6-7 December - Toronto, Canada

1st interactive course in MS advanced managment

IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION

www.excemed.org Marika Hohol

Department of Medicine Division of Neurology St. Michael's Hospital Toronto, Canada

Receipt of honoraria and consultation fee: Biogen, EMD Serono, Genzyme, Novartis; member of a company advisory board, board of directors or other similar group: Biogen, EMD Serono, Genzyme, Novartis, Roche Clinical Diagnosis and Diagnostic Criteria of MS

Marika Hohol BScPhm, MD FRCPC Division of Neurology Department of Medicine University of Toronto Toronto, Canada Disclosure

I have received personal compensation for consulting and/or speaking from Biogen, EMD-Serono, Genzyme, Novartis, and Roche Objectives

• Discuss a clinical approach to the diagnosis and differential diagnosis of MS • Present the most recent revisions to the McDonald diagnostic criteria • Explain the phenotypic classification of MS currently in use Diagnosing

MS can be complex and challenging to diagnose and thus some degree of Early and accurate diagnosis of diagnostic uncertainty is inevitable MS is becoming even more • Diagnosis of exclusion important as emerging data • When should one investigate supports early initiation of for an alternate diagnosis disease modifying treatment • Misdiagnosis can have significant implications Diagnostic Principles

• Perhaps, better to consider MS a diagnosis of inclusion, not exclusion • Identify “classic” symptoms of MS (HISTORY) • Perform a neurological EXAMINATION • Perform relevant INVESTIGATIONS • MRI brain (initial study with gadolinium) +/- spine • CSF analysis when necessary • Visual and somatosensory evoked potentials when necessary • Lab investigations when necessary • For patients transferred to your care, ensure the diagnosis is accurate “Classic” Symptoms of MS

• Initial presentation depends on the location of lesion(s) and type of MS, relapsing (clinically isolated syndrome, CIS, 85%) or primary progressive (PPMS, 15%) • Common CIS presentations include unilateral , partial myelitis, or a brainstem syndrome and typically occur in a younger patient (<40 years), evolve over 24-96 hours, peak within 4 weeks, and spontaneously remit • Enquire about previous neurological symptoms that could indicate an earlier, unrecognized attack, but ensure that these symptoms are characteristic of MS • PPMS is slowly progressive over months to years, most often presenting as an asymmetric myelopathy, less commonly, progressive cerebellar or hemiparesis, and very rarely or visual impairment Typical CIS Presentations

Optic Nerve • Unilateral optic neuritis, • with eye movement • Impaired colour vision • Partial and mainly central vision Brainstem/cerebellum • Double vision • Facial sensory loss or trigeminal neuralgia • Ataxia • Partial myelitis, sensory > motor • Lhermitte’s phenomenon Neurological Signs Supportive of an MS Diagnosis

• Impaired vision and colour vision, central scotoma, RAPD, optic atrophy (chronic) • INO • 6th nerve palsy • • Facial sensory impairment • Limb and/or gait ataxia • Sensory impairment (dorsal column) • Spinal sensory level • Asymmetric spastic hemiparesis, paraparesis, less commonly, quadriparesis Investigations – Brain MRI

• Review actual images – do not rely on reports alone

DIS by McDonald Criteria ≥1 T2 lesion(s) in ≥2 locations

• Multifocal T2-hyperintense well circumscribed irregular, round or oval lesions • Supratentorial (periventricular, corpus callosal, juxtacortical and cortical) and infratentorial • Hypointense T1 (black holes) • Gadolinium enhancing lesions Typical MS Brain Lesions Gadolinium Enhancing MS Brain Lesions

• Homogeneous (nodular) • Closed ring • Linear • Open ring Investigations – Spinal cord MRI

• Recommended in patients with myelopathy or when brain MRI is not diagnostic • Typical lesions extend over 1-2 vertebral segments • Often eccentrically placed abutting pial surface • May enhance Typical MS Cord Lesions Enhancing MS Cord Lesion CSF Analysis

• In most patients with typical clinical and MRI findings, is not necessary, but can provide supportive evidence

• No CSF abnormality is specific for MS (including oligoclonal bands)

CSF Profile in MS: • Mildly raised WBC count, usually less than 25/µl, predominantly lymphocytes

• Mild elevation of protein, normal glucose

• Increased IgG index and/or oligoclonal bands (at least 2 discreet bands of IgG on electrophoresis) not present in plasma , best detected using isoelectric focusing and immunofixation Oligoclonal Bands Evoked Potentials

• An electrical response to stimulation of a sensory pathway, recorded through surface electrodes, amplified and subjected to signal averaging

• Visual, (brainstem auditory) and four limb somatosensory

• Provide supportive evidence by identifying clinically silent lesions

• Prolonged latency and preserved waveform amplitude is suggestive but not specific for MS Visual Laboratory Investigations

• Often done to exclude other conditions • More likely to be false positive than true positive abnormalities and lead to further unnecessary testing and consultations • Studies suggest that routine screening for infectious, alternate inflammatory, genetic or metabolic disorders is unlikely to be helpful in patients with a typical presentation and should be reserved and judiciously used for atypical cases Utilization of Laboratory Tests in the Diagnosis of MS

Shah A et al. P841, ECTRIMS 2017 Laboratory Results in Patients Diagnosed with MS

Shah A et al. P841, ECTRIMS 2017 Changes Made to MS Diagnosis as a Result of Laboratory Testing

Shah A et al. P841, ECTRIMS 2017 Differential Diagnosis: Selected Disorders with a Relapsing-remitting Course

Brownlee WJ et al. Lancet 2017;389:1336-46 Differential Diagnosis: Selective Disorders with a Progressive Course

Brownlee WJ et al. Lancet 2017;389:1336-46 Clinical Red Flags

Clinical Red flags Possible diagnosis General • Hyperacute presentation Ischemia, hemorrhage, , syncope • Fevers, , weight loss, night sweats, travel, CTD symptoms Infection, systemic vasculitis, SLE • Livedo reticularis, early trimester abortions, thrombotic events Antiphospholipid syndrome • Intractable nausea, vomiting, or hiccups NMOSD • Prominent family history Genetic disease Cerebral hemispheres • ADEM, PRES, infectious/autoimmune • Hemianopia or cortical blindness Ischemic , PRES, neoplasm, PML • Insidious significant cognitive decline Neurodegenerative, genetic leukoencephalopathy, leukodystrophy Optic nerve • Progressive optic neuropathy Neoplasm, sarcoidosis, LHON • Altitudinal deficit or monocular blindness Ischemic optic neuropathy, Susac’s syndrome • Clinically severe or simultaneous bilateral ON NMOSD, LHON Spinal cord • Anterior spinal artery syndrome Ischemia • Complete transverse myelitis NMOSD, idiopathic TM, ADEM • Radiculitis Infection, sarcoidosis, carcinomatosis/lymphomatosis • Progressive spastic paraparesis HTLV-1, HIV, B12 deficiency, PLS, compressive myelopathy, dAVF Modified from Toledano M. et al. Curr Neurol Neurosci Rep 2015;15:57 MS Diagnosis by Schumacher Criteria (1965)

• Appropriate age (10-50 years) • CNS white matter disease • Lesions disseminated in time and space • Objective abnormalities • Consistent time course • Attacks lasting > 24 hours; spaced one month apart • Or slow/stepwise progression > 6 months • No better explanation • Diagnosis by a competent clinician (neurologist) Intent of the McDonald Criteria (2001…)

“To present a diagnostic scheme that could be used by the practicing neurologist to better and more reliably diagnose MS….”

BUT

The McDonald Criteria were developed and validated to identify MS in patients with a typical CIS or PPMS presentation and NOT to differentiate MS from other conditions

Integration of the history, examination, imaging and laboratory evidence by a clinician with MS-related expertise remains fundamental in making a reliable diagnosis of MS or an alternate diagnosis General Principles of 2017 Proposed Revisions to the McDonald Criteria

• Based on new data (MRI, CSF and other paraclinical tests) as well as performance of the 2010 Criteria • Simplify or clarify components of 2010 Criteria • Facilitate earlier diagnosis (and treatment) • Preserve specificity • Ensure changes do not weaken the Criteria and are supported by evidence

Cohen J ECTRIMS 2017 Thompson AJ et al. Submitted for publication Earlier Diagnosis of MS Using McDonald Criteria

Mean time to MS Diagnosis

CDMS 23.1 months

2001 criteria 12.0 months

2005 criteria 10.5 months

2010 6.2 months

p< 0.01 for all comparisons with CDMS

Brownlee et al JNNP 2015 2017 Proposed Revisions to the McDonald Criteria: Attack Onset 2017 Proposed Revisions to the McDonald Criteria: Attack Onset

In a patient with a typical CIS and fulfillment of clinical or MRI criteria for DIS and no better explanation for the clinical presentation, demonstration of CSF-specific oligoclonal bands (OCB’s) allows an MS diagnosis to be made Positive OCB’s do not represent DIT but can be used as a substitution for DIT

Addition to the 2010 McDonald Criteria 2017 McDonald Criteria for DIS by MRI DIS ≥1 T2 lesion(s) in ≥2 locations

Periventricular Cortical/juxtacortical Infratentorial Spinal cord

Changes from the 2010 McDonald Criteria: • No distinction between symptomatic and asymptomatic lesions (previously applied to brainstem and spinal cord) • Can use an optic nerve lesion but not if the patient presents with optic neuritis • Cortical lesions can be utilized 2017 McDonald Criteria for DIT by MRI

DIT can be demonstrated by • Simultaneous presence of gadolinium-enhancing and non-enhancing lesions at any time OR • A new T2-hyperintense lesion or gadolinium-enhancing lesion on follow- up MRI with reference to a baseline scan, irrespective of the timing of the baseline scan

Change from the 2010 McDonald Criteria • No distinction between symptomatic and asymptomatic lesions (previously applied to initial scan showing a symptomatic gadolinium-enhancing lesion) 2017 Proposed Revisions to the McDonald Criteria: Progression from Onset

At least one year of disability progression (retrospective or prospective) independent of clinical relapse Plus 2 of 3 of the following: • ≥1 T2-hyperintense lesions in ≥1 area(s) in the brain characteristic of MS (periventricular, cortical/juxtacortical, or infratentorial • ≥2 T2-hyperintense lesions in the spinal cord • Demonstration of CSF-specific oligoclonal bands

Change from the 2010 McDonald Criteria • No distinction between symptomatic and asymptomatic lesions (previously applied to brainstem and spinal cord) • Cortical lesions can be utilized 2017 Proposed Revisions to the McDonald Criteria

At the time of diagnosis, a provisional disease course should be specified* and periodically re-evaluated based on accumulated information.

Addition to the 2010 McDonald Criteria

* Lublin FD, et al. Neurology 2014;83:278-286 Clinical Course of MS: The 2013 Revisions

CIS RRMS SPMS

Active / Not active : (applies to all phenotypes) Relapse(s) or lesion activity on MRI to be assessed at least annually. With / Without progression : Disability progression independent of relapses, evident by history or PPMS objective measure of change, to be determined annually in patients with PPMS or SPMS.

Lublin FD et al. Neurology 2014;83:278-286 Misdiagnosis of MS

• Five to ten percent of patients initially diagnosed with MS are later found to have a different disorder • Misdiagnosis occurs by MS-specialists as well as general neurologists • Common disorders account for most cases • Systemic inflammatory or infectious disorders are rarely misdiagnosed as MS • Misdiagnosis can have harmful consequences • Exposure to immunomodulatory treatments and side effects • Worsening of NMOSD due to incorrect treatment • Psychological • Strict adherence to clinical and radiological criteria should prevent misdiagnosis Clinically Vague Syndrome

MRI has increased misdiagnosis of patients with nonspecific symptoms due to misinterpretation of nonspecific imaging findings • These patients typically report symptoms difficult to localize such as non vertiginous dizziness, migratory or diffuse paresthesias or numbness, , blurry vision, muscle pain and cognitive complaints Non specific lesions vs. MS Diagnoses and syndromes mistaken for MS (N=110)

False positive CSF OCB’s and/or increased IgG in 14/52 patients (27%)

Solomon AJ et al. Neurology 2016;87:1393 Duration of Misdiagnosis of MS

Solomon AJ et al. Neurology 2016;87:1393 Contributors to MS Misdiagnosis

Misinterpretation of MRI • Misinterpretation of non-specific MRI abnormalities as DIS to confirm a diagnosis of MS in a patient with nonspecific neurological symptoms

• Erroneous determination of juxtacortical or periventricular lesion location to fulfill DIS

• Erroneous determination of DIT because of variability of MRI slice orientation or strength of magnet (i.e., MRI’s performed on different scanners leading to the appearance of new lesions)

Inappropriate application of MS diagnostic criteria • In patients presenting with symptoms atypical for a demyelinating attack

• For a historical episode of neurological dysfunction without corroborating evidence of a lesion (based on neurological examination, evoked potentials or imaging)

Solomon AJ et al. Neurology 2016;87:1393 What’s relevant for your clinical practice?

Impact of the 2017 McDonald Criteria on the diagnosis of MS Case Example of 2017 Proposed Revisions to the McDonald Criteria: Attack Onset

• A 28 year old woman presents with horizontal diplopia worsening over 3 days • Neurological examination shows a left INO but is otherwise normal • Brain MRI is as follows with no gadolinium enhancing lesions

• CSF shows CSF-specific oligoclonal bands (not present in serum)

Modified from Chataway J ECTRIMS 2017 Case Example of 2017 Proposed Revisions to the McDonald Criteria: Attack Onset

2010 McDonald Criteria 2017 McDonald Criteria 1 clinical attack 1 clinical attack

Dissemination in space by MRI (≥1 T2 Dissemination in space by MRI (≥1 T2 lesions in ≥2 of 4 characteristic areas) lesions in ≥2 of 4 characteristic areas)

No evidence of Dissemination in Time Dissemination in Time by demonstration of CSF-specific OCB’s Diagnosis: Clinically Isolated Syndrome Diagnosis: MS

Modified from Chataway J ECTRIMS 2017 Case Example of 2017 Proposed Revisions to the McDonald Criteria: Progression from Onset

• A 43 year old man presents with an 1.5 year history of progressive left leg weakness and spasticity, numbness of both legs, erectile dysfunction and urinary urgency • Neurological examination shows an asymmetric spastic myelopathy • Brain MRI and cord MRI is as follows (2 cord lesions in total)

• No CSF available (unsuccessful attempt)

Modified from Chataway J ECTRIMS 2017 Case Example of 2017 Proposed Revisions to the McDonald Criteria: Progression from Onset

2010 McDonald Criteria 2017 McDonald Criteria >1 year of disability progression >1 year of disability progression

Dissemination in space by MRI (≥1 T2 lesions Dissemination in space by MRI (≥1 T2 lesions in ≥1 of 4 characteristic areas) in ≥1 of 4 characteristic areas) Does not meet minimum DIS in spinal cord (≥2 T2 lesions) as symptomatic lesion cannot Meets minimum DIS in spinal cord (≥2 T2 count lesions) as symptomatic lesion(s) can count

No CSF available No CSF available

Diagnosis: Possible MS Diagnosis: PPMS

Modified from Chataway J ECTRIMS 2017 Take-home messages

1. Besides merely confirming DIS/DIT, apply diagnostic rigor in the interpretation of the history, examination, imaging and laboratory evidence and MS-related expertise to make a reliable diagnosis of MS or an alternate diagnosis 2. Confirm the diagnosis of MS in any patient transferred to your care - accept historical events lacking objective corroboration (from patient or physician) with caution 3. Do the initial diagnostic MRI with gadolinium 4. Do not rely on MRI reports - review the MRI yourself (or with a neuroradiologist) 5. Perform selective laboratory investigations only when indicated 6. Have a low threshold to perform a spinal cord MRI and/or CSF examination • Insufficient clinical and/or brain MRI evidence • Non-classical presentation (including progression from onset) • Atypical features • In populations in which MS is less common 7. When in doubt, consider postponing the diagnosis (and treatment) – “the test of time”