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2015台灣神經學學會 住院醫師教育課程 Demyelinating diseases 中醫大附醫 神經部 郭育呈 20150830 Outline

• Diagnosis of • Diagnosis of neuromyelitis optica • Treatment of multiple sclerosis • Treatment of neuromyelitis optica • Other CNS demyelinating diseases-D.D. Multiple sclerosis

• Onset: youth (15-45 y/o, peak 20-30 y/o). F/M=1.4~3 • Caucasians > Asians, Africans • Prevalence increased with latitude – 100/100,000 in Scotland, certain areas of Scandinavia, Canada – 5/100,000 in Asia and Africa – 0.8/100,000 in Taiwan (1977) – 4.34/100,000 in Taiwan (2010) Clinical manifestation of MS • Depends on the areas involved... optic nerve, brainstem, cerebellum, are commonly involved. • In Taiwan: optic-spinal form ( + myelopathy) is the common • Sudden onset of optic neuritis, without any other S/S, is often the 1st symptom of MS • Limb weakness -- most common signs in advanced cases

• Consider MS in young adults with: – internuclear ophthalmoplegia (INO): medial longitudinal fasciculus (MLF) lesion – trigeminal neuralgia (esp. bilateral involvement) – hemifacial spasm Presenting Signs and Symptoms

Optic Nerve Cerebrum • Unilateral painful vision loss · • Numbness · • Weakness • Cognitive impairment Brainstem · • Depression • · • Diplopia Cerebellum • Swallowing problems4 • Walking, balance, and coordination problems • Spinal Cord • Dizziness and vertigo • Bladder dysfunction • Bowel dysfunction · Other • Sexual dysfunction • • Weakness • • Temperature sensitivity and • Spasticity exercise intolerance • Numbness

Courtesy of Dr. Lu SR Increasing disability Time 疾病病程型態 in oneormoresitestheCNS hours, andiscausedby The firstneurologic episode thatlasts atleast 24 Clinically Isolated Symptom altogether Relapses become less frequent and may cease (30%) RRMS prolonged Onset ofgradualneurolog Secondary Progressive permanent deficitsfollowe Unpredictable attackswhic Most commonly pr Most frequent form (40%) Relapse Remitting Steady increase indisa Uncommon (10-15%) Primary Progressive 3 eceded byCIS bility withoutrelapses 復發緩解型 / demyelination d byperiodsofremission ical progression after after ical progression 首次漸進型 h mayornotleave 次發漸進型 臨床單一發作 (RRMS) (PPMS) (SPMS) 4 2 診斷標準

「不同時間」 Dissemination in time • 至少兩次發作 「不同位置」 Dissemination in space Diagnosis of MS • No pathognomonic diagnostic test for MS • The rule of thumb: multiple symptoms or neurological lesions, dissemination in space and time • Exclusion of other conditions !

• MRI, CSF studies, the evoked potential studies are the most important diagnostic tools MRI in MS • MRI: the most valuable diagnostic tool: detect multiple asymmetric lesions in >90% of patients. – T2WI is the standard procedure. – Proton density images & FLAIR enhance the ability to defect periventricular lesions – Gadolinium enhancement: to detect active lesions – New T2 lesion: inflammation T1 black hole: permanent demyelination or axonal loss • MR spectroscopy: – Lipid peak (0.9-1.3): active demyelination – N-acetyl aspartate (NAA) peaks: axonal integrity T2 WI FLAIR

T2 WI T1WI + C l. 52 p61-76 Neuron 2006 vo Diagnostic criteria

• in 1983: clinical and paraclinical • McDonald criteria in 2001 • McDonald criteria revision in 2005 • McDonald criteria revision in 2010 Poser’s diagnostic criteria of MS McDonald Criteria for MS

2001 2005 2010

Dissemination Three of the following four criteria: •>1 T2 lesion in at least in Space 1. At least one Gd-enhancing lesion or 9 T2 hyperintense lesions if there 2 out of four MS-typical is no Gd-enhancing lesion regions of CNS 2. At least one infratentorial lesion periventricular, 3. At least one juxtacortical lesion 4. At least three periventricular lesions juxtacortical, infratentorial, 2001: One spinal cord lesion can substitute for one brain lesion. or spinal cord 2005: A spinal cord lesion can be considered equivalent to a brain infratentorial lesion: an enhancing spinal cord lesion is considered to be equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute together with individual brain lesions to reach the required number of T2 lesions. Dissemination A Gd+ lesion > 3 months after onset of initial clinical event at a site not Simultaneous presence of in Time implicated by the event asymptomatic Gd- enhancing AND non- enhacing lesions at any time Or: Or: Or:

Follow-up scan (>3 months): a A new T2 lesion at any time A new T2 and/or Gd+ new T2 or Gd+ lesion compared to a scan > 30 days lesion(s) on FU MRI after onset of initial clinical event irrespective of timing of baseline scan

J Neurol 2010 臨床出現症狀之前神經元已受損傷

Clinically Relapsing Secondary Isolated Remitting Progressive Syndrome

臨床上第一次發作 神經軸突喪失

Clinical Threshold

Clinical Symptoms 去髓鞘變化

21 Time (Years) 腦部容量和核磁共振MRI變化

C. Relapsing Secondary Preclinical I. Remitting Progressive S.

Brain volume 腦部容量

Relapses and Impairment 復發及功能影響

MRI Burden of Disease 核磁共振 New lesions新病灶

Time (Years) C.I.S., clinical isolated syndrome

Adapted from Goodkin DE. UCSF MS Curriculum. January 1999 愈早治療預期效果會愈好

Preclinical CIS RRMS SPMS

反覆發作後治療

Clinical Threshold

第一次發作後治療

Time

23 Treatment for multiple sclerosis

Treatment of Corticosteroids (IV/oral) to hasten recovery relapses No proven impact on disease activity

Long-term treatment to Disease- modify disease course / potentially delay modifying treatment accumulation of disability No direct impact on symptoms

Symptomatic Drugs to alleviate fatigue, pain, spasticity, treatment stiffness, urinary problems, depression, etc. No direct impact on disease activity Treatment options of MS (1) • Acute: – Steroid pulse therapy (shorten the duration of attack) – Plasma exchange/plasmapheresis

• Disease-modifying agents: – Interferon-β 1a or 1b (immune modulator): • anti-inflammatory properties, ↑the integrity of BBB

– (sphingosine 1-phosphate receptor modulator) sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.

– (immune modulator): • a mixture of synthetic polypeptides (glutamic acid, lysine, alanine and tyrosine), which blocks T-cell activation or possible acts as an altered peptide ligand. Treatment options of MS (2)

• Disease-modifying agents (con’t): – (anti-VLA-4 monoclonal antibody) • an antagonist of VLA4 that blocks it from binding to vascular cell adhesion molecule (VCAM), which is up-regulated on the endothelium during inflammation.

– (immunosuppressant) • intercalates with DNA and inhibits both DNA and RNA synthesis, suppressing T-cell and B-cell immunity

– Immunosuppressive agents (steroid, cytotoxic agents): in selected cases

Neuromyelitis optica (NMO) Taiwan Taiwan Malaysia Japan Kyushu Maida vale (Hung et al (Tsai et al 1988 nationwide 1981 1981 1976) 2004) 1975 No. of 25 43 30 1084 60 204 patients Onset(y/o) 32.1 29.9 29.7 33.0 31.0 31.0 F:M 3.2:1 5:1 5:0 1:3 1:5 2:0 FH No No No Yes (1-2%) No Yes (10%) Initial Visual Spinal cord Spinal cord Visual Visual Numbness symptom Most Visual Motor; - Visual Visual ; common sensory sensory symptom Optic-spinal 44% 20.9% 53% - - 20.8% form

R-R 51% - 74% 85% 64% S-P 30% - - 10% 31% P-P 19% - - 2% 5% Neuromyelitis optica (NMO, Devic’s disease)

• Devic E found in 1894 • Monophasic • Bilateral optic neuritis & transverse myelitis • Both attacks at the same time or in quick succession • Brain spared Wingerchuk DM et al. Neurology 1999

• 71 NMO cases • Monophasic (sequential events, median 5 days) and relapsing (within 3 yrs, median 166 days) • Severe relapse which isolated to optic nerves and spinal cords • Severe disability with a stepwise course (50% 5 yrs) • CSF > 50 cell/mm3 (PMN) • ≧3 vertebral segments • Normal initial brain MRI • Humoral response, Ig/complement deposition- BV < MS > < NMO > < NMO, CE+ > NMO-IgG, serum autoantibody

• Pia • Virchow-Robin space • Microvessels • Aquaporin-4 water channel (AQP4)(BBB) • Autoimmune channelopathy

Lennon et al. Lancet 2004

(sensitivity 99%, specificity 90%)

Brain lesions in NMO

AQP4(+) NMO patients: 79% brain lesions (+) 31% patients had brain lesions at the onset • Corticospinal tracts (posterior limb of internal capsule & cerebral peduncle), 44% • Extensive hemispheric lesions, 29% • Peri-ependymal lesions around aqueduct and 3rd/4th ventricles, 22% • Peri-ependymal lesions around , 40% • Medullary lesions, often contiguous with cervical lesions, 31%

Kim et al, MS 2010 “Tumefactive” or “spilled ink” “Posterior limb, internal capsule  midbrain”

Kim et al, MS 2010 Kim et al, MS 2010 Non-specific dot-like lesions • NMO /c brain lesions vs /s brain lesion: higher annualized relapse rate high frequency of AQP4 Ab  extensive lesions

• Development of brain lesions in NMO may reflect high disease activity and thus be a warning sign. Handbook of Clin Neurol 2014 Kira, Ann N Y Acad Sci 2008 NMO vs. MS

• Optic neuritis in NMO is more severe and more often bilateral on presentation • The spinal cord involvement in NMO typically extends ≥3 vertebral segments • Different pathological findings • No secondary progressive nature in NMO • NMO has worse outcome: the cycle of remission and relapse tends to be more frequent and severe. NMO MS Onset age Adult Younger Female ratio > 90%, Asian 75%, Caucasian Greater disability Severe Mild-moderate (EDSS) & vision Prognosis Relatively poor Relatively good Relapse rate More frequent Less frequent Autoimmune diseases Relatively frequent Relatively rare Brain MRI Hypothalamus, Periventricular, ovoid periaqueduct, extensive Spinal cord MRI LETM (>= 3 seg) Short (< 3 seg) BBB disruption Severe Moderate CSF findings OCB negative (< 15%) OCB positive (> 80%) IL-6/GFAP high IL-6/GFAP low AQP4 autoantibodies 70-90% Negative NMO spectrum disorder (NMOSD)

1. Limited forms of NMO

A. Idiopathic single or recurrent events of LETM (>= 3 vertebral segments) B. Optic neuritis: recurrent or simultaneous bilateral attacks

2. Asian optic-spinal MS

3. Optic neuritis or LETM associated with systemic autoimmune disease 4. Optic neuritis or LETM associated with brain lesions typical of NMO (hypothalamic, corpus callosal, periventricular, or brainstem) NMO: treatment • Acute stage: – IV steroid – Plasma exchange (if steroid-unresponsive) 血漿置換 • Chronic: immunosuppressants 免疫抑制劑 – Azathioprine + prednisolone – Rituximab – Cyclophosphamide – Mitoxantrone – Mycophenolate mofetil – Methotrexate + prednisolone • Steroid + MTX/AZA • Immunosuppressant + intermittent PLEX • Rituximab + MTX/IVIg

(IVIg for children) AII type

Other CNS demyelinating diseases Leukoencephalopathy: possible etiology

• Infection: – HIV & associated infection, HTLV-I, viral , SSPE and other slow viral diseases – Tuberculosis, syphilis, Lyme disease, neurocysticercosis, Whipple's disease • Inflammation: – Acute disseminated (ADEM), multiple sclerosis (MS), neuromyelitis optica (NMO), transverse myelitis, brainstem encephalitis. – Hashimoto‘s , Behçet’s disease • Vascular lesions: – Vasculitis – SLE, antiphospholipid antibody syndrome, isolated angitis of the CNS – Vasculopathy – MoyaMoya disease, Retinococlear vasculopathy of Susac, CADASIL – Cerebral venous thrombosis – Reversible posterior leucoencephalopathy (RPLS) Leukoencephalopathy: possible etiology

• Neoplasm: – Gliomatosis cerebri, primary CNS Lymphoma, neurosarcoidosis. – Paraneoplastic syndrome • Metabolic or nutritional derangement/drug/toxin: – Wernicke's encephalopathy (vitamin B1 deficiency), – Osmotic demyelination syndrome – Subacute combined degeneration (vitamin B12 deficiency) – Toxic: CO, Clioquinol, chemotherapy (mithotrexate, 5-FU) – Radiation • Genetic metabolic encephalopathy – Mitochondrial disorders – Lysosomal, peroxisomal & other storage diseases (ALD, MLD) Acute disseminated encephalomyelitis (ADEM) • An acute demyelinating disorder of CNS • Usually monophasic (relapse uncommon) • Children & young adults most commonly involved • Characterized by multifocal white matter lesions • Manifestation: – Systemic Sx (fever, malaise, myalgia, , nausea, vomiting) 4-21 days before onset of neurological S/S – The neurological S/S: acute onset, peak dysfunction occurs within days – Diverse S/S: fever, headache, meningeal signs, mental change, mild lethargy or coma, optic neuritis, acute cerebellar ataxia, transverse myelitis.... Acute disseminated encephalomyelitis (ADEM)

• A T-cell mediated autoimmune response to basic protein (MBP), triggered by viral infection or vaccination • Treatment: – IV steroid – Plasmapheresis – IV immunoglobulin (IVIG) • Recovery occurs over weeks to months • Favorable long-term outcome • Complete recovery: 50%, mortality rate: 10-30% • Worse outcome in patients with measles or rubella, or after rabies vaccination • Typical Image finding: T1WI low, T2WI high poor margin lesions in periventricle, juxta-cortical white matter. • Relatively minor mass effect. • 15-60% gray matter involvement (thalamus, basal ganglion, typically in symmetric pattern)  D/D with MS • Patients with acute disseminated encephalomyelitis (ADEM) may relapse and some may ultimately convert to MS • ADEM that meets modified McDonald criteria for dissemination in space is associated with a high probability of conversion to multiple sclerosis in Taiwanese patients. (Liao MF et al. Eur J Neurol, 2010) • In contrast, patients whose brain MRI findings did not meeting these criteria may be considered as having classic ADEM because they have a lower probability of conversion to MS. Gadolinium enhancement • 30-100 % with gadolinium-enhancement • Pattern of enhancement variables : (1) complete or incomplete ring shaped (2) gyral , nodular, spotty enhancement rarely meningeal enhancement

Hint : (1) MS may have homogenous enhancement, but ADEM not (2) PML never has contrast enhancement Open ring enhancement How to D/D ADEM with MS ? • D/D with MS: (1) consciousness alteration, (2) absence of OCBs, (3) gray-matter involvement in MRI If 2/3 (+)  PPV for ADEM = 97%, NPV = 75%

• Other hints favored ADEM: multi-focal, poly-symptomatics, age younger than 10 y/o, s/s of meningo-encephalitis, encephalopathy, bil. optic neuritis (D/D with NMO) CSF pleocytosis without OCBs, Large MRI lesion with indistinct borders K type Hereditary Leukodystrophy (ALD/MLD)

– can present in a stepwise fashion with post- infectious exacerbations (eg, , metachromatic leukodystrophy, and mitochondrial cytopathy). – MRI abnormalities in metabolic disorders are characteristically symmetrical, except MELAS . Brain MRI scans of 10-year-old boy with advanced ALD cerebral demonstrates extensive white matter changes in periventricular, central and subcortical white matter in parietooccipital, anterior temporal and posterior frontal lobes,. Neurosarcoidosis

– Incidence : 20 per 100,000 in USA – Typically a chronic disease – Women are more frequently affected than men – Fourth or fifth decade of life – 5~ 10% - CNS involvement – A relapsing-remitting clinical phenotype – Facial nerve paralysis (central or peripheral) and vision loss; meningeal irritation, encephalopathy – Weakness, paresis, paresthesia, diplopia, and are also frequent AJR 2004; 182:289-295 T1-weighted parasagittal MRI of 31-year-old man with neurosarcoidosis obtained after contrast administration shows enhancing lesion (arrow) in brain parenchyma, arising from spread of sarcoidosis granuloma along perivascular spaces Progressive multifocal leukoencephalopathy (PML)

– Clinical symptoms typically develop slower than those of ADEM – Subcortical white matter of occipital lobe ~ cortical blindness – Positive test for human immunodeficiency virus and detection of virus in the CSF by means of PCR or culture of JC Virus (papovavirus ) in CSF – 2-7% of AIDS PML IN OCCIPITAL LOBE, ASYMMETRY

Leukoaraiosis

• Patchy or confluent white matter abnormalities, periventricular or/and deep subcortical regions, revealed as on T2- weighted or FLAIR MRI. • These white matter hyperintensities are found commonly in the community- dwelling elderly population. The prevalence increases with age and the incidence approaches 100% by the age of 85. FLAIR +SWI International consensus guideline of NMO spectrum disorder (Neurology 2015;85:177-189)

Thank you for your attention !