staining
3. Rim, chronic-active
Myelin debris within macrophages detected with oil red-O
Mehta et al. PLOS one 2013;e57573
MS: Lesion categories and iron deposition
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2
3
No or only small amounts of iron
4. Chronic silent white matter lesions
Iron within activated microglia is demonstrated to enhance the release of pro-inflammatory cytokines and free radicals
Rathnasamy et al. CNS & Neurological Disorders - Drug Targets, 2013
Iron deposition in developping plaques
Absinta et al. Nat Rev Neurol 2016
baseline 3 months 9 months
3T
T2-FLAIR
T1-Gad
SWI
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Serial analysis with QS mapping at 3T
•Magnetic susceptibility increases rapidly as it changes from enhanced to non-enhanced •High susceptibility values during the first 2-4 years •Then gradually decreases (susceptibility similar to NAWM)
Chen et al. Radiology 2014; 271:183-92
Susceptibility-weighted MR imaging in focal MS lesions
• Iron in microglia/macrophages with a pro-inflammatory status
• Indicate chronic lesion activity • Future marker of disease activity? • No correlations USPIO/phase imaging
Expanding MS lesions
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Chronic active lesions Associated with • microglia activation • ongoing axonal injury
Partially explain disability progression (pre-existing symptoms)
MRI: Lesion evolution Slowly expanding plaques (smoldering)
2002 2003 2005
MRI: Lesion evolution (SPMS) Slowly expanding plaques (smoldering)
Baseline Two years
Mixed active / inactive and post-demyelinating
Kuhlmann et al. Acta Neuropathol 2017
Mixed active / inactive and post-demyelinating
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Frontal subcortical lesions
No subclinical spinal cord lesions
No juxtacortical, corpus callosum lesions
No ISS
SWI
Incidental findings
FLAIR
Clinical case: young female with migraine
SWI
FLAIR
Ovoid lesions
Juxtacortical lesions
Corpus callosum lesion Juxtacortical lesion
ISS within lesions
Preclinical multiple sclerosis or Radiologically isolated
síndrome (RIS)
Clinical case: young female with migraine
Spinal cord lesion
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Summary
Wide variety of causes may present with multifocal WM lesions
MRI is the preferred imaging technique for diagnostic workup Radiological interpretation with demographic, clinical history,
and lab findings Standardized brain (spinal cord) MRI protocol Comprehensive checklist for evaluation of WM spots is crucial Spinal cord MRI and SWI improve diagnostic specificity
Sánchez Aliaga E, Barkhof F. Handb Clin Neurol 2014;122:291-316; Charil et al. Lancet Neurol 2006;5:841-52; Rovira et al. Nat Rev Neurol 2015;11:471-82