Katrin Parmar Switzerland

The clinical workup of patients suspected of having MS

IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION www.excemed.org Aims of the diagnostic process

• Establish diagnosis - Exclude other, better or differently treatable diseases • Sub-Classification with implications for: - Prognosis - Selection of therapy - Prediction of response to therapy The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 McDonald criteria 2001 revised McDonald criteria 2005

revised McDonald criteria 2010

Schuhmacher et al. 1965 The Diagnostic Criteria

Schuhmacher criteria 1965 Key principles: Poser criteria 1983 ➢ 2 or more lesions inside CNS McDonald criteria ➢ 2 or more episodes of CNS dysfunction (relapses) 2001 OR revised McDonald (chronic) progressioncriteria for defined 2005 observation time (> 6 or 12 mths) ➢ Exclusion of other diagnoses revised McDonald criteria No single diagnostic2010 test is definitive proof - always synthesis of history, neurological findings and

Schuhmacher et al. 1965 results of additional investigations! The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 McDonald criteria changes made: 2001 revised McDonald ➢ inclusion of paraclinical tests; clinical evidencecriteria may be 2005 replaced by laboratory abnormalities at the second site ➢ 4 categories: - clinical probable and definite MS - laboratory-supported probable and definiterevised MS McDonald criteria 2010 criticism: - patients with progressive disease did not fit well in this scheme

Schuhmacher- laboratory et al. 1965; Poser tests et al. 1983; were not performed to comparable standards The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 McDonald criteria 2001 revised McDonald criteria 2005

revised McDonald criteria 2010

Schuhmacher et al. 1965; Poser et al. 1983; McDonald et al. 2001, Polman et al. 2005; Polman et al. 2010 The Diagnostic Criteria

Schuhmacher key statements: criteria 1965 ➢The focus remains on the objective demonstration of dissemination of Poser criteria 1983 lesions in both time and space McDonald criteria 2001 ➢MRI is integrated with clinical and revised McDonald other paraclinicalcriteria 2005 diagnostic methods ➢Three diagnostic groups: "MS"; "possible MS", "no MS" revised McDonald criteria 2010

Schuhmacher et al. 1965; Poser et al. 1983; McDonald et al. 2001, Polman et al. 2005; Polman et al. 2010 The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 key aspects: McDonald criteria 2001 ➢clarify the role of spinal cord lesions revised McDonald ➢simplify the diagnosis of PPMS criteria 2005 ➢„...the 2005 revisions ... should simplify and speed diagnosis, revised McDonald whereas maintaining adequate criteria 2010 sensitivity and specificity“

Schuhmacher et al. 1965; Poser et al. 1983; McDonald et al. 2001, Polman et al. 2005; Polman et al. 2010 The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 key aspects: McDonald criteria 2001 ➢clarify the role of spinal cord lesions revised McDonald ➢simplify the diagnosis of PPMS criteria 2005 ➢„...the 2005 revisions ... should simplify ad speed diagnosis, revised McDonald whereas maintaining adequate criteria 2010 sensitivity and specificit“

Schuhmacher et al. 1965; Poser et al. 1983; McDonald et al. 2001, Polman et al. 2005; Polman et al. 2010 from Compston and Coles 2008 The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 McDonald criteria 2001 revised McDonald criteria 2005

revised McDonald criteria 2010

Schuhmacher et al. 1965; Poser et al. 1983; McDonald et al. 2001, Polman et al. 2005; Polman et al. 2010 The Diagnostic Criteria

Schuhmacher criteria 1965

Poser criteria 1983 key aspects of theMcDonald „2010 criteriacriteria “ : 2001 revised McDonald ➢DIT and DIS can be established in criteria 2005 a single scan ➢„...these revisions ... may allow earlier diagnosis and more uniform revised McDonald criteria and widespread use“ 2010

Schuhmacher et al. 1965; Poser et al. 1983; McDonald et al. 2001, Polman et al. 2005; Polman et al. 2010 McDonald Criteria for MS 2001 - Basic principles:

Clinical Additional Data Needed Presentation 2 A + 2 L none 2 A + 1 L dissemination in space 1 A + 2 L dissemination in time 1 A + 1 L dissemination in both space and time progressive onset CSF and dissemination in both space and time (progression of 12 months) Clinical Symptom Description - Trivial? Inter-examiner agreement in the description of symptoms at the onset of MS in six centers. (Agreement is indicated for each center by kappa index and asymptotic standard error (ASE))

CENTER S Y M P T O M S LT BS ON Basel 0.68 (0.15) 0.46 (0.17) 0.49 (0.16) Bari 0.57 (0.16) 0.77 (0.12) 0.67 (0.18) Florence 0.91 (0.09) 0.93 (0.07) 1.00 (0.00) London 0.77 (0.12) 0.78 (0.12) 0.83 (0.12) Lyon 0.76 (0.16) 0.76 (0.13) 1.00 (0.00) Würzburg 1.00 (0.00) 0.79 (0.12) 0.52 (0.24)

LT = long tract involvement. Refers to any combination of lower extremity dysfunction, upper extremity dysfunction, sensory symptoms, sphincter disturbance, or sexual disturbance. BS = brainstem involvement. Refers to any combination of facial motor, facial sensory, oculomotor symptoms, vestibular and/cochlear, or bulbar dysfunction. ON = .

MP Amato et al. for the EVALUED Study Group, J Neurol 2004 B. Uitdehaag et al., MSJ 2005 Contributors to MS Misdiagnosis (Salomon AT et al., Neurology 2016) Diagnoses and Syndromes Misdiagnosed as MS (Salomon AT et al., Neurology 2016) Differential diagnosis of suspected : a consensus approach

DH Miller, et. al. MSJ 2008; 14:1157-74 Atypical Neurological Syndromes

Cortical blindness Posterior leukoencephalopathy; PML; multiple infarcts Hearing loss Susac’s; Cogan’s syndrome

Migraine CADASIL, mitochondrial, Antiphospholipid Ab Venous thrombosis Behcet’s disease

Cranial neuropathies Sarcoidosis (VII), Lyme (VII) Hemorrhage Tumor, venous infarction

Myoclonus/rigidity Paraneoplastic/Hashimoto’s Systemic Syndromes as red flags

Fever Infection, vasculitis, Sarcoidosis, systemic

Iritis/uveitis Sarcoidosis, PCNSL

Peripheral infarcts Endocarditis, thromboembolic

Inflammatory arthritis Autoimmune, Sarcoidosis, Lyme

Livedo reticularis Antiphospholipid antibody

DVT Behcet’s, Neoplasm, APLAb Sarcoidosis, Lyme, vasculitis, Peripheral neuropathy Vit B12 deficiency Differential diagnosis of suspected multiple sclerosis: a consensus approach

DH Miller, et. al. MSJ 2008; 14:1157-74 Clinically Isolated Syndrome (CIS)

• 85% of patients with multiple sclerosis (MS) have a subacutely evolving CIS, usually due to activity in a single white matter lesion, as their initial clinical event. The remainder have primary progressive MS1

• Currently two main classifiers:

• Clinical manifestation: Symptomatic (CIS; monofocal vs multifocal) vs asymptomatic (RIS)

• MRI: With (MS) or without clinically silent (earlier) events (CIS)

Miller D, et al. Lancet Neurol. 2005;4:281-288. Differential diagnosis of suspected multiple sclerosis: a consensus approach «CIS»

DH Miller et al. ; MSJ 2008; 14:1157-74 « CIS - optic nerve »

DH Miller et al. ; MSJ 2008; 14:1157-74 « CIS – brain stem»

DH Miller et al. ; MSJ 2008; 14:1157-74 « CIS – spinal cord »

DH Miller et al. ; MSJ 2008; 14:1157-74 Relapsing-remitting

Secondary progressive

Primary progressive

Progressive relapsing Time

Adapted from Lublin et al. Neurology. 1996;46:907-911. • Clinical

• MRI

• Pathologic

• Biologic 1996 vs new MS Phenotype Descriptions (Lublin et al 2014) Relapsing Disease

1996 MS Clinical Modifiers 2012 MS Disease Modifiers Subtypes Phenotypes

not active* With full recovery from relapses CIS

active* # Relapsing-Remitting Disease Relapsing Disease

not active*

With sequelae / RR residual deficit after incomplete active* recovery

*Activity determined by clinical relapses and/or MRI activity (CEL; new or unequivocally enlarging T2 lesions assessed at least annually); #CIS, if subsequently clinically active and fulfilling current MS diagnostic criteria, becomes RR MS 1996 vs new MS Phenotype Descriptions (Lublin et al 2014) Progressive Disease

1996 MS Clinical Modifiers 2012 MS Disease Modifiers Subtypes Phenotypes Progressive accumulation of disability from onset Progressive PP with or without temporary accumulation plateaus, minor remissions of disability and improvements from onset active* and with progression# (PP) Progressive accumulation active* but without progression# of disability after initial Progressive Progressive SP relapsing course, with or Disease Disease not active* but with progression# without occasional relapses and minor remissions (SP) not active* and without progression# (stable disease) Progressive accumulation Progressive of disability from onset accumulation PR but clear acute clinical of disability after attacks with or without initial relapsing full recovery course

•Activity determined by clinical relapses assessed at least annually and/or MRI activity (CEL; new & unequivocally enlarging T2 lesions) # Progression measured by clinical evaluation, all assessed at least annually. Unmet needs – work in progress

Improve specificity in diagnosis and better subclassification by additional investigations: • Additional laboratory markers (CSF and Blood) • Antibodies: Anti Aquaporin 4, anti MOG and Anti MBP… KIR 4.1… • Markers of degeneration: Neurofilaments (NfL) in CSF, now also in Blood (!), Chitinase … • Molecular markers: DNA-, RNA-profiles, micro-RNA…

• Electrophysiological measures: • multimodal evoked potentials, • quantitative EEG… Aims of the diagnostic process

• Establish diagnosis - Exclude other, better or differently treatable diseases - revised McDonald criteria 2010 • Sub-Classification with implications for: - Prognosis - Selection of therapy - Prediction of response to therapy Case presentations

If there is still time..... Case presentations

29 y/o personal assistant 32 y/o teacher • short and progressive • frequent headaches for history the past month • slight headache • newly developed • trouble finding her disturbed vision on right words, impaired reading eye • shortly after rising • admission to hospital thermhypesthesia in her left leg • horizontal visual loss, painless • admission to hospital • signs of • tinnitus Case presentations 29 y/o personal assistant 32 y/o teacher

CSF analysis was normal in both cases Case presentations 29 y/o personal assistant 32 y/o teacher red flags of painless, horizontal partial blindness plus tinnitus

>> retinal infracts, MRI pattern

>> SUSAC syndrome CSF analysis was normal in both cases Case presentations 29 y/o personal assistant 32 y/o teacher

Biopsy revealed an inflammatory- demyelinating process >> MS!!

CSF analysis was normal in both cases Case presentations 29 y/o personal assistant 32 y/o teacher

T2w post Gd

CSF analysis was normal in both cases Interdisciplinary Team at the MS- Center in Basel

Thank you for your attention!