Clinical and MRI clues and pitfalls in the diagnosis and ......Clinical and MRI clues and pitfalls...

Clinical and MRI clues and pitfalls in the diagnosisand differential diagnosis of Multiple Sclerosis

Aksel Siva, M.D.MS Clinic & Department Of Neurology

Istanbul University Cerrahpaşa School of [email protected]

MSParis2017 - 7th Joint ECTRIMS - ACTRIMS Meeting, 25 - 28 October 2017

Disclosure

• Received research grants to my department from The Scientific and

Technological Research Council Of Turkey - Health Sciences Research Grants

numbers : 109S070 and 112S052.; and also unrestricted research grants from

Merck-Serono and Novartis to our Clinical Neuroimmunology Unit

• Honoraria or consultation fees and/or travel and registration coverage for

attending several national or international congresses or symposia, from Merck

Serono, Biogen Idec/Gen Pharma of Turkey, Novartis, Genzyme, Roche and Teva.

• Educational presentations at programmes & symposia prepared by Excemed

internationally and at national meetings and symposia sponsored by Bayer-

Schering AG; Merck-Serono;. Novartis, Genzyme and Teva-Turkey; Biogen

Idec/Gen Pharma of Turkey

Introduction…

• The incidence and prevalence rates of MS are increasing, so are the number of misdiagnosed cases as MS!

• One major source of misdiagnosis is misinterpretation of nonspecific clinical and imaging findings and misapplication of MRI diagnostic criteria resulting in an overdiagnosis of MS!

• The differential diagnosis of MS includes the MS spectrum and related disorders that covers subclinical & clinical MS phenotypes, MS variants and inflammatory astrocytopathies, as well as other Ab-associated atypical inflammatory-demyelinating syndromes

• There are a number of systemic diseases in which either the clinical or MRI findings or both may mimic MS, which further cause confusion!

Related publication

*Siva A. Common Clinical and Imaging Conditions Misdiagnosed as Multiple Sclerosis. InMultiple Sclerosis. Guest Editor Darin T. Okuda. Neurologic Clinics of North America, Elsevier, February 2018

Diagnostic criteria in “MS”

• Schumacher et al, 1965

"a clinical (CNS) disease disseminated in time and space"

• Poser et al, 1983

"additional paraclinical and / or laboratory evidence:

neuroimaging, neurophysiology & CSF (IgG/OCB)"

• McDonald et al, 2001 &

• revised McDonald; Polman et al, 2005

“evidence for dissemination in time and space

supported by MRI”

No better explanation to account for symptoms and signs(no alternative neurological disease)

"dissemination in time and space"

Diagnostic criteria in “MS”

MRI dominant

disease

criteria

the incoming

2017/18 revised

new criteria set is

likely to be MRI

dominant as well!

Diagnosing MS

MS is a neuro-inflammatory demyelinating diseasewith neurodegeneration of the CNS, in which there is

• Evidence of dissemination in space (multifocality)Clinical sx & signs + DIS by MRI

• Evidence of dissemination in timeClinical relapses or steady progression + DIT by MRI

• No better explanation to account for symptoms and signs and/or MRI findingsClinical & MRI: no alternative neurological disease

Clinical Hx

Neuro-exam +

findings to be

confirmed by

MRI!

ClinicalSymptoms & Signssuggestive of ”MS”

ImagingCranial & Spinal MRIsuggestive of “MS”

Clinical & Imagingfindings suggestive of MS

Diagnosis and Differential Diagnosis of MS

Patients are admitted to neurology outpatient clinicsbecause of...

RIS CIS RRMS PMSMS variants, mimics or not so rarely something else!

A first concern!

• What should be our firstconcern in the general neurology out-patientclinic?

• Could it be MS?

• What should be our firstconcern in the specializedMS out-patient clinic?

• Could it be not MS?

In a patient who is admitted with symptoms and/or MRI findingssuggestive of MS or MS Spectrum / related disorders

MS Not MS!

Difficulties in MS diagnosis

Evaluation of diagnostic outcomes in patients referred to a university-based MS center for possible MS

(University of Colorado Multiple Sclerosis Center, Denver)

*Carmosino et al. Arch Neurol. 2005


Evaluation of diagnostic outcomes in patients referred to a

university-based MS center for possible MS

# 281 pts → Final MS diagnosis: 33% (McDonald-I)

pts referred on the basis of clinical dx: MS in 46%

pts referred on the basis of MRI dx: MS in 11%

Non-MS dx:

Other neurologic disorders: 31.5 %

Probable psychiatric diagnoses: 22.5 %

No clear diagnosis made: 12.5 %

*Carmosino et al. Arch Neurol. 2005

Difficulties in MS diagnosis*

*Rudick & Miller. Neurology. 2012


*Solomon et al. Neurology, 2012

For MS experts & in MS centers

it is relatively common to see patients

diagnosed as MS, who in fact don’t have MS,

with a significant number of these misdiagnosed cases being on DMD!

26% of misdiagnosed

patients were on DMD for MS


Solomon et al. Neurology 2016

110 misdiagnosed patients in 4 MS

centers(not a population

based study)

vague neurologic symptoms & nonspecific

WM abnormalities in pts with migraine –

fibromyalgia –psychiatric conditions

70% received DMT and 31% experienced

unnecessary morbidity because of

misdiagnosis


In 5 – 35 % of people diagnosed as MS,the ultimate diagnosis is not MS!!!

migraine – fibromyalgia – psychiatric conditionsvague neurologic symptoms with

nonspecific white matter abnormalities on brain MRImisinterpretation and misapplication of radiographic diagnostic criteria

Solomon & Weinshenker. Curr Neurol Neurosci Rep, 2015


Diagnosing MS may be challenging!

Vague neurologic symptoms in young peopleInsignificant neurological findings

Nonspecific white matter abnormalities on brain MRI

False neuroimaging (MR) reportsThe urge (!) to diagnose MS early

MS and its masquerades

May cause over / false – diagnosis of MS!!!

Difficulties in MS diagnosis – the other way around!Missing the MS diagnosis – a recent survey in MS pts*

• 50% of respondents reported having ≧ 5 office/hospital visits before obtaining their MS Dx

• Most were initially misdiagnosed with another condition, including depression (25%),

migraine (15%),

fibromyalgia (14%)

psychiatric disorder (13%)

B12 deficiency (11%),

chronic fatigue syndrome (10%).

Interestingly, these are about the same diagnoses that were the “real” final diagnosis in patients initially misdiagnosed as having MS

of whom most had received unnecessary MS treatments!

*https://multiplesclerosisnewstoday.com/2017/05/01/survey-indicates misdiagnosis-of-ms-and-ineffective-treatments-arecommon/ accessed on May 1, 2017.

5300 MS pts

The Spectrum of MS and related disorders

MS sub+clinical

phenotypes

• RIS

• CIS

• SAMS

• SAPMS

• RRMS

• 20 PMS

• PPMS

MS

variants

•Tumefactive MS

•Balo’s

•Marburg’s

•Solitary sclerosis

•Schilder’s?

MS related disorders(once upon a time ago MS!)

• ADEM

• NMO / NMOSD

• aMOG-related

syndromes

• Others –Ab unknown? -

atypical CNS

inflammatory disorders?

MS diagnosis & misdiagnosis

Steps to MS Dx

• Clinical history

• Neurological examination

• Neuroimaging - MRI

• other laboratory testing (CSF & EP)

Problem areas

Neuroimaging in MS diagnosis

McDonald 2010 diagnostic criteria for MS (CIS!) MRI criteria

What’s new?

McD 2010 MS diagnostic MR findings – DIT*

DIS – Dissemination in space

≥ 1 T2 lesions in ≥ 2 regions of the following CNS areas

• juxtacortical

• periventricular

• infratentorial

• spinal cord

*Polman et al, Ann. Neurol 2011

McD 2010 MS diagnostic MR findings – DISjuxtacortical & periventricular & post fossa & spinal cord

Sub-cortical periventricularJuxta-cortical

Spinal cord lesionsPosterior fossa

lesions

Corpus callosumlesions

Sub-cortical

1

3

4

2

McD 2010 MS diagnostic MR findings – DIT*

DIT – Dissemination in time• ≥ 1 asymptomatic Gd enhancing lesion/s in the initial MRI

• New T2 lesion/s (Gd+Ø) on follow-up MRI

*Polman et al, Ann. Neurol 2011

Nodularenhencement

MS suggestive MR findingsGadolinium enhancing lesions

Open ring pattern

Ringpattern

McD 2010 MS diagnostic MR findingsspinal cord lesions

Spinal cord lesions

multiple Gd +

lesions

MR findings in MSthe nonspecific “plus” findings - "black holes!"

(T1) black holes

MR findings in MSthe nonspecific “plus” findings - ”cerebral atrophy"

2011 / OT, 35, M; SPMS

On DMD since 03/02

at 10 yrs: EDSS: 6

2015 EDSS: 6.5

2001 / OT, 25, M; New Dx

Sx: Visual blurring

EDSS: 1

Enlarged sulci

Severe atrophyof the corpus callosum

*Fillipi et al. Lancet Neurol, 2016

We propose an increase in the number of lesions necessaryto confirm involvement of the periventricular area from one to three,

and to add an additional cardinal CNS location, the optic nerve

An update on MRI criteria for MS diagnosisThe 2016 MAGNIMS consensus guidelines

*Fillipi et al. Lancet Neurol, 2016

An update on MRI criteria for MS diagnosisThe 2016 MAGNIMS consensus guidelines

*Lublin et al Neurology, 2014

Treatment decisions are

based on either clinical

but mostly on MRI

activity / progression

Defining the clinical courseof multiple sclerosis - the 2013 revision*

Disease activityClinical relapse &

MRI activity ➢ Gd(+) ±new or enlarging T2 lesion

Progressionconfirmed EDSS

This new definition is highly

MRI-dependent

MRI pitfalls in MS diagnosis

MRI criteria for MS diagnosis are not developed to differentiate MS from other conditions*

• but to identify high risk CIS patients for converting to MS

In the setting of clinical findings suggestive of MS

overreliance on MRI interpretation

• is the major cause of misdiagnosis

*Solomon & Weinshenker. Curr Neurol Neurosci Rep, 2015

MRI - possibilities and pitfalls in diagnosis of MS

In a patient who has been referred with a “clinical diagnosis” of probable MS

• MRI may confirm the clinical diagnosis of MS

• MRI may be suggestive of an alternative diagnosis

• MRI may exclude / eliminate thr probability of MS!

• MRI sometimes may cause further diagnostic confusion!


How to improve the role of MRI in the differential dx of MS?*

• Revealing the perivenular distribution pattern of MS lesions

– most MS lesions show a central vein

**the “central vein sign” (CVS)

• Detection of increased iron deposition within MS-related lesions

– most chronic focal and some acute focal lesions show increase in iron deposition

• Demonstration of cortical lesions

– Cortical lesions are abundant in patients with MS

*Rovira et al. Nature Reviews – Neurology, 2015; **Mistry et al. JAMA Neurol. 2013 & Mistry et al Multiple Sclerosis Journal 2016

How the MRI diagnosis of MS may be improved?

All pts whose condition was eventually diagnosed

as MS had central veins visible in the majority of

brain lesions at baseline. T2W7-T MRI had 100%

positive and negative predictive value for the diagnosis of MS. Clinical application

of this technique could improve existing diagnostic algorithms...

*Mistry et al. JAMA Neurol. 2013 & Mistry et al Multiple Sclerosis Journal 2016Sati et al. Nature Reviews Neurology, 2016


How to improve the role of MRI in the differential diagnosisof MS?

• Further studies are needed before intracortical lesion

detection, the ‘central vein sign’, and the susceptibility signal

within lesions can be incorporated in the diagnostic work-up of

MS (at standard field strength)

These require MRI systems that

operate at highmagnetic field

strengths (≥3.0 T) & sophisticated

software programs &sequences

Currently not for real-life

“common”practice

*Rovira et al. Nature Reviews – Neurology, 2015


In a patient who is diagnosed and followed as MS

MRI will also assist the clinician to

• Decide when to start long term treatment

• Decide whether the patient is a treatment responder or not!

• Decide when to change a DMD

• Predict the clinical course and prognosis (to a certain extent)

Clinically MS & MR consistent with MS

But, not all white spotsseen on MRI are MS!!!

32, M admitted because of dizziness & numbness in handshe receives an MRI diagnosis (radiologic report) of MS

The clinician agrees with this diagnosis and starts a DMD !A year later continues to describe the same symptoms – no change on MRI

But accepted as a non-responder (!) and his DMD is changed

A young man with dizziness, numbness in handsand T2 lesions on MRI

A year later he comes for another opinion to our center...Neuroexam normal; MRI unchanged! CSF: normal, no OCBs

Further work up including vasculitis/collagen disease panel & serology all normal

Lesions are bilateral & semi-symmetrical & largely subcorticalthere was no gadolinium enhancement in any study!

Follow up MRIs: no change in any MRI – no enhancement in any scanno atrophy – no T1 Black holes


First MRI 2004

Second MRI 2005DMD initiated

Third MRI 2006DMD switched!

MRI 2008Pt self-admittedto our MS center

Dx of MS orother CNS disease

is ruled out!

No spinal cord

lesions

Nocorpus callosum

Nopost fossa

Not MSNot MS


Patient was seen again about 3 years later in Apr 2014 because of dizziness and tension type headache - he was fine over the years with the

exception of a few episodes of dizziness closely related to life events!He was given duloxetine in 05.2014 and responded well.

His neuro-exam is normal and a f/up MRI done on 02/15 was unchanged

Follow up MRI: no change – no enhancement – no atrophy – no T1 Black holesNo posterior fossa and no spinal cord lesions


His final diagnosis is not MS

or any other significant neurologic disease

This individual is someone who turns out to have

Nonspecific neurological symptoms with

“NSWMA - nonspecific white matter abnormalities” on MRI

He also has an anxiety disorder and a tendency for somatization

His MRI changes are unlikely to be related to his symptoms

or to any other disorder

He was overdiagnosed with MS

and received unnecessary & toxic treatments

Difficulties in MS diagnosis by MRI

• Never rely on a radiologist’s report (whom you don’t know)!

• A clinical neurologist should understand neuro-imaging and be able to read what MRI abnormalities may say…

• When you are not sure about what MRI abnormalities may mean, then find a good neuroradiologist (whom you trust) to consult…

MS diagnosis by MRIclinical diagnosis should come first!

• the interpretation of MRI abnormalities and the imagingdifferential diagnosis always should be based on “clinicalgrounds” (Hx & Sx & signs)

• The clinical impression and diagnosis comes first!

imaging/MRI and all other lab tools should be used toconfirm or to exclude a clinical diagnosis!

• The MRI may lead you to a clinical diagnosis, only when it’shighly suggestive of a certain disease (i.e. MS!) and whenyour mind isn’t clear clinically!

Pink Flags!!!

MRI - possibilities and pitfalls in diagnosis of MS differential diagnosis

Neuro-imaging

In a patient, in whom the clinical symptoms are suggestive of MS

The MRI may disclose

• A normal study

• Atypical findings

• MS suggestive findings

• Findings fulfilling MS criteria

• Non-MS pathology (i.e.vasculopathies; neoplastic disorders...)

MRI - possibilities and pitfalls in diagnosis of MS differential diagnosis

Neuro-imaging

In a patient, in whom the clinical Sx are not suggestive of MS

The MRI may disclose

• MS suggestive findings

– incidental – it may be RIS!

– consider re-taking a detailed Hx – it may be MS!

MRI - possibilities and pitfalls in diagnosis of MS “think twice”

In an individual with MRI abnormalities suggestive of MS?

MRI findings atypical for MS – less likely to be MS

• Very small lesions (<3 mm)

• Absence of ovoid lesions

• Absence of posterior fossa & corpus callosum lesions

• Peripheric – subcortical - localization of white matter

lesions rather than periventricular / juxtacortical

• Symmetrical/semi-symmetrical lesions

• Unproportionaly large corpus callosum lesions

Posterior fossa and subcortical lesions on MRI “migraine”

ZC, 26 FAttacks of visual & sensorial aura, followedby a migrainous headacheIn some aura without headache•

Past family Hx: Mother alive/well&HTFather A/Well – has migraineSister A/W - has migraine

When the imaging findings surpassthe clinical features!

36y M with episodes of visual blurringand left hand & arm numbness, followed by headaches

Dx: Migraine with aura & W/up reveals large PFO!

Patient referred because of lesions on the MRI – Q of MS?Most lesions are subcortical; semi-symmetrical and frontal

very few JC & PV lesions - no posterior fossa and no spinal cord lesionsNo enhancement – No atrophy – No T1 black holes

AA 64 F, (28.01.2004)

Semi-symmetrical, semi-specific white matter lesionsCADASIL*

Characteristic MRI lesions in the ant.temporal & frontal poles,U-fibres, the basal ganglia, external capsule, insular regions andlacunar like infarcts within the corona radiata and SC regions.

Frequent sparing of corpus callosum and cerebellum

(

*Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

MRI possibilities and pitfallsin diagnosis and differential diagnosis of MS

MS

corpus callosum lesionssimilar with other T2 MS lesionsmostly will be at the genu & calloso-

septal interface!

The corpus callosum!

MRI possibilities and pitfallsin diagnosis and differential diagnosis of MS

Unproportionaly largecorpus callosum lesions

Susac’s

“Clinical triad”Encephalopathy

RetinopathyHearing ↓

The corpus callosum!

Susac’s Syndrome

*Rennebohm et al. / J Neurol Sci 2010

It is an autoimmune endotheliopathy

affecting the precapillary

arterioles of the brain,retina, and

inner ear

*Rennebohm et al. / Journal of the Neurological Sciences 299 (2010)


MRI abnormalities which may cause further confusion ?

MRI findings – not to be mistaken as MS lesions

• No gadolinium enhancement in any MRI

• Persistent gadolinium enhancement in all MRIs

[vascular lesions e.g., venous developmental anomalies may be

mistaken as enhancing demyelinating lesions]

• Continuous gadolinium enhancement in successive MRIs over

many months [Neurosarcoidosis, some infectious diseases]

• stable, punctate, patchy, and diffuse WM lesions with relatively

few touching the ventricles should be considered indeterminate

All possible in MS, but other diseases should be R/o first


In an individual with MRI abnormalities suggestive of MS?

Neurological imaging – MRI – atypical / unexpected in MS

• Large and multiple “perivascular spaces”

• No change in succesive MRIs – all MRIs are the same!

• Family members with similar / identical MRIs!

• Up/downward (edematous) extension of large brainstem les.

• Lesions with prominent mass effect

• Longitudinally extensive optic nerve lesions ∓ chiasmal involv

• Longitudinally extensive spinal cord lesions

All possible in MS, but other diseases should be R/o first!

MS and its clinical and MRI masquerades

CADASILSusacFabry

PCNSANeuro – Behcet

SLESjogren

Cerebral vasculapathies, which may mimic MS both clinically and on MRI!

These are disorders seen uncommonlymost will have some of the systemic finíngs of the disease

either some of their neuro-clinical or MRI features will be atypical for MS!

MS and its mimics - intraaxial (CNS) NBS*large brainstem lesions with up/downward extension

*NBS Neuro-Behcet

Syndrome

Intra-axial NBS

MS vs NBS – differential diagnosis*

MSMRI

• PV & SC lesions (+++)

BS lesions: small, discrete, extension (–)spinal cord lesions (++/short)

CSF

• Inflammatory changes (-)

OCB (+) [>90%]

CNS – NBSMRI

• PV & SC lesions (±)

BS lesions: large,

diffuse, extension (+)

spinal cord lesions (±long)

CSF

• Inflammatory changes (+)

OCB (–) [<20%]

* Siva & Saip. J Neurol, 2009

MRI possibilities and pitfalls

in MS diagnosis

“Tumefactive lesions”

when they may be MS and when not?

Tumefactive lesions

What could they be?• Brain neoplasms

• CNS lymphoma

• Abscesses

• PML!

• Vasculitic disorders & NBS!

• Tumefactive demyelinative

lesions (TDL)

Clues to the diagnosis of TDL include*

• Less mass effect than expected for their size

• open ring enhancement

• no increased perfusion

• visualisation of veins coursing through the lesion

*Kaschka et al 2014

Tumefactive lesions – MS or not?

Tumefactive demyelinating lesions are well-demarcated, hyperintense on T2, hypointense on T1-wMRI.

Ring enhanc with Gd is characteristic, >open ring, the open portion abuts the GM of the cortex (or BG).

Size of the lesion (>20mm), the relative lack of mass effect, and edema are helpful radiological findings

Biopsy provenacute demyl

Tumefactive lesions – MS

“Tumefactive MS” lesions may be seen with other MS suggestive lesions

then the diagnosis becomes easier!

However, it should be kept in mind that MS and brain tumors

although highly unlikely may be seen together in an unfortunate individual!

MRI possibilities and pitfalls in MS diagnosismultiple brain lesions!

*

Multiple CNS lesions +/- enhancement - What they might be?

• Acute disseminated encephalomyelitis (ADEM)

• Metastatic tumors

• CNS lymphoma

• CNS toxoplasmosis (>HIV related)

• CNS tuberculosis

• CNS cystisercosis

• CNS hydatid cysts

• Other CNS infections

• CLIPPERS!!!

MS and its MRI mimics – multifocal glial tumors

18 02 09

43y, Msubacute

development ofR- hemiparesis!

MS and its mimics – multifocal glial tumors

06 03 09

Brain biopsy:multifocal

GBM!

Multiple brain lesions!A patient with subacute onset of optic neuritis!

42 F teacher

• 07/16 R-ON

• Admitted with a 10 days hx of

visual loss on the right / ⍉pain

• No significant past/family hx

• Neuroexam: R-visual loss

otherwise intact

• MRI & spinal tap done

• extensive w/up initiated

• ivmp 1gx10 days started

MRI 13 JUL 2016

Multiple brain lesions!A patient with subacute onset of optic neuritis!

42y F teacher

• Patient respond well to ivmp and improves initially, but within a week after stopping steroids R-ON reccurs! Optic neve and chiasma continue to enhance…

• Serum studies and serology all (-) Lyme(-) tbc (-) aHIV – pending!

• CSF had shown no cells

• normal biochemistry

no OCB; IgG index: 0.34 IgG: 5.9 ↑

viral w/up shows EBV DNA IgG (+)

others (-)

• Chest x-ray (-)

MRI 13 JUL 2016

A patient with subacute onset of optic neuritis!

42y F teacher, MRI - 01 Aug 2016 - after reccurance of R-ON

eccentrictarget sign

Her lab studiesconfirms her diagnosis

AHIV (+) & CD4+cells:73

Cerebral toxoplasmosis

remains one of the

most commonfocal brain lesions

in patients with AIDS

Multiple brain lesions!A patient with hearing loss and facial numbness!

• 33 M with a past Hx of psoriasis

• Gradual onset R-hearing loss over two weeks followed by

• L-facial numbness

• Neuroexam – R↓hearing, otherwise nonsignificant

• MRI study - multiple enhancing lesions!

• CSF study – no cells! Protein slightly elevated (56)

OCB (+) pattern IV (similar bands both in serum/CSF)

A patient with hearing loss and facial numbness!

Extra-axial cranial nerve enhancement

suggestive of infiltration!

Intra-axial PV ependymal

enhancement suggestive of infiltration!

A patient with hearing loss and facial numbness!

• 33 M with a past Hx of psoriasis

• Gradual onset R-hearing loss over two weeks followed by

• L-facial numbness

• Neuroexam – R↓hearing, otherwise nonsignificant

• MRI study - multiple enhancing lesions!

• CSF study – no cells! Protein slightly elevated (56)

OCB (+) pattern IV (similar bands both in serum/CSF)

• Thorax CT(+) - nonsignificant

• PET whole body study – nonsignificant

• Brain biopsy – diffuse large cell - B cell lymphoma

Multiple brain lesions!19 yrs old girl with dysarthria & ataxia

• 19 F – living in another city & seen in her hometown a year ago

• 04/16 – First admission: Gradual onset R-facial & tongue numbness; followed by dysarthria & ataxia

• MRI study - multiple juxta/sub-cortical and posterior fossa enhancing lesions including dorsal pons right middle cerebellar ped

• CSF study – no cells! Protein slightly elevated (49 mg/dL)

OCB (+) pattern III

• Dx: SAMS!

• Rx – IVMP X 5 days, improves but Sx & signs return in 20 days after stopping steroids! Re-treated with IVMP – over the next couple of months a fluctuating course dependent on steroids & INFb-1b is started, but she got worst!

19 yrs old girl with dysarthria & ataxia


• 04/17 – 19 yrs F – referred to our center

• CBC, Serum and urine analyses, ACE levels, syphilis, Borrelia,

Brusella, HIV, Hepatitis panel, tuberculous quantiferon test all were

negative; hemathologic w/up; thorax CT & PET studies did not reveal

any pathology

• CSF (repeat study) slightly high protein level (48 mg/dl) no cells!

Microbiology/cito (-) IgG index 0.68

• No evidence of lymphoma, sarcoidosis, vasculitic, infectious diseases

• A brain biopsy was performed


…microscopic examination showed lymphocytic infiltration with perivascular cuffing and peripherally, partial inflammatory infiltration with lymphocyte predominance which caused secondary hyalinization. The majority of the cells which constituted lymphoid infiltrating cells included CD3 + T lymphocytes. The vast majority of T lymphocytes were CD4+ and to a lesser extent, CD8+ T suppressors were observed. T lymphocytes, particularly in the perivascular area, were accompanied by CD20 + B lymphocytes to a small degree. A small number of plasmacytomas which were observed to show kappa and lambda positivity equally were accompanied by lymphocytes No granuloma formation was observed. CD34 positivity was present in the vessel walls and there was no evidence of primary vasculitis. No inflammatory agent was observed with tissue Giemsa and PAS staining. Current histopathologic findings were considered to be compatible with CLIPPERS Syndrome…[neuropathology - Prof. Buge Oz]

Biopsy site

CLIPPERS

• Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)*

• A recently described treatable, inflammatory brainstem predominant encephalomyelitis*

• Dif Dx (Major – mimicking diseases)– Lymphoma

– Histiocytosis (Langerhans / ECD)

– MS

– Vasculitis

• New diagnostic criteria proposed…**

*Pittock et al BRAIN, 2010; **Tobin et al; BRAIN (in press)

MRI possibilities and pitfalls in MS diagnosis

Other (atypical) primary

inflammatory demyelinating disorders

&

Other MRI mimics of MS

MRI possibilities and pitfalls in MS diagnosisOther inflammatory demyelinating disorders

• Acute disseminated encephalomyelitis (ADEM)

• Multiple CNS large lesions with simultaneous enhancement

• Neuromyelitis optica spectrum disorders (NMO/NMOSD)

• Single symptomatic spinal lesion – long / LETM &

nonspesific lesions

• MOG-Ab related inflammatory demyelinating syndromes

• ADEM-suggestive lesions / multiple spinal lesions !

• Idiopathic transverse myelitis

• Single symptomatic spinal lesion – short / no other lesions

• Isolated – idiopathic ON

• Single symptomatic optic nerve lesion / no other lesions

Atypical inflammatory demyelinatingsyndromes of the CNS*

Recognition of these syndromes is crucial because they differfrom multiple sclerosis and other demyelinating and nondemyelinating

conditions in their prognosis and treatment

• Atypical inflammatory demyelinating syndromes are rare disorders that differ from MS owing to unusual clinical or MRI findings or show poor response to treatments used for MS

• These syndromes include NMO/NMOSD, ADEM, tumefactive demyelination, Balo’s concentric sclerosis, Schilder’s disease, and Marburg’s MS

*Hardy et al. Lancet Neurol 2016

Atypical inflammatory demyelinatingsyndromes of the CNS*

When to suspect atypical demyelinating syndromes, inflammatory astrocytopathies or other diseases mimicking multiple sclerosis?*

In patients who presents with;

• an atypical syndrome

• atypical MRI findings

(eg, one large presumed demyelinating MRI lesion or multiple

demyelinating-like lesions showing simultaneous gad enhancement)

• a typical syndrome with atypical MRI findings or an atypical syndrome with typical MRI findings!

• an atypical course

(eg, rapid and severe clinical deterioration)

• not responding or deteriorating following effective MS treatment

*modified from Hardy et al. Lancet Neurol 2016

Atypical inflammatory demyelinating syndromes of the CNS

Which “antibodies” may be studied in patients who are suspected

to have atypical demyelinating syndromes, inflammatory

astrocytopathies or other inflammatory diseases mimicking MS?*

• AQP4-IgG

• aMOG—IgG

• aNMDAr-IgG and other Abs for autoimmune encephalopathies

• Antibody-panel for vasculitic/collagen (rheumatologic) disorders

(ANA, adsDNA; RF; SSA & SSB; ACl)

• Antibody panel for paraneoplastic disorders

• Antibodies for infectious disorders

Progressive solitary sclerosis*

Solitary sclerosis

• progressive motor impairment

• a single radiologically identified CNS demyelinating

lesion of the CST in cerebral,

brainstem, cervico-medullary

junction or spinal cord white

matter

• absence of other demyelinating

CNS lesions

• no history of relapses or

involvement of CNS sites

*Schmalstieg et al. Neurology, 2012; Lattazi et al MSJ 2014; Keegan et al. Neurology, 2016

Acute Disseminated Encephalomyelitis

ADEM is an acute monophasic disease

with polysymptomaticpresentation that generally includes encephalopathy

It requires early anti-inflammatory

treatment, whereaslong-term

immunomodulatory therapies are

considered unnecessarydue to the self-limiting nature of the disease


31 M with severe headache of 10 days and dullness - biopsy proven ADEM – fullrecovery – no further events after this episode- Courtesy of S.Saip, M.D.

13.10.2005


Multiple relatively large edematous WM lesions with simultaneous enhancementCourtesy of S.Saip, M.D.

13.10.2005

ADEM – MRI findings

• MRI shows diffuse, poorly demarcated, large, >1–2 cm lesions involving predominantly the cerebral white matter

• the subcortical and deep white matter is more often affected than periventricular regions

• lesions are not oriented perpendicular to the lateral ventricles

• all lesions have same age – may show simultaneous enhancement

• one third of cases show additional cord lesions

• Lesions are new – there are no black holes•

• deep grey matter (thalamus, basal ganglia) lesions may be seen

• no new MRI findings after 3 months of the incident ADEM

Neuromyelitis Optica Spectrum Disorders

Weinshenker, Archives Neurol, 2007

…and the spinal cord!


In an individual with parenchymal spinal MRI abnormalitiessuggestive of inflammatory pathology...possibilities are;

When it is a “small spinal cord lesion” [<3 segments]

• MS

• Transverse myelitis

• Short segment or recovering NMO / NMOSD – myelitis

• Myelitis associated with systemic vasculitic or collagen

tissue disorders

• Tumors (i.e.astrocytoma; ependymoma)

• Infectious disorders


MS - Spinal cord lesions

• do not extend over more than three vertebral segments

• are eccentric /laterally located (on axial images)

• may have focal (nodular or peripheral) gad-enhancement

• other CNS lesions are likely

• Dif. Dx. Isolated myelitis; tumors; PVS; vascular; infectious;

NMOSD (short segmental lesions may also be seen at

onset and during periods of recovery in NMOSD)


MSBrain MR+

Spinal lesionSmall

peripheralGd+

RecoveringNMO-myelitis

Transversemyelitis


In an individual with parenchymal (intra-axial) spinal MRI abnormalities

suggestive of inflammatory pathology...possibilities;

When it is a “longitudinally extensive spinal cord lesion” [>3 segments]

• NMO / NMOSD – myelitis

• Transverse myelitis

• MS – multiple small lesions in contiguity suggestive of a single LETM-lesion

• Myelitis assoiated with systemic vasculitides & collagen tissue disorders

• Spinal venous dural fistula

• Tumors (i.e.astrocytoma; ependymoma)

• Infectious disorders (i.e. viral, tbc, lyme)

• Granulomatous disorders (i.e. Sarcoidosis)

• Metabolic & toxic disorders

• Inherited disorders

Longitudinally extensivespinal cord lesionsLETM / NMO / NMOSD

widespreadheterogenous Gd

enhancement

“Brighter T2-hyperintense spotty lesions (T1W-hypo)

within the spinal cord lesion may differentiate

NMO from MS!*

*Yonezu et al. MS J 2014 & Hyun et al JNNP 2015

Bright spottylesions*

MRI possibilities and pitfalls in MS diagnosis - LETMOther inflammatory demyelinating disorders - NMOSD

MOG-Ab+ related inflammatory demyelinating syndromes

No spesific patternto be suspected in ptswith ADEM-like lesions

ortumefactive lesions

orin pts with no or atypical

cerebral lesions and multiple spinal cord lesions

± dorsocaudal LETM

NS, 49 F - Dx. APS & SLE & MS? NMOSD? AQP4-Ab all times negativeRx with oral AC + mycophenolate mofetil (MMF) + GA - MOG-Ab recently was detected (+)

Longitudinally extensive spinal cord lesions

Longitudinally extensive spinal cord lesionneurosarcoidosis

Long linear subpial Gd

enhancement

52F recent onset of disturbing paresthesiasand mild weakness of lower extremities

neurosarcoidosis

tridenthead sign

3-pronged spear like

appearence

Long & largespinal cord

lesions

MRI possibilities and pitfalls in diagnosisInflammatory granulomatous disorders- Neurosarcoidosis

*

Neurosarcoidosis

• Basal meningitis / Leptomeningeal enhancement in about 40%

• Hydrocephalus

• Hypothalamic involvement and/or pituitary fossa involvement

• Parenchymal – nonspecific lesions - areas of increased T2 signal with or

without enhancement at SC and/or PV regions

• intraparenchymal lesions exhibit Gad enhancement that persists without

treatment!

• Sarcoid myelitis can be longitudinally extensive. Root involvement as well as

linear and/or nodular enhancement along the surface of the spinal cord ±

intramedullary extension suggests sarcoidosis

MRI possibilities and pitfalls in MS diagnosisInflammatory granulomatous disorders- Neurosarcoidosis

55 yrs university prof admitted with dysarthria, imbalance, L-sided weaknesswith known past Hx of sarcoidosis

"Bagel Sign" patternA central lesion with

hypointensecore and hyper-intense

rim with or without contrast enhancement

T2W mid-sagittal image reveals a

longitudinally extensive central spinal cord

lesion, a swollen spinal cord

and T2W hypointensitycorresponding to the center of “Bagel Sign”

as observed in axial T2W image

Longitudinally extensive spinal cord lesions - NBD

Bagel Sign*

*Myelopathy in Behc ̧et’s Disease: The Bagel Sign

*Uygunoglu et al. Ann Neurol, 2017

Longitudinally extensive spinal cord lesions

spinal venous dural fistula

Gd +enchancing

vascularstructures

peri-cordialvascular

abnormalitiesLETMlower dorsalspinal cord

52y M with progressivespastic paraparesis

draining dilated intra & perimedullary veins

“serpent-like” tortuous strutures

Longitudinally extensive spinal cord lesionsDifferential diagnosis

58 yrs old womanwith gradually progressive

numbness and tingling sensationon her L-arm and hand with recent onset ipsilateral mild weakness

Dif Dx included spinal (most likely primary) tumor, hoping that the final dxmay turn out to be a spondylitic myelopathy or a form of inflam myelitis!Biopsy -unfortunately- confirmed the dx as a grade II-III glial tumor

Another not so good-looking long & largespinal cord lesion!

Subacute combined degeneration of the spinal cord due to vitamin B12

(cobalamin) deficiency* • symmetrical high T2 signal post &

lateral columns • cervical and upper thoracic cord• inverted V-shape sign• unlikely to enhance• rarely early cord swelling

Copper deficiency myelopathy a similar type of myelopathy

more common as a neurological complication of bariatric surgery**

a-Tocopherol deficiency & some other metabolic-toxic myelopathies*

similar spinal MRI findings

Longitudinal(ly extensive) spinal cord lesionsMetabolic & toxic myelopathies*

InvertedV-shape

sign

*Hedera P. Handb Clin Neurol. 2016Kumar. Semin Neurol 2012

**Kumar et al. Neuroradiology, 2006 & Jaiser & Winston J Neurol. 2010

Bagelsign

Tridenthead sign

Brightspottylesion

NBS Neurosarcoidosis NMO

Longitudinally extensive spinal cord lesionsDifferential diagnosis*

*Siva A. Neurol Clinics North America, in press;Uygunoglu et al, Ann Neurol 2017; Zawlewski et al. Neurology 2016; Yonezu et al. MSJ 2014 & Hyun et al JNNP 2015

Longitudinal spinal cord lesionsDifferential diagnosis – inherited disorders

A 32y F with subacute onset of paraparesis progressing to significant gaitdifficulty over a month; then having a fluctuating course with limited progression and depression

Leukoencephalopathy with brainstem and spinal cord involvement and high (or normal) lactateSelective pyramidal tract involvement and cerebellar connections are involved as well as the intraparenchymal trajectories of the trigeminalnerve and long tract involvement of the spinal cord are almost diagnostic


MRI mimics of MS

MRI possibilities and pitfalls in diagnosis

*Weisfeld-Adams et al. Brain, 2015

Single gene disorders that share clinical & radiologic characteristics with MS

• lysosomal storage disorders

• neurometabolic disorders

• various mitochondrial diseases

• several other miscellaneous disorders

MRI possibilities and pitfalls in MS diagnosismitochondrial disorders

This is a group of rare multisystem disorders caused by a variety of genetic

defects affecting the mitochondrial metabolism

• Multisystem involvement

• Clinical presentation

• A positive family history

• Cortical & deep gray matter involvement in a non-vascular pattern

• Asymmetrical or symmetrical white matter non-specific involvement

• Calcified cerebral lesions might be the clue

Leber’s hereditary optic neuropathy, chronic progressive ophthalmoplegia

and mitochondrial encephalomyelopathy, lactic acidosis and stroke-like

episodes (MELAS) might be difficult to distinguish radiologically from MS


Single gene disorders sharing clinical & radiologic characteristics with MS

Presence of the following findings - not suggestive of MS…

• Symmetrical WM involvement of the cerebral hemispheres

• Cerebral involvement limited to long tracts (>post int cap & brain stem)

• Spinal cord involvement limited to long tracts – longitudinal lesions

• T1 hyperintensities of thalamic pulvinar

• T2 (symmetric) hyperintensities of dentate nucleus

• Multiple subcortical cystic cavitations

Absence of the following findings - not likely in MS…

• Lack of ovoid lesions

• Lack of spinal cord involvement

• Lack of Gad-enhancement (exception – adrenoleucodystrophies)

* Adapted from Weisfeld-Adams et al. Brain, 2015

No MRI finding should be interpreted

independent from the clinical presentation

There is only one exception!The “Radiologically Isolated Syndrome”

Radiologically Isolated Syndrome – dx criteria*

Okuda et al. Neurology, 2009

No clinical symptoms or signs suggestive MS

An initial MRI fulfilling at least 3/4 Barkhof criteria for DIS

MRI done for other reasons unrelated to MS

MRI – CNS anomalies not attributable to another diseaseprocess or to any other medical condition

MRI anomalies not associated with any functional impairment

should MRI criteriafor RIS

needs to be updatedaccording to the new

McDonald 2010+ beyond criteria?

Barkhof criteria forDIS - 3 of 4:

≥9 T2 lesions or 1 Gd+ ≥3 PV / ≥1 PF / ≥1 JC

MRI possibilities and pitfalls

in diagnosis of MS

WRAP-UP


Shortcomings that may lead to erroneous diagnoses in patients “who are suspected to have MS”*

• MRI examinations –that- are nonstandardized and often of inadequate quality

• scans –that- might be read by radiologists lacking expertise in this field and without consideration of relevant clinical and laboratory data

• the simplified and less-restrictive McDonald’s 2010 MRI criteria –that- might compromise diagnostic specificity leading to overdiagnosis



Shortcomings that may lead to erroneous diagnoses in patients “who are suspected to have MS”*

• MRI examinations –that- are nonstandardized and often of inadequate quality

• scans –that- might be read by radiologists lacking expertise in this field and without consideration of relevant clinical and laboratory data

• the simplified and less-restrictive McDonald’s 2010 MRI criteria –that- might compromise diagnostic specificity leading to overdiagnosis


and –that-is real-

life“common”practice

Incorrect MRI reports and its consequences

Incorrect radiological-MRI reports

• False T1 Gd+ lesions

• Incorrectly reported additional T2 lesions

• Overreadings...

Such incorrect reports may result in unnecessary IVMP treatments and/or

inappropriate DMT switches!!!

Problem areas in MRI diagnosis of MS

Technical

• Having f/up MRI studies at different centers / with dif MRs

• Lack of standardization of MRI studies

• Lack of knowledge of MS MRI protocols at the study centers

• Different slice thicknesses / different sequences

• Application of Gd-contrast at low dose

• Scanning without waiting after giving the Gd-contrast media


Incorrect MRI evaluations – radiologist related causes

• Lack of knowledge – lack of proper training

• Lack of experience

• Overload of work – too many MRI reports / too little time

• The non-professional understanding of “I will report

everything I see - or I think I see - and will leave it to the clinician

to decide what they are!”


Incorrect MRI evaluations – neurologist related causes

• Not looking to the images – just reading the report!

• Not interpreting the MRI her/him-self, lack of

neuroradiology training!

• The unfortunate changes in the healthcare and

educational systems, in which the “patient centric

evaluation and care” understanding is losing grounds or

completely forgotten!

Not likely to be MS!

Normal CSF & (-) OCBs ⇒ think twice!

Normal MRI* ⇒ unlikely to be MS

Normal MRI & CSF ➢ can’t be MS!!!

*MRI of brain and spinal cord

The other side of the coin!

Abnormal CSF ➣ (+) OCBs not always MS!

Abnormal MRI ➣ not always MS

or not clinically significant “MS!”

…we need to see the whole pictureand we need to see the patient

through the clinician’s eyes in her/his MRI

Clinical and MRI clues and pitfalls in the diagnosis and ......Clinical and MRI clues and pitfalls...

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Transcript of Clinical and MRI clues and pitfalls in the diagnosis and ......Clinical and MRI clues and pitfalls...