Teaching Course 8 Differential diagnoses and diagnostic ... · Teaching Course 8 Differential diagnoses and diagnostic dilemmas Chairs: S. Fredrikson (Stockholm, SE) A. Siva (Istanbul,

Teaching Course 8 Differential diagnoses and diagnostic dilemmas

Chairs: S. Fredrikson (Stockholm, SE)

A. Siva (Istanbul, TR)

15 Diagnostic and differential diagnostic aspects in MS

S. Fredrikson (Stockholm, SE)

16 MRI – possibilities and pitfalls in diagnosis of MS

A. Siva (Istanbul, TR)

17 Heterogeneity of idiopathic inflammatory demyelinating

disease

S. Vukusic (Lyon, FR)

19/08/2015 Name Surname 1

Diagnostic and differential diagnostic

aspects of multiple sclerosis

Teaching course 8, ECTRIMS 2015

Sten Fredrikson

Professor of Neurology

Division of Neurology

Department of Clinical Neuroscience

Karolinska Institutet

Stockholm, Sweden

”Multiple sclerosis is what a good

clinician would call multiple

sclerosis”

John Kurtzke, 1970

”Nothing shuts off critical

neurological thought processes

faster than a diagnosis of

multiple sclerosis”

Semin Neurol 1985:5:94-98

Key Steps in the Diagnostic Process

§ History:

à Previous episodes

à Other diseases

à Family history

§ Comprehensive physical examination:

à ‘Objective evidence’

à Other lesions

§ Additional tests:

à MRI

à CSF

Megacystic MS

Balo-like MS

Infiltrative

MS

Benign MS

RIS

Tumefactive

MS

PPMS SPMS

RRMS

Devic

Schilder

Marburg

NMO AHL

ADEM

CIS

Idiopathic inflammatory

demyelinating lesion

The evolution of MS

Clinical

Threshold

MRI Activity

Total lesion load

CIS RRMS SPMS RIS

McDonald

MS Poser

CDMS

First clinical

event

Adapted from Trapp BD et al. Neuroscientist. 1999;5(1):48-57

Figure 3. Overview of the indications for MRI

in published cohorts, n=394. 4,6 –12,23,26 ...

Granberg T et al. Mult Scler 2012;19:271-280

Copyright © by SAGE Publications

RIS

Radiologically isolated syndrome

§ Approximately two-thirds of persons with RIS show radiological

progression and one-third develop neurological symptoms

during mean follow-up times of up to five years. Cervical cord

lesions are important predictors of clinical conversion.

Mult Scler Jour 2013 Mar;19(3):271-80..

Radiologically isolated syndrome--incidental magnetic resonance imaging

findings suggestive of multiple sclerosis, a systematic review.


What is a Clinically Isolated Syndrome?

§ A clinically isolated syndrome (CIS) is a first acute or subacute

episode of neurological dysfunction with a high suspicion of

development of multiple sclerosis

§ A CIS is usually the first clinical event in an MS patient

§ Magnetic resonance imaging (MRI) findings compatible with:

à No or minimal oedema/mass effect

à T2-hyperintense lesions

à Contrast enhancing lesions

à Location of lesion

§ Spontaneous or steroid responsive remissions

To exclude other pathologies that may underly the same syndrome

(Always look for RED FLAGS, Miller DH, Mult Scler 2008:14:1157-74)

10 Tobias Granberg

Multiple sclerosis and diagnosis

§ The main principle: dissemination in time (DIT) and space (DIS)

§ Schumacher 19655

§ Poser 19836

§ McDonald 20017

§ Reviderade McDonald 2005 (Polman)8

§ Reviderade McDonald 2010 (Polman)9

§ Demonstration of DIS and DIT with MRI:

§ Paty 198810

§ Barkhof 199711

§ Reviderade Barkhof (Tintoré) 200012

§ Swanton 200613

5. Schumacher GA, et al. Problems of Experimental

Trials of Therapy in Multiple Sclerosis: Report by the

Panel on the Evaluation of Experimental Trials of

Therapy in Multiple Sclerosis. Ann N Y Acad Sci.

1965;122(1):552–68.

6. Poser CM, et al. New diagnostic criteria for multiple

sclerosis: Guidelines for research protocols. Ann

Neurol. 1983;13(3):227–31.

7. McDonald WI, et al. Recommended diagnostic criteria

for multiple sclerosis: guidelines from the International

Panel on the diagnosis of multiple sclerosis. Ann

Neurol. 2001;50(1):121–7.

8. Polman CH, et al. Diagnostic criteria for multiple

sclerosis: 2005 revisions to the “McDonald

Criteria.”Ann Neurol. 2005;58(6):840–6.

9. Polman CH, et al. Diagnostic criteria for multiple

sclerosis: 2010 Revisions to the McDonald criteria. Ann

Neurol. 2011;69(2):292–302.

10. Paty DW, et al. MRI in the diagnosis of MS: a

prospective study with comparison of clinical

evaluation, evoked potentials, oligoclonal banding, and

CT. Neurology. 1988;38(2):180–5.

11. Barkhof F, et al. Comparison of MRI criteria at first

presentation to predict conversion to clinically definite

multiple sclerosis. Brain. 1997;120(11):2059–69.

12. Tintoré M, et al. Isolated demyelinating syndromes:

comparison of different MR imaging criteria to predict

conversion to clinically definite multiple sclerosis. Am J

Neuroradiol. 2000;21(4):702–6.

13. Swanton JK, et al. Modification of MRI criteria for

multiple sclerosis in patients with clinically isolated

syndromes. J Neurol Neurosurg Psychiatry.

2006;77(7):830–3.

20 mars 2014

Ann Neurol 2011:69:292-

Recent radiological classifications

for MS lesions


Tintoré M, et al. Isolated demyelinating syndromes: comparison of different MR

imaging criteria to predict conversion to clinically definite multiple sclerosis. Am J

Neuroradiol. 2000;21(4):702–6.

Swanton JK, et al. Modification of MRI criteria for multiple sclerosis in patients with

clinically isolated syndromes. J Neurol Neurosurg Psychiatry. 2006;77(7):830–3.

Diagnostic criteria for Multiple Sclerosis:

2010 Revisions to the McDonald Criteria Ann Neurol 2011:69:292-302

Oligoclonal bands

Nature Rev Neurol 2013:9:267-276

Frequencies of abnormal CSF

variables in clinically definite MS

Oligoclonal IgG in CSF >95%

Increased IgG index 70-80%

Increased cell count 50%

Abnormal albumin ratio 12%

Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report

J Neurol Neurosurg Psych 1994:57:897-902

Andersson M, Alvarez-Cermeno J, Bernardi G, Cogato I, Fredman P, Frederiksen J,

Fredrikson S, Gallo P, Grimaldi LM, Gronning M, Keir G, Lamers K, Link H, Magalhaes

A, Massaro AR, Ohman S, Reiber H, Rönnbäck L, Schluep M, Schuller E, Sindic CJM,

Thompson EJ, Trojano M, Wurster W.

Differential diagnosis based on

presenting symptoms from the brainstem,

spinal cord, optic nerves or cerebrum.

Mult Scler 2008:14:1157-74

MS Less common Atypical

Internuclear

ophthalmoplegia

Facial palsy,

facial myokymia

Ataxia and

multidirectional

nystagmus

Deafness Vascular territory

syndrome, e.g.,

lateral medullary

Sixth nerve palsy One-and-a-half

syndrome

Third nerve palsy

Facial numbness Trigeminal

neuralgia

Progressive

trigeminal sensory

neuropathy

Paroxysmal

tonic spasms

Focal dystonia,

torticollis

Brain stem presentation


Unilateral optic

neuritis

Bilateral

simultaneous

optic neuritis

Progressive optic

neuropathy

Pain on eye

movement

No pain Severe, continuous

orbital pain

Partial and mainly

central visual

blurring

No light

perception

Persistent

complete loss of

vision

Normal disc or

mild disc swelling

Severe disc

swelling

Neuroretinitis

(optic disc swelling

with macular star)

Uveitis (mild,

posterior)

Uveitis (severe,

anterior)

Optic nerve presentation


Partial myelopathy Complete transverse

myelitis

Anterior spinal artery

territory lesion (sparing

posterior columns only)

Lhermitte’s symptom Radiculopathy,

areflexia

Cauda equina

syndrome

Deafferented hand Segmental loss of

pain and

temperature

sensation

Sharp sensory level to

all modalities &

localised spinal pain

Numbness Partial Brown-

Sequard syndrome

(sparing posterior

columns)

Complete Brown-

Sequard syndrome

Urinary urgency,

incontinence, erectile

dysfunction

Faecal incontinence Acute urinary retention

Progressive spastic

paraplegia

(asymmetrical)

Progressive spastic

paraplegia

(symmetrical)

Progressive sensory

ataxia (posterior

columns)

Spinal cord presentation

Cerebral presentation


Mild subcortical

cognitive

impairment

Epilepsy Encephalopathy

(obtundation,

confusion,

drowsiness)

Hemianopia Cortical blindness

Hemiparesis Chorea,

myoclonus

Generalized

movement disorder

or Parkinsonian

syndrome

Some differential diagnosis to MS

§ ADEM, NMO, AHL, PML, Balo

§ Systemic: Sarcoidosis, SLE, Behcet, Sjögren, Wegener

§ Vascular: Stroke, Vasculitis, CADASIL, anti-phospholipid

syndrome, AV-malformations, hemangioma

§ Metabolic: Leukodystrophies (metachromatic/adreno-),

mitochondrial disorders (MERFF, MELAS, Leber), B12-

deficiency

§ Genetic: SCAs, Friedreich, HSP

§ Neoplastic: Lymphomas, paraneoplastic syndromes

§ Infection: HIV, syphilis, Borrelia, herpes, Whipple

§ Psychiatric

§ Others (toxic, compression, neuromuscular (MG) etc)

RED FLAGS § Lung involvement

§ Multiple cranial neuropathies or polyradiculopathy

§ Peripheral neuropathy

§ Tendon xanthomas

§ Cerebral venous sinus thrombosis

§ Cardiac disease

§ Myopathy

§ Renal involvement

§ Cortical infarcts

§ Haemorrhages/microhaemorrhages

§ Extrapyramidal features/ Movement disorders

§ Livedo reticularis

§ Retinopathy

§ Calcifications on CT scans

§ Bone lesions

§ Diabetes insipidus

§ Increase serum lactate level

§ Selective involvement of the anterior temporal and inferior frontal lobe

§ Hematological manifestations

§ Lacunar infarcts

§ Mucosal ulcers

§ Myorhythmia

§ Hypothalamic disturbance

§ Recurrent spontaneous abortion or thrombotic events

§ Simultaneous enhancement of all lesions

§ Rash

§ Arthritis, polyarthalgias, myalgias

§ Amyotrophy

§ Headache or meningismus

BUT REMEMBER:

§ Age?

§ Abrupt onset?

§ Lack of typical symptoms?

§ Family history?

§ Normal examination?

§ Normal MRI/CSF?

What differ age related changes on MRI from MS?


Red flags on MRI

§ Persistent Gd-enhancement and continued enlargement of

lesions

§ Persistently unifocal manifestations

§ Large and infiltrating brainstem lesions

§ Predominance of lesions at the cortical/subcortical junction

§ Meningeal enhancement

§ T2-hyperintensity in the dentate nuclei

§ No "black holes“

§ Large lesions

§ Marked asymmetry of WM lesions

§ No enhancement

Blood tests in MS diagnosis???


In conclusion…

MS remains a diagnosis requiring an

expert neurologist

Differential diagnosis are many, but they can

usually be excluded by considering “red flags”

Although a disease specific marker does not exist, a

robust diagnosis can usually be established early

after onset in most cases after weighing

clinical-, CSF- and MRI-data

References

§ Miller DH, et al: Differential diagnosis of suspected multiple

sclerosis: a consensus approach. Mult Scler 2008:14:1157-1174

§ Rolak LA, Fleming JO: The differential diagnosis of multiple sclerosis. The neurologist. 2007:13:57-72

§ Stangel M et al: The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nature Rev Neurol 2013:9:267-276

§ Hahn JS, et al: Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology 2007:68 (suppl 2):S13-S22

§ Polman CH et al: Diagnostic criteria for Multiple Sclerosis:2010 revisions to the McDonald Criteria. Ann Neurol 2011:69:292-302

§ Lublin F et al: Defining the clinical course of multiple sclerosis. The 2013 revisions. Neurology 2014:83:278-286

1

Multiple Sclerosis Differential diagnoses and diagnostic dilemmas

MRI - possibilities and pitfalls in diagnosis of MS

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

Istanbul University Cerrahpaşa School Of Medicine [email protected]

ECTRIMS 07 October 2015, Barcelona

Diagnostic criteria in “MS”

•  Schumacher et al, 1965 "a clinical 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” Diagnosing MS

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

•  Evidence of dissemination in space (multifocality)

•  Evidence of dissemination in time (recurrent attacks or steady progression)

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

Multiple Sclerosis

The basis of diagnosis is to clinically establish that • disease activity has affected more than one part of the CNS "dissemination in space" and • on more than one occasion "dissemination in time" However, we now know that • MS is an ongoing disease and • MS involves more widely – diffusely the CNS

…and, how do we now

that?

Clinical Hx Neuro-exam and, by MRI!

Clinical Hx Neuro-exam and, by MRI!

Clinical Symptoms & Signs suggestive of ”MS”

Imaging Cranial & Spinal MRI suggestive of “MS”

Clinical & Imaging findings suggestive of MS

Diagnosis and Differential Diagnosis of MS

Patients are admitted to neurology outpatient clinics because of...

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

2

A first concern!

•  What should be our first concern in the general neurology out-patient clinic?

•  Could it be MS?

•  What should be our first concern in the MS out-patient clinic?

•  Could it not be MS

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

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


*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!


*Solomon et al. Neurology, 2012

The most common alternative diagnoses in patients misdiagnosed with MS* NSWMA - nonspecific white matter abnormalities 81 % SVID - small vessel ischemic disease 78.5 % Migraine 50 % Psychiatric disease 44.8 % Fibromyalgia 31 % NMO - Neuromyelitis optica 40.5 % Misdiagnosed patients on DMD for MS 26 %


Diagnosing MS may be challenging!

Vague neurologic symptoms in young people Insignificant neurological findings

Nonspecific white matter abnormalities on brain MRI

False neuroimaging (MR) reports The urge (!) to diagnose MS early

MS and its masquerades

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

3

MS diagnosis

Steps to MS Dx

•  Clinical history

•  Neurological examination

•  Neuroimaging - MRI

•  aother laboratory testing (CSF & EP)


The diagnostic spectrum of MRI in MS •  RIS •  CIS •  Clinical MS •  MS variants •  NMOSD and other autoimmune

neuroinflammatory-neurodegenerative CNS diseases

•  Non-MS CNS disseases

The Spectrum of Multiple Sclerosis

MS phenotypes •  RIS •  CIS •  SAMS •  SAPMS •  RRMS •  20 PMS •  PPMS

MS variants • Tumefactive MS • Balo’s • Marburg’s • Schilder’s?

MS related disorders (once upon a time ago MS!) •  ADEM •  NMO / NMOSD •  aMOG-related

syndromes •  Others – yet Antb

unknown - atypical CNS inflammatory disorders?


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 sometimes may cause further diagnostic confusion!


In a patient who has been referred with an “MRI diagnosis” of probable MS (radiology report/non-expert reading)

A proper MRI reading; •  may confirm the clinical diagnosis of MS •  may be suggestive but not confirmative, necessitating

further w/up & f/up for MS •  may not be conclusive and leads for further work-up for

non-MS other neuro-inflammatory demy. diseases •  may exclude the clinical diagnosis of MS and offer an

alternative diagnosis

confirmative

suggestive

explorative

eliminative


In a patient who is diagnosed and followed with a diagnosis of MS, MRI may assist the clinician to, •  Decide to start long term treatment •  Decide whether the patient is a treatment responder •  Decide to change a DMD •  Predict the clinical course and prognosis (to a certain

extent)

4

Defining the clinical course of multiple sclerosis - the 2013 revision*

*Lublin et al Neurology, 2014

This new definition is highly

MRI-dependent

Neuroimaging in MS diagnosis

CT in MS diagnosis – its first years!

Acta Neurol Scand 53; 386-389, 1976

Department of Neuroradiology, Rigshospitalet, Copenhagen, Denmark

Computer Tomography of the Brain in Multiple Sclerosis A radiological study of 110 patients with special reference to demonstration of cerebral plaques

Carsten Gyldensted

Computerised Axial Tomography in Multiple Sclerosis L.A. Cala and F.L. Mastaglia

Department of Radiology, Perth Medical Centre, Perth, Western Australia

University Department of Medicine, Perth Medical Centre Lancet, March 27, 1976

MRI in MS diagnosis – its first years!

MS 2010 diagnostic criteria MRI (CIS!)

What’s new? …and

today!

McDonald 2010 - MRI diagnostic criteria

DIS – Dissemination in space ≥ 1 T2 lesions in ≥ 2 regions of the following CNS areas •  juxtacortical •  periventricular •  infratentorial •  spinal cord 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

5

McD 2010 MS diagnostic MR findings periventricular & juxtakcortical areas

Sub-cortical

periventricular Juxta-cortical

pv Posterior fossa lesions

McD 2010 MS diagnostic MR findings posterior fossa lesions

Posterior fossa lesions

McD 2010 MS diagnostic MR findings posterior fossa lesions

MS suggestive MR findings corpus callosum lesions

Spinal cord lesions

McD 2010 MS diagnostic MR findings spinal cord lesions

McD 2010 MS diagnostic MR findings spinal cord lesions

Spinal cord lesions

multiple Gd +

lesions

6

MS suggestive MR findings Gadolinium enhancing lesions

Ring pattern Nodular

enhencement

Open ring pattern

MS suggestive MR findings Gadolinium enhancing lesions

MR findings in MS "black holes!"

(T1) black holes

Clinically MS & MR consistent with MS

Not all white spots seen on MRI are MS!!!

32, Male (seen in another center) Admitted because of dizziness, starting a year ago following an upper resp infec. He describes that his dizziness worsen at times, but is not directly related to cranio-cervical movements. Sometimes in association with dizziness he experiences a mild nausea and mild visual blurring, but has no headaches, no instability and doesn't vomit. Physical exam: normal Neurological exam: unremarkable Past medical history: Smokes a pack a day, otherwise insignificant Family history: insignificant

A young man with dizziness and numbness in hands

7

32, M admitted because of dizziness with normal exam. The patient is referrred for an MRI study – which shows bilateral mostly subcortical T2 hyperintensities, these were read as being

“nonsignificant” WM hyperintensities in the radiology report

The consultant neurologist doesn’t think MS or other neurological disorder and prescribes an SSRI!

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

32, M admitted because of dizziness – MRI initially read as nonsignificant neuro-exam normal; first neurologist doesn’t think MS!

A year later he is re-admitted to another center, he reports now numbness in hands and dizziness, he has a repeat an MRI study in

another center where this MRI, although unchanged from the initial MRI done a year ago is read as suggestive of MS


32, M admitted because of dizziness and numbness in hands, his MRI was read as suggestive of MS

However, these MRI studies are not fulfilling the MRI criteria for MS (McDonald 2010)

•  There are bilateral multiple subcortical T2 hyperintensities •  Despite a relatively high number of subcortical lesions, juxtacortical and

periventricular lesions are hardly seen •  There are no posterior fossa (and no corpus callosum) lesions

(at this stage there was not a spinal cord MRI)

•  There is neither symptomatic nor asymptomatic “Gad-enhancing” lesion •  There was no change compared with the MRI done about a year ago •  No new or enlarging T2 lesions; no Gadolinium enhancing lesion


“Dissemination in space” criteria not fulfilled!

“Dissemination in time” criteria not fulfilled!

32, M admitted because of dizziness – MRI initially read as nonsignificant neuro-exam normal; first neurologist doesn’t think MS!

A year later another neurologist makes a diagnosis of MS and starts DMT! One year later continues to describe same symptoms – no change on MRI

Accepted as a non-responder, DMD switched

About another year later he comes for another opinion to our center... Neuroexam normal; MRI unchanged!

Work up – including vasculitis/collagen disease panel & serology all normal CSF: normal, no OCB


Lesions are bilateral - semisymmetrical – largely subcortikal – no gadolinium enhancement

No posterior fossa lesion

No corpus callosum lesion

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

Not MS


First MRI 2004

Second MRI 2005 DMD initiated

Third MRI 2006 DMD switched!

MRI 2008 Pt self-admitted to our MS center

No spinal cord lesion


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 was normal and a f/up MRI done on 08/14 was unchanged.

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

8


His final diagnosis is not MS or any other significant neurologic disease

This individual is someone who turns out to have “NSWMA - nonspecific white matter abnormalities” on his 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

.

Differential Diagnosis in MS – Imaging (MRI)

•  UBOs ! •  Enlarged Wirchow-Robin (perivascular) spaces •  Migraine •  Antiphosfolipid antibody syndrome •  Vasculitic (primary/secondary) syndromes & CTD

–  PACNS; NBS; SLE, Sjogrens syndrome; neuro-Behcet’s •  Fabry disease •  CADASIL •  Leber hereditary optic neuropathy •  Adult onset leukodistrophies •  Ischemic-degenerative changes in the elderly

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 MRI clinical diagnosis should come first!

•  All MRI abnormalities, in which MS turns out to be a

diagnostic possibility, the imaging differential diagnosis should be based on “clinical grounds”

•  The clinical impression and diagnosis comes first! Ø imaging/MRI and all other lab tools should be used to

confirm or to exclude a clinical diagnosis!

•  The MRI may lead you to a clinical diagnosis, only when it’s highly suggestive of a certain disease (i.e. MS!) and when your 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...)

9

MRI - possibilities and pitfalls in diagnosis of MS differential diagnosis

Neuro-imaging In a patient, in whom the clinical symptoms 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! Demographic possibilities and pitfalls !

•  Childhood-onset (age << 16) [consider the probability of dysmyelinating diseases] •  Late-onset (age >> 50) [consider the probability of ischemic-demyelinating changes] •  (+) Strong family history ≥ 2 family members have identical MRI abnormalities [consider genetic diseases]


In an individual with MRI abnormalities suggestive of MS! Clinical possibilities and pitfalls •  (+) Patient have systemic symptoms suggestive of a

connective tissue disorder or a vasculitic syndrome [consider systemic inflammatory autoimmune diseases] •  (+) Patient have systemic symptoms suggestive of an

infectious disease [consider infectious diseases such as Lyme, HIV, HTLV I&II, tbc] •  (+) Patient have systemic psychiatric symptoms!

[consider somatoform disorders; anxiety & depression; fibromyalgia! in the setting of NSWMA]


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 •  Symmetrical/semi-symmetrical lesions •  Unproportionaly large corpus callosum lesions


In an individual with MRI abnormalities suggestive of MS! Neurological imaging – MRI – atypical / unexpected in MS •  No change in succesive MRIs – all MRIs are the same! •  No gadolinium enhancement in any MRI •  Lesions with prominent mass effect •  Up/downward (edematous) extension of large brainstem les. •  Longitudinally extensive spinal cord lesions (LECL) •  Family members with similar MRIs! All possible in MS, but other diseases should be R/o first!


In an individual with parenchymal (intra-axial) spinal MRI abnormalities suggestive of inflammatory pathology...possibilities;

When it is a “small spinal cord lesion” [<3 segments] •  MS •  Transverse myelitis •  Atypical or recovering NMO / NMOSD – myelitis •  Myelitis assoiated with systemic vasculitides & collagen tissue disorders •  Tumors (i.e.astrocytoma; ependymoma) •  Infectious disorders

10


MS Brain MR+

Spinal lesion Small

Lateral Gd+

Recovering NMO-myelitis

Transverse myelitis?


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] •  MS – multiple small lesions in contiguity suggestive of a single LETM-lesion •  Transverse myelitis •  NMO / NMOSD – myelitis •  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)

Longitudinally extensive spinal cord lesions suggestive of NMO

Longitudinally extensivespinal cord lesions LETM / NMO / NMOSD

widespread Gd enhancement

Spinal cord lesions

peri-cordial vascular abnormalities spinal venous dural fistula

Gd + enchancing

vasc structures

Longitudinally extensive lesions 2o to dural fistules

Subclinical lesions on MRI in young people what to think?

Subclinical lesions on MRI and migraine

ZC, 26 yrs old F Attacks of visual & sensorial aura, followed by a migrainous headache

In some aura without headache • 

Past family Hx: Mother alive/well&HT Father A/Well – has migraine Sister A/W - has migraine

Work-up ? TTE / TEE to R/o - PFO & ASA Doppler R/o embolic showers?

11

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 proven acute demyl

Tumefactive lesions – MS

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

MS and its MRI mimics – multifocal tumors

18 02 09

MS and its mimics – multifocal tumors

06 03 09

12

MS and its MRI mimics multifocal high grade glioma

18 02 09

...we biopsied the most superficial lesion last week. Although the lesion is quite odd looking, our neuropathologist is convinced that it is a high-grade glioma. The reason it appears to be unusual is that there is a great deal of inflammation and fibrosis. I think this is a result of the hemorrhage into the tumor, rather than the tumor itself

MS and its MRI masquerades

MS and its clinical and MRI masquerades

•  PCNSA •  Neuro – Behcet •  SLE •  Sjogren •  CADASIL •  Susac •  Fabry

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

These are disorders seen uncommonly either some of their clinical or MRI features will be atypical for MS!

MS and its mimics Primary CNS vasculitis

Diagnostic criteria

1.  recent history or presence of an acquired neurologic deficit unexplained by other causes; encephalopathy

Various symptoms and findings at diagnosis of PCNSV* (Most with multiple manifestations) headache, altered cognition, visual symptoms, focal neurologic manifestations, persistent neurologic deficit or stroke

2  evidence of vasculitis in a CNS biopsy specimen; or

3. a cerebral angiogram with changes characteristic of vasculitis

*Calabrese and Mallek, Medicine, 1988 & Salvarini et al Ann Neurol 2007

•  Systemic vasculitides and connective tissue diseases may involve either the CNS or PMS, or both

•  In most instances this involvement is the result of inflammation of the blood vessels and less commonly due to thrombotic vasopathies - nervous system involvement secondary to different form of vasculopathies.

•  Other vasculopathic disorders (i.e. lymphoproliferative diseases and other malignancies, some infections and related conditions, drugs and substance abuse) may also affect the CNS and may result in clinical and MRI features that may mimic MS!!!

Systemic vascular inflammatory diseases with nervous system involvement – do they cause confusion with

MS diagnosis???

Behcet’s disease Uygunoğlu & Saip & Siva

13

Neuro - Behçet Syndrome

Neurological involvement directly related to BS*

•  Headache (non-structural) •  Cerebral venous sinus thrombosis (extra-axial NBS) •  Central nervous system involvement (intra-axial NBS) •  Neuro-Psycho-Behçet Syndrome •  Peripheral nervous system involvement •  Subclinical NBS

*Siva & Saip. J Neurol, 2009

MS and its mimics - intraaxial (CNS) NBS

NBS •  Neurological involvement

is unlikely prior to the onset

of systemic signs & Sx of BD

•  Neuroimaging is highly,

suggestive of NBS


Spinal involvement in NBS is

in the form of LETM AQP4-Abs are absent

the major CNS region to be involved in NBS is the brainstem lesions are large and extend to deep hemispheric strutures

uncommonly subcortical lesions may be seen

Gd enhancement may be seen

in acute lesions


14

MS and its mimics - intraaxial (CNS) NBS MS vs NBS – differential diagnosis I*

MS •  F > M Sx/S common at onset •  ON; sensory; motor; spinal

cord; BS; Cblr Sx/S uncommon at onset •  Headache,

cranial neuropathies

CNS – NBS •  M > F Sx/S common at onset •  Headache; motor;

Cblr; BS (INO rare) Sx/S uncommon at onset •  ON; sensory;

spinal cord

*Siva & Saip. J Neurol, 2009

MS vs NBS – differential diagnosis II*

MS MRI •  PV & SC lesions (+++)

BS lesions: small, discrete, extension (–) spinal cord lesions (++) CSF •  Inflammatory changes (-)

OCB (+) [>90%]

CNS – NBS MRI •  PV & SC lesions (±)

BS lesions: large, diffuse, extension (+) spinal cord lesions (±)

CSF •  Inflammatory changes (+)

OCB (–) [<20%]

* Siva & Saip. J Neurol, 2009

MS and its mimics Systemic lupus erythematosus 30 yrs F with SLE & neuro complication

SLE diagnosis known Systemic involvement prior to nervous system involvement

CADASIL

Cerebral Autosomal Dominant Arteriopathy

with Subcortical Infarcts and Leukoencephalopathy

AA 64 F, (28.01.2004)

Semi-specific white matter lesions – CADASIL*

Characteristic MRI lesions in the ant.temporal & frontal poles, U-fibres, the basal ganglia, external capsule, insular regions and lacunar 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

15

CADASIL

•  The primary disease process is a vasculopathy a (nonatheromatous, nonamyloid angiopathy)

•  Although the disease manifests itself as brain dysfunction,

this vasculopathy is systemic

•  The clinical spectrum of CADASIL is heterogeneous

•  inherited in an autosomal dominant pattern (19q13)

•  Characteristic MRI lesions in the ant.temporal lobes, frontal poles, the basal ganglia, capsula extrema and lacunar like infarcts within the corona radiata and SC

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 possibilities and pitfalls in diagnosis of MS WRAP-UP

MRI possibilities and pitfalls in diagnosis

*Rovira et al. Nature Reviews – Neurology, 2015

MRI possibilities and pitfalls in diagnosis The MAGNIMS study group guidelines*

Shortcomings of MRI studies in general practice •  Nonstandardized MRI examinations are often of inadequate quality •  MRI reports are likely to be read by people lacking expertise in the field

of MS and without consideration of relevant clinical and laboratory data •  These can lead to erroneous diagnoses The MAGNIMS study group guidelines* •  to better define and optimize the use of brain and spinal cord MRI in the

diagnostic process for MS •  recommendations to promote standardized strategies that apply to the

planning, performance and interpretation of MRI for clinical use *Rovira et al. Nature Reviews – Neurology, 2015

16

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


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

Sub-cortical periventricular Juxta-cortical

Spinal cord lesions Posterior fossa lesions

Corpus callosum lesions

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


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!”

The diagnosis of MS by MRI is not always an easy task!

Heterogeneity of idiopathic inflammatory demyelination ECTRIMS Teaching Course

Page 1/6

Heterogeneity of idiopathic inflammatory demyelination

ECTRIMS Teaching Course #8 “Differential diagnosis and diagnostic dilemma”

Wednesday 7 October 2015

Sandra VUKUSIC1-4

1 Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques,

Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, F-6977, France; 2 Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et

Neuro-inflammation, Lyon, F-69003, France; 3 Université de Lyon, Lyon, F-69003, France;

4 Université Lyon 1, Lyon, F-69003, France;

Correspondance to: Prof. Sandra VUKUSIC – Service de Neurologie A – Hôpital Neurologique Pierre Wertheimer 59 boulevard Pinel – 69677 BRON cedex – France e-mail: [email protected] Tel: +33 4 72 35 75 22 – Fax: +33 4 72 35 75 25 Financial Disclosure Statement

Dr. Vukusic has received consulting and lecturing fees, travel grants and research support from Bayer-

Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Sanofi Aventis and Teva Pharma.

None of these relationships results in a conflict of interest in the scope of this paper.

mailto:[email protected]


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Idiopathic inflammatory demyelinating disorders of the central nervous system (CNS) represent a wide

range of clinical phenotypes. They exclusively affect the CNS and their immunopathogenesis remains

poorly understood.

In the last decade, advances in clinical descriptions, imaging techniques, immunological testing and

pathology have allowed defining new disease entities. However, it remains unclear whether these

entities represent different diseases or part of a wide spectrum of idiopathic inflammatory

demyelinating disorders of the CNS.

Multiple sclerosis (MS) is the most frequent of these disorders. Its diagnostic criteria have clearly

improved in the recent years, although we still miss a specific diagnostic test. In particular, early

clinical stages (so-called clinically isolated syndromes (CIS), optic neuritis, myelitis or other focal

lesions) might be difficult to classify without temporal data.

Thus, a similar initial presentation of optic neuritis or myelitis might remain isolated and monophasic,

or evolve either to MS or to neuromyelitis pptica (NMO). A relapsing brainstem involvement could be

MS, but also CLIPPERS (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement

Responsive to Steroids) and even NMO spectrum disorders (NMOSD).

By contrast, a very “noisy” clinical and radiological presentation, especially in children, might be an

acute disseminated encephalomyelitis (ADEM) that is supposed to be a monophasic condition…

unless new and more typical neurological episodes, sometimes several years after, lead to a final

diagnosis of MS… or NMO.

In 2005, the description by Lennon et al. of anti-aquaporin 4 autoantibodies (AQP-4) has been a major

step in our comprehension of the immunopathogenesis of inflammatory CNS demyelination. It allowed

delineating a particular clinical phenotype, affecting specifically the optic nerves and the spinal cord,

which was previously considered and treated as MS. But more interestingly, it also lead later to extend

the clinical spectrum of what are now called “aquaporinopathies” or NMOSD, including a much wider

range of clinical and/or radiological presentations.

Is history about to be repeated with anti-myelin oligodendrocyte glycoprotein (MOG) auto-antibodies?

Are anti-MOG positive patients representing a new entity or is it just a prognostic markers?


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The objective of this lecture will be to discuss the spectrum of idiopathic inflammatory demyelinating

disorders of the central nervous system.

The presentation will be based on typical case reports, followed by an overview of the current state of

knowledge about each clinical phenotype.

In particular, the following disorders will be discussed:

- Acute demyelinating encephalomyelitis (ADEM) and related disorders

- Neuromyelitis optica spectrum disorders and anti-MOG autoantibodies associated disorders

- Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids

(CLIPPERS)


Page 4/6

Selected references

Acute disseminated encephalomyelitis

Krupp LB, Tardieu M, Amato MP et al. International Pediatric Multiple Sclerosis Study Group

criteria for pediatric multiple sclerosis and immune-mediated central nervous system

demyelinating disorders : revisions to the 2007 definitions. Mult Scler 2013;19:1261-1267.

Krupp LB, Banwell B, Tenembaum S for the International Pediatric MS Study Group.

Consensus definition proposed for pediatric MS and related disorders. Neurology 2007;68:S7-

12.

Ketelslegers IA, Neuteboom RF, Boon M, Castman-Berrevoets CE, Hintzen RQ for the Dutch

Pediatric MS Study Group. A comparison of MRI criteria for diagnosing pediatric ADEM and

MS. Neurology 2010;74:1412-1415.

Callen D, Shroff MM, Branson HM et al. Role of MRI in the differentiation of ADEM from MS in

children. Neurology 2009;72:968-973.

Mikaeloff Y, Adamsbaum C, Husson B et al for the KIDSEP Study Group on Radiology. MRI

prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain

2004;127:1942-1947.

Neuromyelitis optica spectrum disorders

Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm

2015;21:e110.

Pittock SJ, Lucchinetti CF. Neuromyelitis optica and the evolving spectrum of autoimmune

aquaporin-4 channelopathies: a decade later. Ann N Y Acad Sci 2015. doi:

10.1111/nyas.12794. [Epub ahead of print]

Wingerchuk DM, Banwell B, Bennett JL et al. International consensus diagnostic criteria

for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89.

Panel C

https://legacy.chu-lyon.fr/pubmed/26185772





















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Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to

Steroids (CLIPPERS)

Pittock SJ, Debruyne J, Krecke KN et al. Chronic lymphocytic inflammation with pontine

perivascular enhancement responsive to steroids (CLIPPERS). Brain 2010;133:2626-2634.

Simon NG, Parratt JD, Barnett MH et al. Expanding the clinical, radiological and

neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular

enhancement responsive to steroids (CLIPPERS). J Neurol Neursurg Psychiatry 2012;83:15-

22.

Kira J. The expanding phenotype of CLIPPERS: is it a disease or a syndrome? J Neurol

Neurosurg Psychiatry 2012;83:2-3.

Taieb G, Duflos C, Renard D et al. Long-term outcome of CLIPPERS (chronic lymphocytic

inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive

series of 12 patients. Arch Neurol 2012;69:847-855.

Dudesek A, Rimmele F, Tesar S et al. CLIPPERS: chronic lymphocytic inflammation with

pontine perivascular enhancement responsive to steroids. Review of an increasingly

recognized entity within the spectrum of inflammatory central nervous system disorders. Clin

Exp Immunol 2014;175:385-396.

Taieb G, Renard D, Labauge P. Should CLIPPERS be considered a prelymphoma state ir a

new inflammatory disease? JAMA Neurol 2013;70:1200-1201.

Relapsing Inflammatory Optic Neuropathy (RION)/Chronic Relapsing Inflammatory Optic

Neuropathy (CRION)

Petzold A, Plant GT. Diagnosis and classification of autoimmune optic neuropathy. Autoimm

Rev 2014;13:539-545.

Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of

122 cases reported. J Neurol 2014;261:17-26.

Kidd D., Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy

(CRION). Brain 2003;126:276-84.


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Anti-MOG autoantibodies associated disorders

Cobo-Calvo Á, Sepúlveda M, Bernard-Valnet R et al. Antibodies to myelin oligodendrocyte

glycoprotein in aquaporin 4 antibody seronegative longitudinally extensive transverse myelitis:

Clinical and prognostic implications. Mult Scler 2015 Jul 24. pii: 1352458515591071.

Waters P, Woodhall M, O'Connor KC et al. MOG cell-based assay detects non-MS patients

with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm 2015;2:e89.

Hacohen Y, Absoud M, Deiva K et al. Myelin oligodendrocyte glycoprotein antibodies are

associated with a non-MS course in children. Neurol Neuroimmunol Neuroinflamm

2015;2:e81.

Zamvil SS, Slavin AJ. Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory

disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm

2015;2:e62.

Baumann M, Sahin K, Lechner C et al. Clinical and neuroradiological differences of paediatric

acute disseminating encephalomyelitis with and without antibodies to the myelin

oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry 2015;86:265-72.

Kitley J, Waters P, Woodhall M et al. Neuromyelitis optica spectrum disorders with aquaporin-

4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol

2014;71:276-83. Sato DK, Callegaro D, Lana-Peixoto MA et al. Distinction between MOG

antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology

2014;82:474-81.

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