Teaching Course 13

Improving the differential diagnosis of MS using MRI

Chairs: J. Palace (Oxford, UK) F. Barkhof (Amsterdam, NL)

22 Aging and vascular diseases F. Barkhof (Amsterdam, NL)

23 Neuromyelitis spectrum disorders J. Palace (Oxford, UK)

24 MS mimics A. Rovira (Barcelona, ES)

Normal aging and age-related

vascular changes

Frederik Barkhof

• types of white matter lesions

– visible: WMH, microbleeds, VRS, lacunes

– invisible: microinfarcts, rarefaction

• clinical relevance of ischemia

– LADIS study

• pathophysiological concepts

– hypoperfusion, emboli, arteriosclerosis,

inflammation (metabolic syndrome)

Agenda

Normal ageing: histopathology Virchow-Robin spaces (VRS)

Normal aging – VRS Normal ageing phenomena: VRS

• widened Virchow-Robin spaces (VRS)

– perivascular extension of subarachnoid space

• around anterior commissure

– normal in early adulthood

• at the vertex

– normal in senecum

• incidentally giant VRS

• État criblé – widening of VRS in basal ganglia

– always abnormal and mostly associated with WMC

WMH and État criblé VRS @ 7T in MS patients

marker of neurodegeneration?

Kilsdonk I. MSJ 2015

More VRS in MS (median 11) than HC (median 4), p = 0.001.

VRS size did not differ between both groups.

VRS count in MS associated with sBVF (rho −0.40, p = 0.02),

but not with lesion count (p = 0.22)

Normal ageing: WM lesions Normal aging – caps & bands

Normal ageing: caps and bands

• periventricular “caps” and “bands”

– mild ependymal loss, subependymal gliosis

and widened extracellular space

– synonym: ependymitis granularis

• pencil-thin lining > 40-50 years of age

• regular caps/bands > 65 years of age

– irregular/discontinuous bands common

• may coincide with deep WML in ischemia

– difficult to separate

Small vessel disease – WMH & lacunes

*9734095

Small vessel disease – Fazekas score LADIS study - enrichment

N=639, strongly enriched for Fazekas grades 2 and 3

Independent in activities of daily living (ADL)

Survival or ADL independent

Inzitari, BMJ 2009

• MS patients more often smoked (51.7% vs 36.5%,

p=0.001) and had hypertension (33.9% vs 24.7%,

p=0.035) than HCs

• In the MS group, hypertension and heart disease

were associated with decreased GM and cortical

volumes (p<0.05)

• Overweight/obesity was associated with increased

T1-LV (p<0.39) and smoking with decreased whole

brain volume (p=0.049)

CVR and MS – impact on MRI

Kappus, JNNP 2015

• Hypoperfusion

– Chronic heart failure, carotid artery stenosis

• Embolism

– atrial fibrilation, aortic/carotid plaques

• Arteriosclerosis

– diabetes mellitus, hypertension

• Inflammation

– metabolic syndrome, obesitas

Pathophysiology Small vessel disease – pathophysiology

• Obliteration, occlusion

• Tortuosity, coiling

• Increased resistance

• Decreased

autoregulation

• Endothelial changes

• BBB changes

• Perivascular changes

Reduced perfusion in severe WMH

Bastos-Leite AJ, AJNR 2008

Cerebral blood flow in aging

van Es AC, PLoS One 2010

Progression of WMH

*5039676 Gouw A, Stroke 2009

Incident lacunes – LADIS study

Incident lacunes and cognition

• LADIS study 3 year FU data

• New lacunes lead to decline in

– executive function + speed & motor control

– but not memory and global cognitive function

– independent of baseline WMH and lacunes

• Progression of WMH additive effect

– stronger decline in executive function

Jokinen H, Neurology 2011

Basal ganglia and thalamic lacunes

Giannakopoulos, Acta Neuropathol 2007

Gouw AA JNNP 2011

Cortical microinfarcts (CMI)

• Small (<200 micron) infarctions

– gliosis, retraction, scarring

• Macroscopically hard to detect

– can be numerous

• Strongly related to cognition

– independent of AD pathology

– Gold G, Brain 2007

CMI and dementia

Religious order study

n=425

CMI in 30%

Arvanitakis Z, Stroke 2011

Summary measure of AD pathology

Pro

ba

bili

ty o

f d

em

en

tia

Accuracy for dementia 85%

Combined NFT & CMI/BGT

Gold G, Brain 2007 BGT CMI

Cortical micro-infarcts @ 7T

Courtesy Geert-Jan Biessels

Normal ageing: atrophy and rarefaction

WM integrity decline in aging vs. AD

Damoiseaux HBM 2009

WM integrity AD vs. VaD

Zarei M, Stroke 2009

Cerebral microbleeds (SWI)

Lobar MBs in CAA and Alzheimer’s disease

MBs - clinical associations

• Risk factors: hypertension, age, sex, ethnicity,

APOE e4, low cholesterol, smoking, alcohol

• MRI markers of SVD: WMH, lacunes

• Elevated risk for (subsequent) stroke

– and hemorrhagic transformation

• Clinical deterioration & mortality

• Cognition: deleterious in normal aging & AD

Anti-amyloid therapy – ARIA*

Before During After

*ARIA – Amyloid Related Imaging Abnormalities

Ostrowski S, Arch Neurol 2011

ARIA and amyloid-PET

Ostrowski S, Arch Neurol 2011

Summary

• pleomorphic effects of ischemia

– WMH, lacunes, MBs, micro-infarcts, atrophy

• pathophysiology multiplex

– systemic and local

• brain volume and focal lesions both important

– brain reserve modulating?

• interplay of vascular and Alzheimer pathology

– separate targets for intervention

ECTRIMS LONDON 2016 MAGNIMS teaching session Improving the differential diagnosis of multiple sclerosis using MRI 2) Neuromyelitis spectrum disorders. Jackie Palace (Oxford, UK) Neurosciences, Oxford University Hospitals Trust, UK

Introduction

The diagnosis of multiple sclerosis (MS) in the majority of cases is straight

forward, with a patient presenting with a typical clinical history and

confirmatory investigations. However clinical mimics of MS and non-MS diseases

associated with white matter lesions, can lead to misdiagnoses. Thus the correct

use and interpretation of the MRI is an important diagnostic aid.

Aquaporin 4 antibodies

The AQP4 water channel is the main water channel in the central nervous system

(CNS) and is located on the astrocyte foot process. Around 60% of neuromyelitis

optica spectrum disorders (NMOSD) have aquaporin 4 antibodies (AQP4-Abs)

and the remainder are negative. AQP4-Ab disease is now recognized as a

primary astrocytopathy1 rather than a primary demyelinating disease, and the

distribution of AQP4 within the CNS is partly responsible for the distribution of

the MRI features.

MOG antibodies

Myelin oligodendrocyte glycoprotein (MOG) is located on the surface of the

myelin sheath in the CNS and is important for its structural integrity. Previous

reports of MOG-Abs in healthy and other disease controls relate to antibody

assays detecting antibodies to denatured MOG2,3. Recent work suggests around

18-30% of those with seronegative NMOSD have antibodies to conformationally

intact MOG and these antibodies are also identified in a subgroup of patients

with acute disseminated encephalomyelitis (ADEM)4,5,6. These antibodies when

using reliable assays are not detected in other control populations.

Conventional Imaging features7,8,9,

The presence of a longitudinally extensive transverse myelitis (LETM) defined as

a contiguous lesion spanning 3 or more vertebral segments, in patients with

attacks of transverse myelitis (TM) is the most useful characteristic

distinguishing NMOSD from MS. However LETM is also a feature of monophasic

or post infectious conditions such as ADEM, and is said to be more frequent in

childhood MS. Whereas in MS TM, axial views of the spinal cord demonstrate

asymmetrical lesions often posteriorly or laterally placed, NMOSD TM tend to

have central or holocord involvement. Acute T1 hypointensity and extension into

the brainstem are also typical features of NMOSD TM and not of MS.

Although the initial diagnostic criteria for NMO required patients to have a

normal brain MRI (outside of optic nerve abnormalities), and subsequently to

have a non-MS-like brain MRI, it is now recognized that NMOSD patients can

have imaging features which fulfil the MS brain imaging diagnostic criteria10.

However non-specific white matter lesions are the commonest NMOSD brain

MRI abnormalities.

There are imaging features which usefully differentiate between MS and NMOSD,

with various specificities and sensitivities.

The presence of Dawson’s fingers, lesions adjacent to the lateral ventricles and in

the inferior temporal lobe, S-shaped U-fibre lesions, cortical lesions and the

presence of central veins in the majority of lesions support a diagnosis of MS.

Lesions in areas rich in AQP4 such as the peri-ependymal regions, particularly in

the area postrema, and diencephalic lesions are more specific for NMOSD.

Optic nerve imaging can be useful; In MS short unilateral extracranial lesions are

typical whereas posterior, bilateral, long optic nerve lesions often involving the

chiasm are typical of NMOSD optic neuritis.

Fluffy cerebral brain lesions, deep grey matter lesions, longitudinally extensive

transverse myelitis, and conus involvement are typical of MOG-Ab disease11.

Non-Conventional Imaging features12

Non-conventional imaging studies have reported variable results – sometimes

because AQP4-Ab antibody positive and negative patients have been combined

and possibly because there are ethnic variations. However whereas atrophy

outside of lesion related damage, widespread normal appearing brain tissue

abnormalities and silent activity is well recognized in MS these features are

uncommon in NMOSD.

Differentiating MS, AQP4 and MOG antibody diseases

Although the features of MS can be well differentiated from the antibody

mediated NMOSDs using algorithms, there is much overlap between the imaging

features of those patients with AQP4 and MOG antibodies. This observation is

seen in adults and children. This supports the pathogenic separation of MS from

MOG antibody disease. Of note children have larger lesions, more numerous and

bilateral lesions, more fluffy lesions and deep grey matter lesions than adults

across all diseases (Jurynczyk submitted).

References

1 Fujihara et al Clinical and Experimental Neuroimmunology 3 (2012) 58–73

2 Karni et al, J Neurol (2016) 263:370–379

3 Berger et al, N Engl J Med 2003349139–145.145

4 Reindl et al Nat. Rev. Neurol. 9, 455–461 (2013)

5 Kitley et al, JAMA Neurol. 2013;70(11):1375-1381

6 Piccolo et al, J Neurol 2016;263:370–379

7 Matthews and Palace Mult Scler Relat Disord 2014;3(3):284-93

8 Jurynczyk et al, J Neurol Neurosurg Psychiatry 2015;86(1):20-5.

9 Kim et al, Neurology. 2015 Mar 17; 84(11): 1165–1173

10 Matthews et al, Neurology 2013;80(14):1330-7

11 Kitley et al JAMA Neurol.2014;71(3):276-283

12 Kremer et al, JAMA Neurol, 2015;72(7):815-822 .

1

Àlex RoviraUnitat de Neurorradiología. Servei de Radiologia

Hospital Vall d’HebronBarcelona

alex.rovira@idi.gencat.cat

“Multiple Sclerosis mimics”

Teaching Course 8 - Improving the differential diagnosis of MS using MRI

www.magnims.eu

32nd Congress of ECTRIMS21st Annual Conference of RIMS

London, United Kingdom, 14- 17 September 2016

T2 and CE T1-WI

• 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

• Most important paraclinical tool for diagnosing and monitoring MS

T2-weighted(FLAIR)

Post-contrastT1-weighted

MR imaging in MS

Bakshi et al. Lancet Neurol 2008;7:615–25

Incidental findingVirchow-Robin spacesnormal population (5-10%)migraine (x4)

Hipoxic-ischemic vasculopathiessmall-vessel diseasehyperhomocysthenimiaCADASILSusac’s syndrome

Primary demyelinating diseasesmultiple sclerosis and variantsADEMneuromyelitis optica

Vasculitisprimary systemic: lupus, Behçet, APLAS

MiscellaneousneurosarcoidosisLyme diseasePMLmetabolic: Fabry, Leber, xantomatosis, adult forms of leukodystrophyeffects of radiation therapy or drugs lymphomametastasic disease

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

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 whothey 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

Solomon et al. Curr Neurol Neurosci Rep 2013; Charil et al. Lancet Neurol 2006; 5: 841–52;Solomon et al. Neurology 2012;78:1986-91; Rudick et al. Neurology. 2013;80:777; Kim et al. Mult Scler. 2013;19:1060-7

•Most frequent contemporary reason for misdiagnosis•MR features not considered in the context of careful clinical evaluation•Overdiagnosis of RIS

Misdiagnosis of MS: overreliance on MRI interpretation

•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; approx 40.000 subjects in US)

Comprehensive checklist for evaluation of WM spots

Brief and precise diagnostic impression that must consider:

DemographicsFamily historyVascular risk factorsClinical information and question Lab findings

Diagnostic strategy in subjects with incidental multifocal brain T2 lesions of unknown origin

Systematic reading

•Lesion distribution / involvementsubcortical/periventricularU-fiberscortical grey matterdeep grey mattercorpus callosumbrainstem spinal cord

•Lesion shape•Enhancement pattern•Features on special sequences: SWI•Ancillary findings

microbleedsvascular abnormalities

Kanecar et al. Radiol Clin N Am 2014; 52:241-61; Sánchez Aliaga E, Barkhof F. Handb Clin Neurol 2014;122:291-316

2

Cerebrovascular disease

Multiple Sclerosis

Corpus callosum involvement

Gean-Marton et al. 1991;180:215-221; Simon et al. Radiology 1986;160:363-367

Türe et al. Neurosurgery. 1996;39:1075-84

Vascular lesionsMS

R Wotfram-Gabel et al. Surg Radiol Anat 1992;14:17-21

Corpus callosum involvement

33 year-old woman with a three week clinical picture of behavioural disturbance, bradipsychia, sommnolence, headache, and memory loss

33 year-old woman with a three week clinical picture of behavioural disturbance, bradipsychia, sommnolence, headache, visual loss, hypoacusia and memory loss

Are the findings suggestive of MS?

Diagnostic criteria Type of CIS: ON, BS, SC, multifocal, hemispheric, UK Dissemination in space y/n Juxtacortical y/n Periventricular y/n Brainstem/cerebellum y/n Spinal cord y/n Dissemination in time y/n Enhancing/non enhancing y/n New T2 y/n

33 year-old woman with a three week clinical picture of behavioural disturbance, bradipsychia, sommnolence, headache, visual loss, hypoacusia and memory loss

Are the findings suggestive of MS?: NO

Diagnostic criteria Type of CIS: multifocal Dissemination in space Y Juxtacortical y Periventricular y Brainstem/cerebellum y Spinal cord n Dissemination in time Y Enhancing/non enhancing y New T2 NA

• Encephalopathy• Sensorineural hearing loss• Central lesions in corpus callosum

• Diagnostic work-up during admision:

– Arteriography: normal

– Ophthalmologic evaluation

Branch retinal artery occlusion (BRAO)Cotton-wool spots Retinal infarcts

33 year-old woman with a three week clinical picture of behavioural disturbance, bradipsychia, sommnolence, headache, and memory loss

3

•Focal T2 white / grey matter lesions supra and infratentorial (infarcts)•Small and widespread•Enhancement•Diffusion restriction•Constant involvement of the corpus callosum (central)•Cortex, basal ganglia, brainstem amd cerebellum also involved

•Leptomeningeal enhancement (1/3) Susac et al. Neurology 2003

Characteristic MRI features:

Susac syndrome

Snowballs String of pearls

Leptomeningeal enhancement

Courtesy F. Bonneville (Toulouse)

Susac syndrome vs Multiple Sclerosis

Features Susac syndrome Multiple sclerosis

Corpus callosum lesions Constant and central frequent, inferior

“String of pearls” in posterior limb of IC

frequent rare

Leptomeningeal enhancement 33% absent

Deep grey matter lesions 77% rare (thalamus)

Diffusion restriction yes (acute lesions) rare (acute lesions)

Spinal cord lesions absent frequent

Rennebohm et al. J Neurol Sci 2010; Susac et al. Neurology 2003

Susac syndrome

Multiple sclerosis

MS

Corpus callosum involvement

Uchino et al. Eur Radiol 2006;16:905-14; Susac et al. Neurology 2003;61:1783-7; O’Sullivan et al. Neurology 2001;56;628-34

SUSAC(100%)

Small-vessel disease(diabetes)

CADASIL(40%)

NMO(30%)

Courtesy M. Castillo (Chapell Hill)

Corpus callosum involvement

Virchow Robin (corpus callosum)

25 year-old womanMigraine

Dilated Virchow-Robin spaces

Dilated Virchow-Robin spaces

• Virchow-Robin spaces (VRs) surround the walls of vessels as they course from the subarachnoid space through the brain parenchyma

• Appear in all age groups (small)• Higher frequency and size with advancing age• Signal intensity almost identical to that of CSF • Associated with: neuropsychiatric disorders, MS, mild traumatic brain injury, and small-

vessel disease

R. M. Kwee, and T. C. Kwee. Radiographics 2007; Law et al. AJNR 2005; Wuerfel et al. Brain 2008; Doubal et al. Stroke 2010; Kilsdonk et al. MSJ 2015

Along the lenticulostriate arteries entering the basal ganglia through the anterior

perforated substance

Along the paths of the perforating medullary arteries as they enter the cortical

gray matter over the high convexities and extend into the white matter

In the midbrain

Type II VRs Type III VRsType I VRs

4

Features Dilated Virchow-Robin spaces Multiple sclerosis

Periventricular lesions absent yes

Spinal cord lesions absent yes

Signal intensity CSF-like high (T2-FLAIR)

Shape ovoid/linear ovoid

SVD (infarcts, DM, microbleeds) +/- absent

Contrast enhancement absent +/-

Dilated Virchow-Robin spaces vs Multiple Sclerosis*

* An ssociation with MS has been described. 1. Tarasoff-Conway et al. Nat Rev Neurol 2015; 2. Law et al. AJNR 2005; 3. Wuerfel et al. Brain 2008; 4. Kilsdonk et al. MSJ 2015

Corpus callosum involvement: VRS and MS

Dilated Virchow-Robin in Multiple Sclerosis

1. Tarasoff-Conway et al. Nat Rev Neurol 2015; 2. Law et al. AJNR 2005; 3. Wuerfel et al. Brain 2008; 4. Kilsdonk et al. MSJ 2015

• VRs role in leucocyte trafficking, in modulating immune responses, and in removal ofprotein waste1

• Associated with early stage of lesion development2

• Larger VRs volume in MS patients not related to brain atrophy, but to active inflammation(gad)3

• Increase number (not size) in MS4

• Associated with supratentorial brain atrophy, but not with lesion count (neurodegenerativemarker in MS?)4

The number of VRS was negatively associated with sBVF (rho = −0.40, p= 0.02), but not with T2 lesion

count, EDSS 4

Early stage of lesion development2

Distribution pattern

Incidental findings/aging WM changes

Multiple sclerosis

46 year-old woman with a five month clinical picture of recurrent headache

Clinical case 2 CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

•Inherited, autosomal dominant small vessel arteriopathy (mutations in Notch3 gene)

•Luminal narrowing/obliteration of the small and medium-sized leptomeningeal

arteries and the long perforating arteries of the brain

•Prevalence : 2-4 /100.000

•4th to 6th decades

•Migraine, recurrent ischemic stroke, mood disturbance, seizures and progressive

cognitive decline in young adults

“Recurrent ischemic strokes in middle age adults without vascular risk factors”

5

Multiple lacunar infarctsDiffuse white matter T2 signal changes

Symptomatic/asymptomatic patients

Temporal pole; U fibers at the vertex, external capsule /insular regionInvolvement of corpus callosum up to 40%Cortex and infratentorial WM sparedMicrobleeds on T2* or SWI

van den Boom et al. Radiology 2002, 2003

Characteristic radiological features

“Cerebral angiography with high risk of complications (11% permanent)”

Dichgans M. Lancet 1997

CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CADASIL

Summary of radiological features

Multiple lacunar infarcts

Diffuse white matter T2 signal changes

•Temporal pole•U fibers at the vertex•External capsule /insular region

Microbleeds on T2* or SWI

Involvement of corpus callosum

Van den Boom et al. Radiology 2003;229:683-90; Singhal et al. Am J Neuroradiol 2005;26:2481-7

Multiple sclerosis

CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CADASIL

CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CADASIL

Small vessel disease

CADASIL vs Multiple Sclerosis

Features CADASIL Multiple sclerosis

Multifocal / diffuse WM brain lesions frequent frequent

Temporal lobe involvement (U-fibers) frequent absent

Extrenal capsule / subinsular frequent +/-

U fibers vertex frequent frequent

Microbleeds frequent absent

Lacunar infarcts frequent absent

Corpus callosum up to 40% >70%

Spinal cord lesions rare frequent

Van den Boom et al. Radiology 2003;229:683-90; Singhal et al. Am J Neuroradiol 2005;26:2481-7

Central nervous system vasculitis

Primary angiitis of the CNS (PACNS)

Vasculitis associated with systemic disease• Systemic lupus erythematosus• Neuro-Behçet’s disease• Sjögren syndrome• Antiphospholipid antibody syndrome

6

Abnormal in 90-100% of patients (diagnosis unlikely if MRI is normal)

Diffuse / focal supratentorial areas of increased signal on T2W images

Multiple cortical / subcortical infarcts

Pseudotumoral lesions

Gadolinium enhancement in one-third of cases; leptomeningeal enhancement may

occur in 10% to 15%

Restricted diffusion suggestive of acute stroke

Concentric vessel-wall thickening and intramural enhancement (fat supressed CE -

T1W)

MRI features (non specific):

Primary angiitis of the CNS Primary angiitis of the CNS

Primary angiitis of the CNS

Classic angiographic vasculitis pattern multiple focal or long segmental areas of narrowing of small and medium vessels poor correlation between DSA and MRA MRA provides false negative results in more than 1/3

MRA DSAT2-FLAIR

DWI

Concomitant involvement of the brain and spinal cord

Primary angiitis of the CNS

Pseudotumoral, relapsing

Primary angiitis of the CNS

initial

5 months

18 months

Brain biopsy revealed evidence of necrotising lymphocytic vasculitis.

PACNS vs Multiple Sclerosis

Features PACNS Multiple sclerosis

Multifocal / diffuse WM brain lesions Frequent (almost 100%) frequent

Cortical/subcortical infarcts yes absent

Dural masess +/- absent

Pseudotumoral lesions +/- +/-

Enhancement focal lesions 1/3 constant in new lesions

Diffusion restriction yes (acute lesions) rare (acute lesions)

Leptomeningeal enhancement 10-15% absent

Concentric vessel wall enhancement +/- absent

Segmental arterial stenosis +/- absent

Hemorrhage: brain and SAH +/- absent

Spinal cord lesions +/- frequent

Salvarani et al. Lancet 2012; Obusez et al. Am J Neuroradiol 2014; Campi et al. Am J Neuroradiol 2001

7

• Systemic lupus erythematosus• Neuro-Behçet’s disease• Sjögren syndrome• Antiphospholipid antibody syndrome

Vasculitis associated with systemic disease

• small, punctate, focal lesions in the subcortical and periventricular white matter

• diffuse brain atrophy• territorial/lacunar infarcts• Intracranial hemorrhage

NPSLE

APLA

Vasculitis associated with systemic disease vs MS

Features Systemic vasculitis Multiple sclerosis

Multifocal WM brain lesions frequent frequent

Cortical/subcortical/basal ganglia infarctions +/- absent

Large confluent brainstem and basal ganglia lesions

Neuro-Behçet absent

Dural thrombosis Neuro-Behçet absent

Restricted diffusivity yes (acute lesions) rare (acute lesions)

Pseudotumoral lesions Neuro-Behçet +/-

Hemorrhage: brain +/- absent

Spinal cord lesions rare (LETM)NMO-like lesions in Sjogren

frequent

Sarbu et al. Autoimm Rev 2015; Muscal E, Brey RL. Lupus 2010; Kaichi et al. Am J Neuroradiol 2014; Stosic et al. J Neurol 2010; Al-Araji et al. JNNP 2003; Koçer et al. Am J Neuroradiol 1999

Perivenular topography of MS plaques“Dawson‘s fingers“

Post-mortem pathology studies show central vein

in > 90% white matter lesions

Jens Wuerfel (Berlin)

Dawson J. Trans Roy Soc Edinb 1916; 50:517-740

Horowitz et al. Am J Neuroradiol 1989;10:303-5

venuleplaque

FLAIR* sequence (3D GRE + 2D FLAIR at 3T)Central vein visibility

Tallantyre et al. Neurology 2011;76:534-9

7T

Presence of a central vein could be a marker to discriminate between MS and non-MS WM lesions

SWI in T2 lesions (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 vascular brain lesions

Mistry et al. MSJ 2015

Microangiopathic lesions vs MS (FLAIR* 3T)

100% agreement in stratifying patients based on the 45% threshold100% accuracy in discriminating MS from vascular patients

8

Intralesional susceptibility signal (ISS) in MS (3T)

SWIFLAIR

Intralesional susceptibility signal (ISS) 48% of non-enhancing MS lesions58% of enhancing MS lesions

Susceptibility-weighted MR imaging

Likely represents iron-rich macrophages / microgliaMyelin 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

T2-FLAIR

Migraine-related WMLs vs Multiple Sclerosis (3T)

Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209

T2-FLAIR SWI

Areas of intralesional signal loss on SWI increases

diagnostic specificity and accuracyMS

Migraine

Migraine-related WMLs vs Multiple Sclerosis (3T)

Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209

Susceptibility-weighted MR imagingDeterminants 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 bythe presence of free radicals

• T2*/phase contrast in chronic MS lesions appear to be influencedby the topography of iron-laden macrophages and ferritin withinlesions

Absinta et al. Ann Neurol 2013

Fat embolism

Courtesy Dr. Antoni Rovira (Sabadell)

25 year old man. Dyspnea, skin rash, encephalopathy

Kuo et al. Am J Neuroradiol 2013

• associated with displaced long bone fracture of the lower extremities • characterized by: respiratory disability, petechial skin rash, and neurologic symptoms

typically seen between 12 and 72 hours after the injury. • Incidence of 0.9%–2.2%.• although usually self-limiting, it may be fatal.

Fat embolism: features

Features Fat embolism (acute phase) Multiple sclerosis

Multifocal diffuse WMLs frequent frequent

Petechial hemorrhages frequent none

Restricted diffusivity frequent rare

Associated with long bone fractures

frequent no

9

Microbleeds: SWI

CADASILFat embolism CAA Hypertensivemicroangiopathy

MS RIS

Microbleeds (heme-iron) Iron-laden macrophages (non heme-iron)

Nodular pattern Ring / Nodular pattern

43 year old man. Mild headache.

Courtesy of Pia Sundgren. Lund (Sweden)

Neurosarcoidosis

Neurosarcoidosis

CNS is involved in 5–15% of cases

•The diagnosis of neurosarcoidosis is difficult, especially in the absence of an establisheddiagnosis of systemic sarcoidosis (50% of patients with NS)

•Differentiation from other chronic inflammatory diseases such as MS or CNS vasculitis isespecially difficult since they share common clinical, CSF and MRI findings

Diagnostic tests:

•Imaging: Chest CT, gallium scan•CSF analysis:

↑proteins and cells,ACE (poor sensitivity of 24–55%)oligoclonal bandssIL2-R (Petereit et al. J Neurol 2010)

Systemic granulomatous disease of unknown origin

Neurosarcoidosis

Courtesy Dra. Gonzalez Platas (Las Palmas)

•Dural masses (≈ meningioma)•Cranial nerves (ON, V, oculomotor) enhancement (34-50%)•Leptomeningeal enhancement: frontobasal, suprasellar (1/3)•Multiple focal white matter lesions (enhancing or non-enhancing)•Granulomatous lesions hypophisis and hypothalamus •Spinal lesions

Courtesy R. Glikstein / C. Torres , Ottawa

Shah et al. Am J Neuroradiol 2009; Dumas et al. Radiology 2000

Neurosarcoidosis

•Spinal lesionsNot uncommonRarely the first manifestationTumefactive spinal cord lesion (LETM)Spinal arachnoiditisDural lesions Shah et al. Am J Neuroradiol 2009; Dumas et al. Radiology 2000

Neurosarcoidosis vs Multiple Sclerosis

Features Neurosarcoidosis Multiple sclerosis

Multifocal WM brain lesions +/- frequent

Spinal cord lesions not uncommon (LETM) frequent

Dural masess +/- absent

Hipothalamic/ suprasellarinvolvement

+/- rare

Leptomeningeal enhancement 33% absent

Cranial nerve enhancement frequent 70% rare (5%)

Shah et al. Am J Neuroradiol 2009; Dumas et al. Radiology 2000

10

Disorders/conditions Prevalence

Incidental nonspecific MRI abnormalities high

Dilated Virchow-Robin spaces high

Migraine high

Inflammatory: SUSAC, vasculitis, sarcoidosis medium

Infections: Lyme disease, HTLV, Whipple rare

Other: DAI, fat embolism medium

Non-hipoxic/ischemic acquired mimickers of Multiple Sclerosis Summary

Wide variety of causes may present with multifocal WMlesions

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

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