Demyelinating Disoreders DR. Abdulkader Daif, MD Consultant and professor of Neurology KKUH, College of Medicine Riyadh. SA Demyelinating Disoreders

DEMYELINATING DISEASES Central nervous syetem: Multiple sclerosis(MS) Neuromyelitis optica(NMO) Peripheral nervous syetem: Acute inflammatory demyelinating polyneuropathy (AIDP)

Multiple Sclerosis: Making the Diagnosis Topical Outline MS Background & Diagnostic Approach Diagnostic Criteria & Evaluation MS Variants Differential Diagnosis Clinical Cases 3

Classification of demyelinating disorders of the CNS Primary demyelinating diseases – MS, ADEM, AHL Secondary demyelinating diseases CPM, PML, SADC, Leukodystrophies and metabolic disorders e.g sudanophilic leucodystrophy, metachromatic leucodystrophy, adrenoleucodystrophy, Krabbes leucodystrophy, Canavans disease Toxic demyelination - Hexachlorophane, cyanide, carbon monoxide, chronic solvent vapour abuse.

Definition of Multiple Sclerosis An inflammatory demyelinating disease of the CNS where there is: Dissemination in space Dissemination in time No alternative neurologic disease MS is a clinical diagnosis 5

Multiple Sclerosis Epidemiology (Wallin M, et al Baker Clin Neurol CD-2003) The most common progressive neurologic disease of young adults Affects 350,000 persons in the USA Risk Factors: Female sex White race Northern latitude (USA) High socioeconomic status Scandinavian ancestry 6

Approach to the Diagnosis of MS (Modified from Fleming J, MS & Its Masquerades, AAN-2003) I flow chart starts with the neurological evaluation and splits into 3 groups: Group 1. Findings of typical MS means MS and “treats for MS”, Group 2. Minor or Unusual Findings means MS Possible and “close follow-up &/or focused work-up, Group 3. Normal Findings means MS unlikely and “reassure and evaluate when appropriate Close follow-up &/or Focused work-up Reassure & evaluate when appropriate Treat for MS 7

Multiple Sclerosis Subtypes (Lublin F, et al Neurology 1996) Asymptomatic Symptomatic Relapsing-remitting (85% at onset) Primary progressive (10%) Secondary Progressive (transitional form) Progressive Relapsing (5%) 8

Multiple Sclerosis Subtypes (Coyle P, CNS News 2002; adapted from Lublin F, et al Neurology 1996) A diagram of the MS subtypes: relapsing-remitting, primary progressive, secondary-progressive, and progressive-relapsing 9

Clinical Features Suggestive of MS Onset between 15-50 years Blurred or double vision Lhermitte’s sign Fatigue Heat sensitivity Bladder symptoms Cognitive or affective changes 10

MS Disease Timeline (Fox RJ, Sweeny PJ, Cleveland Clinic, May 2002) A MS disease time line showing preclinical phase, relapsing-remitting phase, and secondary progressive phase and tracking brain volume, clinical disability, disease burden and MRI activity over 20 years 11

McDonald Diagnostic Criteria Primary Progressive MS Insidious course with steady progression of clinical deficits with paraclinical evidence: DIS by MRI in combination with VER & positive CSF DIT by MRI or continued progression for 1 yr 12

McDonald Diagnostic Criteria MRI-High Specificity & Sensitivity for MS Typical MS demyelinating lesions meeting at least 3 of the following 4 criteria: At least 1 Gd lesion or at least 9 T2 lesions At least one infratentorial lesion At least one juxtacortical lesion At least 3 periventricular lesions 13

McDonald Diagnostic Criteria MRI-Dissemination in Space Stringent MRI Criteria At least 3 of the 4 criteria must be met: 1 Gd enhancing lesion or 9 T2 lesions > 1 Infratentarial lesion > 1 Juxtacortical lesion > 3 Periventricular lesions MRI + CSF Criteria Both of the following must be met: > 2 lesions consistent with MS CSF showing OCB or increased IgG index 14

McDonald Diagnostic Criteria MRI-Dissemination in Time If the first MRI is performed 3 months after the clinical event, 1 of the 2 below must be found: > 1 Gd lesion not at site of original attack; or MRI 3 months later showing a new T2 or Gd lesion If the first MRI is performed < 3 months after the clinical event, then a second MRI done 3 months after the attack provides evidence for DIT if 1 of the 2 below must be found: New Gd lesion on the second MRI Later MRI showing new T2 or Gd lesion 15

McDonald Diagnostic Criteria Correct Application Clinical & lab findings typical of MS No better explanation of patient’s findings Unusual cases require close follow-up Criteria may be applied flexibly but not casually Revisions to criteria may be needed in future 16

McDonald Diagnostic Criteria Prospective Performance (Dalton, et al Ann Neurol 2002) Diagnosis of MS by McDonald Diagnostic Criteria in CIS patients at one year after presentation compared to reanalysis of these patients by Poser criteria at three years: Sensitivity: 83% Specificity: 83% PPV: 75% NPV: 89% 17

Focused Neurologic Exam (Adapted from Whitney D, Int J MS Care, 2001) MSt: Attention, psychomotor slowing CN: VA, fundoscopic exam, VFs, swinging flashlight, EOM evaluating for paresis (INO) & nystagmus Reflexes: asymmetries, Babinski sign Motor: spasticity, pyramidal pattern of weakness Sensory: Thoracic or cervical level Gait: integrates many functions, 25’ timed walk Bladder: PVR (if symptomatic) 18

Imaging & Lab Work-up for MS (Modified from Fleming J, MS & Its Masquerades, AAN-2003) Brain MRI with Gd VERs CBC, Chem 7, Liver enz, UA Lyme serology (based on exposure history) ANA, RPR, ESR B12 TSH HIV CSF (based on clinical and MRI) C & T Spine MRI (if Brain MRI nl or indicated clinically) CXR 19

MRI INDICATIONS Ι 1. Initial evaluation after a CIS or based on past history that is suspicious Baseline imaging evaluation in MS 3. Spinal cord imaging a. Symptoms s.c. (+ brain) b. Findings in brain MR ? J.H. Simon, D. Li, et al Standardized MR Imaging Protocol for Multiple Sclerosis: Consortium of MS Centers Consensus Guidelines AJNR Am. J. Neuroradiol., Feb 2006; 27: 455 - 461

MRI INDICATIONS ΙΙ Follow up 5. Contrast when clinical indications a. Unexpected worsening b. Reassess burden for initiation of Tx c. Suspicion of secondary Dx routine periodically (yearly) optional 5. Contrast initial baseline exam Periodic follow up Routine Gd MR to aid treatment decisions, but there is insufficient evidence to conclude that enhancement alone should drive treatment decisions. J.H. Simon, D. Li, et al Standardized MR Imaging Protocol for Multiple Sclerosis: Consortium of MS Centers Consensus Guidelines AJNR Am. J. Neuroradiol., Feb 2006; 27: 455 - 461

K. Kollia et al, AJNR, 30:699 –702 Apr 2009 1. MS lesions vary in size and location and have a periventricular predominance. It would be unusual to have sparing of this region in MS. The lesions typically develop in a perivenular pattern as immune cells migrate across the blood-brain barrier and induce a cascade of inflammation and demyelination. These areas may appear as Dawson fingers or elongated flame-shaped lesions best seen on sagittal FLAIR images oriented along subependymal veins in the corona radiata and centrum semiovale, perpendicular to the walls of the ventricle K. Kollia et al, AJNR, 30:699 –702 Apr 2009

‘’Black holes’’

MRI criteria dissemination in space 3 of 4 1 Gd+ or 9 T2-hyperintense lesions if there is no enhancing lesion At least one infratentorial lesion 3. At least one juxtacortical lesion At least 3 periventricular lesions (Note: One spinal cord lesion can be substituted for one brain lesion.) McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis οf multiple sclerosis. Ann Neurol 2001;50:121–27

MRI criteria dissemination in time 1. MRI > 3mo after clinical event, Gd+ site # original 2. MRI > 3 mo after clinical event, Gd- repeat MRI in additional 3mo new Τ2 or new Gd+ McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis οf multiple sclerosis. Ann Neurol 2001;50:121–27

SPINAL CORD 50-90% MS up to 25% only site involved cervical dorsolateral, < 2 vertebral bodies < half transverse diameter Multifocal Cord atrophy

Visual Evoked Potentials (Baker’s Clin Neurol 2003) A chart showing the visual evoked potentials 29

Oligoclonal Bands A diagram shows the absence of oligoclonal bands and the presence of them in CSF Baker's Clinical Neurology, CDROM-2003 30

MS Variants Marburg variant Balo’s Concentric Sclerosis Schilder’s Disease Disseminated subpial demyelination Mass Lesion 31

Other Disorders Neuromyelitis Optica (Devic Syndrome) Relapsing (55%), monophasic (35%) MRI: cord lesions, chiasmal signal changes CSF: generally >100 wbc,  protein, rare OCB Postinfectious encephalomyelitis or ADEM Monophasic with preceeding event common (70%) Most common in children Altered LOC and seizures common MRI: bilateral symmetric lesions 32

Clinically Isolated Syndromes Optic Neuritis Risk factors for MS (60-75%) History of minor neurologic sxs Unilateral optic neuritis Brain MRI lesions Abnormal CSF Abormal VERs 33

Clinically Isolated Syndromes Transverse Myelitis Risk factors for MS Incomplete transverse myelitis Asymmetric motor or sensory findings Brain MRI lesions Abnormal CSF Abnormal VER and SSEPs Others (Brainstem, Cerebellum) 34

Red Flags for Misdiagnosing MS MRI changes without clinical correlate Known psychiatric disease Normal neurologic examination Atypical clinical features Disease onset at the extremes of age Extraneural systemic disease Prominent gray matter symptoms 35

Breaking the news of an MS diagnosis Communicate with the patient face-to-face Explain prognosis and treatment using lay terms Give hope to the patient by: encouraging pursuit of personal/career goals Correcting pessimistic impressions of MS Provide information on future follow-up and patient support resources 36

Case #1 31 year old Asian female presents with subacute onset of right sided trunk numbness (T4 level) and asymmetric leg weakness. No prior neurologic symptoms or signs. MRI of cord shows patchy upper thoracic T2- signal lesion. CSF: 100 wbc, increased protein & negative OCBs. 40

Case #2 18 year old male high school senior presents with 48 hours of blurred vision, bilateral leg weakness with right arm ataxia. He appears to be alert but is a bit slow to respond to questions. No recent illnesses or significant PMH. MRI shows bilateral brainstem, occipital and cerebellar T2-lesions some of which enhance. His family is extremely concerned and ask your opinion on his diagnosis and prognosis. 41