Clinical and MRI clues and pitfalls in the diagnosis and differential diagnosis of

Aksel Siva, M.D. MS Clinic & Department Of Istanbul University Cerrahpaşa School of Medicine [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 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 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. In Multiple 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) disseminated in time and space" • Poser et al, 1983

"additional paraclinical and"/disseminator laboratoryion in evidence: neuroimaging, neurophysiologytime &and CSF space (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) 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 Clinical Hx Neuro-exam + findings to be MS is a neuro-inflammatory demyelinating diseaseconfirmed by MRI! with of the CNS, in which there is • Evidence of dissemination in space (multifocality) Clinical sx & signs + DIS by MRI • Evidence of dissemination in time Clinical relapses or steady progression + DIT by MRI • No better explanation to account for symptoms and signs and/or MRI findings Clinical & MRI: no alternative neurological disease Diagnosis and Differential Diagnosis of MS Patients are admitted to neurology outpatient clinics because of...

Clinical Imaging Symptoms & Signs Cranial & Spinal MRI suggestive of ”MS” suggestive of “MS” Clinical & Imaging findings suggestive of MS

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

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

• What should be our first • What should be our first concern in the general concern in the specialized neurology out-patient MS out-patient clinic? clinic? • Could it be MS? • Could it be not MS?

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 Difficulties in MS diagnosis

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 Difficulties in MS diagnosis

26% of misdiagnosed patients were on DMD for MS

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 Difficulties in MS diagnosis

110 misdiagnosed patients in 4 MS centers (not a population 70% received DMT based study) and 31% experienced unnecessary morbidity because of misdiagnosis vague neurologic symptoms & nonspecific WM abnormalities in pts with – fibromyalgia – psychiatric conditions

Solomon et al. Neurology 2016 Difficulties in MS diagnosis

In 5 – 35 % of people diagnosed as MS, the ultimate diagnosis is not MS!!! migraine – fibromyalgia – psychiatric conditions vague neurologic symptoms with nonspecific abnormalities on MRI misinterpretation and misapplication of radiographic diagnostic criteria

Solomon & Weinshenker. Curr Neurol Neurosci Rep, 2015 Difficulties in MS diagnosis

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!!! 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 5300 MS pts 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 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. The Spectrum of MS and related disorders

MS sub+clinical MS MS related disorders phenotypes variants (once upon a time ago MS!) • RIS •Tumefactive MS • ADEM • CIS •Balo’s • NMO / NMOSD • SAMS •Marburg’s • aMOG-related • SAPMS •Solitary sclerosis syndromes • RRMS •Schilder’s? • Others –Ab unknown? - atypical CNS • 20 PMS inflammatory disorders? • PPMS MS diagnosis & misdiagnosis

Steps to MS Dx Problem areas • Clinical history

• Neurological examination

• Neuroimaging - MRI

• other laboratory testing (CSF & EP) 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 •

*Polman et al, Ann. Neurol 2011 McD 2010 MS diagnostic MR findings – DIS juxtacortical & periventricular & post fossa & spinal cord

Juxta-cortical Sub-cortical Sub-cortical periventricular

1 2

4

3

Posterior fossa Spinal cord lesions lesions lesions 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 MS suggestive MR findings Gadolinium enhancing lesions

Open ring pattern

Ring Nodular pattern enhencement McD 2010 MS diagnostic MR findings spinal cord lesions

multiple Gd + lesions

Spinal cord lesions MR findings in MS the nonspecific “plus” findings - "black holes!"

(T1) black holes MR findings in MS the nonspecific “plus” findings - ”cerebral "

Severe atrophy of the corpus callosum 2001 / OT, 25, M; New Dx Sx: Visual blurring EDSS: 1

Enlarged sulci

2011 / OT, 35, M; SPMS On DMD since 03/02 at 10 yrs: EDSS: 6 2015 EDSS: 6.5 An update on MRI criteria for MS diagnosis The 2016 MAGNIMS consensus guidelines

We propose an increase in the number of lesions necessary to confirm involvement of the periventricular area from one to three, and to add an additional cardinal CNS location, the

*Fillipi et al. Lancet Neurol, 2016 An update on MRI criteria for MS diagnosis The 2016 MAGNIMS consensus guidelines

*Fillipi et al. Lancet Neurol, 2016 Defining the clinical course of multiple sclerosis - the 2013 revision*

Disease activity Clinical relapse & MRI activity ➢ Gd(+) ± new or enlarging T2 lesion Progression confirmed EDSS

This new definition is highly MRI-dependent

Treatment decisions are based on either clinical but mostly on MRI activity / progression

*Lublin et al Neurology, 2014 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! MRI - possibilities and pitfalls in diagnosis of MS

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 2016 Sati et al. Nature Reviews Neurology, 2016 MRI - possibilities and pitfalls in diagnosis of MS

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

• Further studies are needed before intracorticalThese requirelesion detection, the ‘central vein sign’, and theMRIsusceptibility systems thatsignal operate at high within lesions can be incorporated in the Currentlydiagnostic notwork -up of magnetic field for real-life MS (at standard field strength) strengths (≥3.0 T) “common” & sophisticated practice software programs & sequences

*Rovira et al. Nature Reviews – Neurology, 2015 MRI - possibilities and pitfalls in diagnosis of MS

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 spots seen on MRI are MS!!! A young man with dizziness, numbness in hands and T2 lesions on MRI

32, M admitted because of dizziness & numbness in hands he 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 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 A young man with dizziness, numbness in hands and T2 lesions on MRI

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

NotNot MSMS Follow up MRIs: no change in any MRI – no enhancement in any scan no atrophy – no T1 Black holes No First MRI 2004 MRI 2008 post fossa Pt self-admitted Second MRI 2005 No DMD initiated to our MS center corpus callosum Dx of MS or Third MRI 2006 No other CNS disease DMD switched! spinal cord is ruled out! lesions A young man with dizziness, numbness in hands and T2 lesions on MRI

Patient was seen again about 3 years later in Apr 2014 because of dizziness and tension type - 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 holes No posterior fossa and no spinal cord lesions A young man with dizziness, numbness in hands and T2 lesions on MRI

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 MRI clinical diagnosis should come first!

• the interpretation of MRI abnormalities and the imaging differential diagnosis always should be based on “clinical grounds” (Hx & Sx & signs)

• The clinical impression and diagnosis comes first!  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...) 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 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 When the imaging findings surpass the clinical features!

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 lesions No enhancement – No atrophy – No T1 black holes

36y M with episodes of visual blurring and left hand & arm numbness, followed by Dx: Migraine with aura & W/up reveals large PFO! Semi-symmetrical, 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 infarctsAA within 64 F, the (28.01.2004) corona radiata and SC regions. Frequent sparing of corpus callosum and cerebellum

(

*Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy MRI possibilities and pitfalls Thein diagnosis corpus and differential diagnosis of MS callosum!

MS

corpus callosum lesions similar with other T2 MS lesions mostly will be at the genu & calloso- septal interface! MRI possibilities and pitfalls Thein corpus diagnosis and differential diagnosis of MS callosum!

Susac’s

“Clinical triad” Unproportionaly large corpus callosum lesions Retinopathy Hearing ↓ Susac’s Syndrome

It is an autoimmune endotheliopathy affecting the precapillary arterioles of the brain,retina, and inner ear

*Rennebohm et al. / J Neurol Sci 2010 *Rennebohm et al. / Journal of the Neurological Sciences 299 (2010) MRI - possibilities and pitfalls in diagnosis of MS “think twice”

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

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

Cerebral vasculapathies, which may mimic MS both clinically and on MRI! CADASIL Susac Fabry PCNSA Neuro – Behcet SLE Sjogren These are disorders seen uncommonly most 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*

MS CNS – NBS MRI MRI • PV & SC lesions (+++) • PV & SC lesions (±) BS lesions: small, BS lesions: large, discrete, extension (–) diffuse, extension (+) spinal cord lesions (++/short) spinal cord lesions (±long) CSF CSF • Inflammatory changes (-) • Inflammatory changes (+) OCB (+) [>90%] 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? Clues to the diagnosis of • Brain neoplasms TDL include* • CNS lymphoma • Less mass effect than • Abscesses expected for their size • PML! • open ring enhancement • Vasculitic disorders & NBS! • no increased perfusion • Tumefactive demyelinative • visualisation of veins lesions (TDL) coursing through the lesion

*Kaschka et al 2014 Tumefactive lesions – MS or not?

Biopsy proven acute demyl

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 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 diagnosis multiple brain lesions!

Multiple CNS lesions +/- enhancement - What they might be? • Acute disseminated (ADEM) • Metastatic tumors • CNS lymphoma • CNS toxoplasmosis (>HIV related) • CNS tuberculosis • CNS cystisercosis • CNS hydatid cysts • Other CNS • CLIPPERS!!!

* MS and its MRI mimics – multifocal glial tumors

43y, M subacute 18 02 09 development of R- ! MS and its mimics – multifocal glial tumors

06 03 09

Brain biopsy: multifocal GBM! Multiple brain lesions! A patient with subacute onset of optic !

42 F teacher • 07/16 R-ON • Admitted with a 10 days hx of visual loss on the right / ⍉ • 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 !

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 (-) MRI 13 JUL 2016 • Chest x-ray (-) A patient with subacute onset of optic neuritis!

eccentric target sign

Her lab studies confirms her diagnosis AHIV (+) & CD4+cells:73 Cerebral toxoplasmosis remains one of the most common focal brain lesions in patients with AIDS

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

Intra-axial PV ependymal Extra-axial cranial enhancement nerve enhancement suggestive of suggestive of infiltration! 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 &

• 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 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 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 19 yrs old girl with dysarthria & ataxia

…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 Biopsy area, were accompanied by CD20 + B lymphocytes site 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] CLIPPERS

• Chronic lymphocytic 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 diagnosis Other 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 • Single symptomatic spinal lesion – short / no other lesions • Isolated – idiopathic ON • Single symptomatic optic nerve lesion / no other lesions Atypical inflammatory demyelinating syndromes of the CNS*

• 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

Recognition of these syndromes is crucial because they differ from multiple sclerosis and other demyelinating and nondemyelinating conditions in their prognosis and treatment

*Hardy et al. Lancet Neurol 2016 Atypical inflammatory demyelinating syndromes 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 • 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 polysymptomatic presentation that generally includes encephalopathy It requires early anti-inflammatory treatment, whereas long-term immunomodulatory therapies are considered unnecessary due to the self-limiting nature of the disease Acute Disseminated Encephalomyelitis

13.10.2005

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

13.10.2005

Multiple relatively large edematous WM lesions with simultaneous enhancement Courtesy of S.Saip, M.D. 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 (, 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! MRI - possibilities and pitfalls in diagnosis of MS “think twice”

In an individual with parenchymal spinal MRI abnormalities suggestive 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 MRI possibilities and pitfalls in MS diagnosis

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

MS Recovering Brain MR+ NMO-myelitis Spinal lesion Small peripheral Gd+ MRI - possibilities and pitfalls in diagnosis of MS “think twice”

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

widespread heterogenous Gd enhancement

Bright spotty lesions* “Brighter T2- hyperintense spotty lesions (T1W-hypo) within the spinal cord lesion may differentiate Longitudinally extensivespinal cord lesions NMO from MS!* LETM / NMO / NMOSD

*Yonezu et al. MS J 2014 & Hyun et al JNNP 2015 MOG-Ab+ related inflammatory demyelinating syndromes

No spesific pattern to be suspected in pts with ADEM-like lesions or tumefactive lesions or in 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 negative Rx with oral AC + mycophenolate mofetil (MMF) + GA - MOG-Ab recently was detected (+) Longitudinally extensive spinal cord lesions

Long & large neurosarcoidosis spinal cord lesions

trident head sign Long linear subpial Gd 3-pronged spear like enhancement appearence 52F recent onset of disturbing Longitudinally extensive spinal cord lesion and mild weakness of lower extremities neurosarcoidosis MRI possibilities and pitfalls in diagnosis Inflammatory granulomatous disorders- Neurosarcoidosis

Neurosarcoidosis • Basal / Leptomeningeal enhancement in about 40% • • 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 diagnosis Inflammatory granulomatous disorders- Neurosarcoidosis

55 yrs university prof admitted with dysarthria, imbalance, L-sided weakness with known past Hx of sarcoidosis Longitudinally extensive spinal cord lesions - NBD

* in Behcet’ş Disease: The Bagel Sign "Bagel Sign" pattern A central lesion with hypointense core 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 hypointensity corresponding to the center of “Bagel Sign” Bagel Sign* as observed in axial *Uygunoglu et al. Ann Neurol, 2017 T2W image Longitudinally extensive spinal cord lesions

peri-cordial vascular LETM abnormalities lower dorsal Gd + spinal cord enchancing vascular structures

draining dilated intra & perimedullary veins “serpent-like” tortuous strutures 52y M with progressive spastic paraparesis spinal venous dural fistula Longitudinally extensive spinal cord lesions Differential diagnosis

Another not so good- looking long & large spinal cord lesion! 58 yrs old woman with gradually progressive numbness and tingling sensation on her L-arm and hand with recent onset ipsilateral mild weakness

Dif Dx included spinal (most likely primary) tumor, hoping that the final dx may 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 Longitudinal(ly extensive) spinal cord lesions Metabolic & toxic *

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 Inverted myelopathy V-shape a similar type of myelopathy sign more common as a neurological complication of bariatric surgery** a-Tocopherol deficiency & some other metabolic-toxic myelopathies* *Hedera P. Handb Clin Neurol. 2016 similar spinal MRI findings Kumar. Semin Neurol 2012 **Kumar et al. Neuroradiology, 2006 & Jaiser & Winston J Neurol. 2010 Longitudinally extensive spinal cord lesions Differential diagnosis*

NBS Neurosarcoidosis NMO

Bagel Trident Bright sign head sign spotty lesion

*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 lesions Differential 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) lactate Selective 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 possibilities and pitfalls in MS diagnosis MRI mimics of MS MRI possibilities and pitfalls in diagnosis

Single gene disorders that share clinical & radiologic characteristics with MS • lysosomal storage disorders • neurometabolic disorders • various mitochondrial diseases • several other miscellaneous disorders

*Weisfeld-Adams et al. Brain, 2015 MRI possibilities and pitfalls in MS diagnosis mitochondrial 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 , chronic progressive ophthalmoplegia and mitochondrial encephalomyelopathy, lactic acidosis and -like episodes (MELAS) might be difficult to distinguish radiologically from MS MRI possibilities and pitfalls in diagnosis

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 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*

No clinical symptoms or signs suggestive MS Barkhof criteria for An initial MRIDIS - fulfilling3 of 4: at least 3/4 Barkhof criteria for DIS ≥9 T2 lesions or 1 Gd+ ≥3MRI PV / ≥done1 PF / for≥1 JC other reasons unrelatedshould MRI to criteria MS MRI – CNS anomalies not attributable tofor anotherRIS disease needs to be updated process or to any other medicalaccording conditionto the new McDonald 2010+ MRI anomalies not associated with any beyondfunctionalcriteria impairment?

Okuda et al. Neurology, 2009 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

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

*Rovira et al. Nature Reviews – Neurology, 2015 MRI possibilities and pitfalls in diagnosis

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 relevantand –that clinical- and is real- laboratory data life • the simplified and less-restrictive McDonald’s“common” 2010 MRI practice criteria –that- might compromise diagnostic specificity leading to overdiagnosis

*Rovira et al. Nature Reviews – Neurology, 2015 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 Problem areas in MRI diagnosis of MS

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!” Problem areas in MRI diagnosis of MS

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 picture and we need to see the patient through the clinician’s eyes in her/his MRI