Update on AQP4 Channelopathy and MOG Opathy

Update on AQP4 channelopathy and MOG opathy

Sasitorn Siritho, MD Bumrungrad International Hospital Siriraj Neuroimmunlogy Center (SNIC) Current knowledge of NMOSD • Autoimmune astrocytopathy • AQP4-structure • Pathogenesis of NMOSD • Autoimmune AQP -4 induced damage beyond the CNS Current knowledge of MOG • Autoimmune Demyalination • MOG-structure • Pathogenesis of MOG - dysfunction AQP4- structure

• First discovered in 1994 (1) • AQP4 monomer : 6 helical transmembrane regions + 2 short helix segments (2). • 2 main isoforms : methionine is the starting point (3) • M1-AQP4 • M23-AQP4 • AQP4 monomer assembly->homotetramer or hetero-tetramer • tetramers aggregated on the cell membrane to form OAP • only M23-AQP4 can form OAP • when M1-AQP4 is co-expressed with M23-AQP4, limit size of OAP that is formed by M23- AQP4 (4)

Marios C. Nature Reviews .Neuroscience 14, 265-277.2013

Roger Sayle , Hertfordshire UK 1Hasegawa et al., 1994, 2. Ho et al., 2009, 3) Crane and Verkman, 2009,4) Furman et al., 2003 Erlend A. Nagelhus, Ole P. Ottersen Physiol Rev 2013;93:1543-1562 Grazia Paola Nicchia WIREs Membr Transp Signal 2013, 2:143–154 Jonathan M. Crane. JBC. VOL. 286, NO. 18, pp. 16516 –16524 Byung-Ju Jin. Biophysical Journal Volume 100 June 2011 What the meaning of different isoforms?

Binding of AQP4-IgG to AQP4 on the surface of astrocytes (Iorio and Pittock, 2014; Papadopoulos et al., 2014; Pittock and Lucchinetti, 2016): • Preferential internalization of M1-AQP4 • Reorganization and aggregation of M23-AQP4 • Leading to the aggregation of OAP with greater relative molecular mass • As the number of AQP4 on the cell membrane decreased, the water transport capacity decreased and astrocyte function was damaged

Autoimmune AQP -4 induced damage beyond the CNS

NMOSD-associated myopathy (Cosgrove et al., 2014; Deguchi et al., 2012; Di Filippo et al., 2012; Guo et al., 2014; Iyer et al., 2013; Langille and Desai, 2015; Malik et al., 2014; Nakayama-Ichiyama et al., 2011; Okada et al., 2013; Suzuki et al., 2010; Yokoyama et al., 2012). HYperCKemia • AQP4-IgG caused the loss of AQP4 on the sarcolemma, -> destroying steady state of calcium in type II muscle fibers =>damage of the integrity of sarcolemma -> CK leakage, no obvious muscle fiber necrosis (Guo et al., 2014).

Dian He. Et al. MSRD 18(2017)41-46 Autoimmune AQP -4 induced damage beyond the CNS

 Case report of an association • Inner ear organs damage • Meniere disease, Labyrinthitis, SNHL • Gastrointestinal tract damage • Gluten sensitivity or celiac disease (CD) • Co-positive with gastric parietal cell -Ab • Co-positive with serum anti-gliadin IgA –Ab and anti-tissue transglutaminase-Ab • Skin • Psoriasis, Dermatitis Herpetiformis • Blood system damage • Recurrent thrombocytopenia and hemolytic anemia • AIHA • Marginal Lymphoma • Kidney damage • Membranous nephropathy • Nephrotic Syndrome • Lung damage • ARDS • Sarcoidosis

Dian He. Et al. MSRD 18(2017)41-46 Ann N Y Acad Sci PMC 2017 February 01 Tissue with AQP4 expression organized via biological system

Autoimmune AQP4 channelopathy. Proposed diagnostic criteria for NMOSD, based on the core diagnostic criteria Some patients may have autoimmune MOG oligodendrogliopathy. The area of the circle overlapping with the red AQP4-IgG+ circle : proportion of patients with that neurological manifestation considered NMOSD (e.g., < 5% sON; 5–25% rON; 40% sLETM; 70–90% rLETM. Why AQP4-IgG often causes CNS lesions but less in peripheral organs ? And with different severity?

1) Different distributions of AQP4 isoforms • The expression ratio of M23/M1 affects the number and size of OAP formation • Organs, such as the CNS, that are associated with abundant M23-AQP4 expression -> more damaging diseases (Matiello et al., 2013). 2) Increase in the number of OAP and a formation of high molecular weight OAP • Amount of OAPs of muscle fibers in patients with AQP4-IgG-related myopathy is larger than that in healthy muscle fibers, and the relative molecular mass is greater (Malik et al., 2014). 3. Diverse number of complement regulatory factors expressed in different organs • AQP4 was expressed in astrocytes with a lack of CD46, CD55 and CD59 expression in normal brain tissue (Saadoun and Papadopoulos) • AQP4 and CD59 co-expression occurred when astrocytes were cultured alone. However, when the astrocytes were co-cultured with endothelial cells, astrocyte foot processes expressed AQP4 but lacked CD59 expression. • AQP4 was co-expressed with CD46 and CD55 in the kidney tissue, and AQP4 and CD46 were co-expressed in gastric wall and skeletal muscle • Diverse expression of AQP4 isoforms and complement regulatory factors may determine individual susceptibility to disease onset 4) Distinct phenotype : High Th1 to Th17 ratio ? Brain lesions vs High Th17 to Th1 ratio ? spinal cord lesions

Dian He. Et al. MSRD 18(2017)41-46 Pathogenesis of NMOSD 1) primary immunizing event of unknown provenance (2) T lymphocytes take part in breaking the tolerance and in recruitment of other leukocytes; (3) plasmablasts produce AQP4-IgGs, which enter the CNS through (4) endothelial transcytosis or at areas of increased BBB permeability and then bind selectively to AQP4; (5) complement activation, leading to CDC and subsequent astrocyte death; (6) neutrophil and eosinophil rise in the periphery and their subsequent CNS infiltration (7) neutrophil and eosinophil infiltration (8) 2 demyelination caused by, among others, myelin phagocytosis, and bystander injury by proinflammatory factors. Where do AQP4 antibodies fit in the pathogenesis of NMO? 

•

Kinoshita M. MSI 2012, article 862169 How AQP4-Ab traffic to the CNS? Circumventricular organs

Leaking BBB • Non-specific inflammation or • infiltration of CNS specific T-cell specific

• GRP78 Gross PM, Weindl A (1987). Journal of Cerebral Blood Flow and Metabolism. 7 (6): 663–72.

http://journal.frontiersin.org/article/10.3389/fnint.2013.00061/full Stolp HB (2013). Front. Integr. Neurosci. 7:61. Glymphatic system Antoine Louveau. jci.org Volume 127 No 9 September 2017 Anti-endothelial cell antibody GRP:Glucose regulated protein

The effect of GRP78 antibodies on the pathogenesis of NMO 1. The binding of GRP78 autoantibodies to cell surface GRP78. 2. The induction of NF-κB nuclear translocation. 3. The enhancement of macromolecular permeability and the penetration of AQP4 antibodies into the brain. 4. The binding of AQP4 antibodies to AQP4 on astrocytes. 5. The production of IL-6 by astrocytes. 6. The activation of IL-6 signaling in endothelial cells and the further induction of blood-brain barrier breakdown. Proposed Roles of CDC and ADCC in NMOSD pathogenesis

CDC is a major mechanism in NMOSD pathogenesis

AQP4-IgG + AQP4 clusters +C1q Fc region

Formation of MAC (C5b–C9)

Astrocyte damage

ADCC is also essential mechanism •mediated by Fcγ receptor III • Inactivation of FcγRIII in mice prevents ADCC produced by NK-cells and phagocytosis of IgG1-opsonized cells by Mø •also enhanced by NE recruitment

C5a has a dual role in the cross-talk between CDC and ADCC

Ratelade J. Acta Neuropathol 2013 A coordinated alteration of AQP4 and membrane-associated astrocytic proteins as key elements of NMO pathogenesis (Intrathecal production?/ Diffusion/Passing breakdown BBB in/into the CNS of IgGAQP4+

Contact of AQP4-IgG and AQP4 on astrocyte endfeet Complement (CDC), NK-cell  AQP4 expression ?internalization (ADCC),  (also in other myelinated CNS structures) but  GFAP expression) GLT1 endocytosis Proinflammatory AQP4 loss (not restricted to perivascular area) without marked astrocyte loss) cell, cytokines/ Protein modification and  chemokines, Astrocyte dysfunction + morphological modification membrane expression (?D7-D14:damaged mitochondria @ cytoplasm+astrocyte processes=>tissue T and B-cell disorganization +>loss of Astrocyte processes) GLU uptake Astrocyte loss release GLU produced by astrocyte, Structural disturbance of the GLs; ADG, Col IV notably in spinal cord and GJs between astrocytes & OGs; Cx

Severe State of energy deprivation of OGs destruction Myelin disorganization (D21 by PLP)+olig2 OGs loss

Axonal loss Damaged mitochondria were Oligodendrocyte loss and 2 demyelination #axons (NF-M), fragmented+reduced thickness also observed in the axons Treatment in NMOSD The numbers (1–8) indicate some pharmacological targets in NMO : (1) IL-6 inhibitors Tocilizumab (Actemra, Toactemra; Genentech) SA237 (Chugai) (2) CD20: Rituximab (3) CD19: MEDI-551 (Medimmune LLC) (4) Glutamate antagonists (5) AQP4-IgG blocking and inactivation strategies: high-affinity, nonpathogenic anti-AQP4 antibody (aquaporumab) competes with pathogenic AQP4-IgG for AQP4 binding (6) Complement activation pathways and complement drug targets: eculizumab (Soliris) inhibits C5 C1inh (Cinryse) inhibits C1 (7) anti-neutrophil: sivelestat (Elaspol) (8) anti-eosinophil Antihistamines Cetirizine Ketotifen reduce cytotoxicity mediated by AQP4-IgG and eosinophils in in vitro models. Eosinophil-stabilizing agents are currently being studied in small numbers of patients with NMO.

Pittock. et al. Ann N Y Acad Sci 2016 Feb : 1366(1): 20-39

Recent Clinical Trials

• Eculizumab (Soliris) • PREVENT study (NCT01892345): A Double Blind Trial To Evaluate The Safety And Efficacy of Eculizumab In Relapsing NMO Patients • Inebilizumab (MEDI-551) • N-MOmentum study (NCT02200770): A Double-masked, Placebo-controlled Study With Open Label Period to Evaluate MEDI-551 in NMO and NMOSD • SA237 • SAKuraStar (NCT02073279): Efficacy and Safety Study as Monotherapy of SA237 to Treat NMO and NMOSD • SAKuraSky (NCT02028884): Efficacy and Safety Study as Add-on Therapy of SA237 to Treat NMO and NMOSD Eculizumab (Soliris)

. First in class terminal complement inhibitor . Approved for the treatment of 2 rare, life-threatening disorders with excessive activation of complement: • Paroxysmal Nocturnal Hemoglobinuria (PNH) • Atypical Hemolytic Uremic Syndrome (aHUS) • (AchR antibody-positive generalized MG) . PK: • Half-life 12 days, steady state in 60 days • No accumulation, no dose-related toxicity • No antidote . IV infusion every 2 weeks required

22 (A) Eculizumab is a humanized MAb that was derived from the murine anti-human C5 antibody m5G1.1. Eculizumab carries the CDR of the mouse anti-human C5 IgG, inserted into a germline framework region, including the hinge region from human IgG2, which does not bind Fc receptors, and the CH2–CH3 domains from human IgG4, which are unable to activate complement. These modifications minimize immunogenicity and prevent proinflammatory responses mediated by the IgG Fc portion.

(B) A molecular model of the C5 convertase portion C3bBb (in cyan and beige, respectively) in a complex with a substrate molecule C5 (green). The second C3b molecule of the C3bBbC3b complex is depicted as a dashed line because its location is still unknown. Mapping the 21- residue-long peptide, in the middle of which is the m5G1.1 epitope Zuber et al., 2012 KSSKC (red), on this structure reveals the molecular mechanism of action of eculizumab. Because the C5 convertases of the classical and the alternative pathway are very similar, we suggest that eculizumab prevents the entry of the substrate molecule C5 into the C5 convertases. Shannon R HInson. Handbook of Clinical Neurology. Vol133, chapter 21. Autoimmune Neurology PREVENT Study • Inclusion criteria • Male or female ; ≥ 18 years old • NMO or NMOSD

Screening Period Study Period • All must be NMO-IgG seropositive • Clinical evidence of ≥ 2 relapses in last 12 mths or 3 relapses in the last 24 mths (with Background NMO Meds + ≥1 relapse in the 12 mths Eculizumab: N = 88 • EDSS ≤7 Relapse History AQP4-IgG (+) Open Label • IS is allowed (maintenance dose prior to Ecu 2: P 1 Extension Study screening and remain on a stable dose

Randomization ECU- NMO-302 during the study) Background NMO Meds + • Max steroid dose: prednisone 20 mg/D Placebo: N = 44 Exclusion Criteria • RTX within 3 mths • MTX within 3 mths • IVIg within 3 wks prior to screening Eculizumab 900mg iv weekly x 4 -> 1200mg iv q 2 weeks for 2 years

“Double blind study ends when 24 adjudicated relapses have accrued” 24 Primary endpoint • Time to first adjudicated on-trial relapse • treatment with Soliris® reduced the risk of NMOSD relapse by 94.2 % vs Placebo (p < 0.0001) • At 48 weeks, 97.9 % patients receiving Soliris® were free of relapse vs 63.2 % of patients receiving placebo. • Generally well tolerated with a safety profile • No cases of meningococcal infection were observed. Inebilizumab (MEDI-551): NMO scientific rationale

Bone marrow Blood/lymph system Bone marrow

MHC II

CD20 and CD19 spare stem cells and plasma cells

CD19 more broadly includes small population of less mature B cells and plasmablasts

• A remarkable expansion of B cell subsets in seropositive NMO vs HC and MS • The expansion of this subset of B cells corresponded to CD19 subsets of plasma cells and it was increased in the same subjects during relapse CD19+ B-lineage plasmablasts are responsible for the production of AQP4-Ab

Source: Chihara N, et al. Proc Natl Acad Sci USA 2011;108:3701-6. Inebilizumab (MEDI-551): an anti-CD19 mAb

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MS 2 Phase 1 trial

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D a y s p o s t-tre a tm e n t 27 • AQP4-IgG positive (80%) and AQP4- IgG negative (20%); use 2006 criteria • 1 attack in last year or 2 attacks in last 2 years • >18 years of age • EDSS 7.5 (8.0)

Target • 99 sites activated in 25 countries • Up to 252 subjects (actual size 231) • 67 adjudicated attacks 1.Lactating and pregnant females 2.Treatment with any investigational agent within 4 weeks of screening 3.Known history of a severe allergy or reaction to any component of the investigational product formulation or history of anaphylaxis following any biologic therapy. 4.Known active severe bacterial, viral, or other infection or any major episode of infection requiring hospitalization. 5.History of alcohol, drug, or chemical abuse, or a recent history of such abuse < 1 year prior to randomization 6.Receipt of the following at any time prior to randomization: • Alemtuzumab • Total lymphoid irradiation • Bone marrow transplant • T-cell vaccination therapy 7.Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal. 8.Receipt of IVIG within 1 month prior to randomization. 9.Receipt of any of the following within 3 months prior to randomization: • Natalizumab • Cyclosporin • Methotrexate • Mitoxantrone • Cyclophosphamide • Tocilizumab • Eculizumab 10.History of Hepatitis B and/or Hepatitis C (Hep B/C at screening) 11.Known history of a primary immunodeficiency (congenital or acquired) or an underlying condition such as human immunodeficiency virus (HIV) infection 12.History of malignancies, apart from squamous cell or basal cell carcinoma of the skin treated with documented success of curative therapy > 3 months prior to randomization 13.Any concomitant disease other than NMO/NMOSD that required treatment with oral or intravenous steroids at doses over 20 mg a day for over 21 days Inebilizumab (MEDI-551 )

• Primary Outcome Measures :Time to onset of an adjudicated NMO/NMOSD attack • Secondary Outcome Measures :Attack Rate • Number of Participants with AEs as a Measure of Safety and

As per Jan 3,2019

77% reduction in risk of NMOSD attack vs placebo Reduction in the risk of worsening disability, as measured by the EDSS Acceptable safety profile SA237 Clinical Studies for subjects with NMO/SD Rationale for targeting IL-6

. Interleukin-6 (IL-6) plays important roles in regulating inflammation and stimulates growth and survival of plasmablasts

. Plasmablasts produce auto-antibodies such as AQP-IgG*

. Blocking IL-6 activity suppresses the growth and survival of plasmablasts, leads to reduction in production of AQP4 and possibly other factors

. Possibility for beneficial effects of IL-6 targeting in NMOSD is suggested by the experience with the IL-6 blocker tocilizumab − Ayzenberg et al. JAMA Neurol 2013 − Araki et al. Neurology 2014 − Ringelstein et al JAMA Neurol 2015 * Chihara et al.32 PNAS 2011 SA237: a recycling antibody for s.c. use SA237 is a fully humanized anti-human IL-6 receptor (IL-6R) neutralizing MAb Randomization 2 SA237:1Placebo

“44 protocol defined relapses”

Subjects : 90 adults , ≥1 relapse in previous year, EDSS ≤ 6.5 Objectives 1. Demonstrate difference in time to relapse between SA237 vs Placebo 2. Evaluate on pain, fatigue and disability 3. Study immune parameters and neuroimaging by MRI A phase III multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of satralizumab added to baseline therapy in patients with NMOSD The Sakura Sky Study

Satralizumab 1 : Placebo 1

Inclusion: • 83 male / female ; 13-73 years • NMO (2006)/ NMOSD (2007) • All with AQP4 antibodies • protocol-defined relapse = 26

Randomized 1:1 ; Satralizumab (120 mg) vs P added to baseline therapy (Aza, MMF and/or corticosteroids) Satralizumab 120 mg sc at wk 0, 2, and 4 -> subsequent sc at 4-week intervals SAkuraSky Study

Sakura SKY Total NMO/SD vs P AQP4-pos NMO/SD vs P AQP4-neg NMO/SD vs P N=83 N=55 N=28

RRR 62% vs P 79% vs P 34% vs P HR= 0.38 (95% CI: 0.16-0.88), HR=0.21 [95% CI: 0.06-0.75 HR=0.66 [95% CI: 0.20-2.23 p*=0.0184

Relapse free at wk 48 88.9% vs 66% 91.5% vs 59.9% 84.4% vs 75.5% Relapse free at wk 96 77.6%vs 58.7% 91.5% vs 53.3% 56.3 % vs 67.1%

Mean treatment duration 2 years Primary endpoint : time to first protocol-defined relapse (PDR) in the double-blind period *P stratified log-rank test

SAEs, including serious infections, was similar between the two groups No death or anaphylactic reactions were observed Future drug

Nicolas Collongues. Drugs (2019) 79:125–142 https://doi.org/10.1007/s40265-018-1039-7 Pipeline research

Gut microbiota

Restoring immune tolerance in NMOSD “MOG-encephalomyelitis (MOG-EM)” “MOG-antibody related disorder” “MOG associated disease” “MOG antibody disease” “MONEM” Myelin-Oligodendrocyte Glycoprotein (MOG)

MOG: a minor myelin Ag and constitutes only 0.05% of CNS myelin proteins vs 30% for MBP, 50% for PLP

Myelin sheath

Axon

Loss of function? About MOG: • Expressed exclusively in the CNS • MOG peptides are encephalitogenic • Accessible to antibodies - External layer of the myelin sheath • Belongs to immunoglobulin superfamily - Adhesion molecule? Immune function? Di Pauli & Berger. Frontiers in Immunology | www.frontiersin.org November 2018 | Volume 9 | Article 2753

MOG-Ab have been found in a subset of patients with ADEM, NMOSD, monophasic, and rON, and TM, demyelinating syndromes overlapping with anti-NMDA receptor encephalitis or glycine receptor α-1 subunit Ab positive ON CRION used definition by Petzold A. J Neurol. 2014;261:17 – 26. 2 Lee eat al. Journal of Neuroinflammation (2018)15:302 (1) Most CRION (92%) were MOG-IgG with relapsing courses (2) RION without steroid dependency (hence not meeting the criteria for CRION) were not positive for MOG-IgG (3) Among patients with MOG-IgG-associated ON, the absence of steroid dependency in the early stages of the disease (2.3 mths from onset) (4) The MOG-IgG titers were related with disease course, which may be helpful for predicting the prognosis of disease

MOG-IgG 92% in CRION, 0% in RION 29% in monophasic iON

Lee. Journal of neuroinflammation 2018;15:302 11 non-CRION- MOG+ group only monophasic disease courses

The CRION-MOG+ group had more frequent ON attacks, and thinner RNFL and GCIP layer thicknesses, than the non-CRION- MOG+ group.

The CRION-MOG+ group experienced steroid-dependent worsening/relapse in the early stages of the disease (2.3 months from disease onset)

Lee. Journal of neuroinflammation 2018;15:302 CLINICAL PRESENTATION of MOG positive

MRI Poorly demarcated, widespread lesion Normal brain MRI Age-dependent clinical presentations

< 20 yr : ADEM (36%) 20–45 yrs: ON 45 yrs : ON/TM : > 90% of adult TM is rare in children BON, 15% sTM better recovery Some showed severe courses & 39% relapsing lack of response to DMT

NMOSD criteria were fulfilled in only 19% of MOG Ab patients. seizures and encephalitis-like presentations are more common in MOG Ab vs AQP-4  diseases 3 recent case reports cortical encephalitis MOG Ab are predictive not only of non-MS disease with a specificity of 100% but also of a recurrent non-MS disease course with a specificity of 75% including NMOSD, rON, MDEM, and ADEM followed by ON (ADEMON) Clinical Manifestation MOG positive associated disease Clinical manifestation Trimodal age associated phenotype more benign clinical course including lower relapse rates and longer time to have a second attack. presence of MOG Abs in approx 40 % of children with ADEM large, bilateral and widespread lesions LETM Relapsing 36% (UK-252MOG); ARR 0.2 (less than NMOSD) Relapsing esp with ON, NMOSD phenotype Outcome More favorable Less frequently suffer motor disability and better EDSS TM Better recovery Similar frequency of severe attacks at onset and similar relapse rates ON Severe visual loss in acute phase, good visual recovery RNFLT Conflicting evidence Disability Permanent disability was described in nearly half after 16 month Permanent bladder and erectile dysfunction 1/4 Persistent MOG positive Persistent 72% (largest cohort) associated with relapsing 60% Conversion to neg => predictive marker for disease free? serial testing as a long-term disease marker and potential Rx marker CSF 10% found intrathecal IgG synthesis CSF reactivity only been shown in cases of high serum levels Parameters MOG positive associated diseases Noted

Brain MRI • 40-77% abnormalities at onset • Spec 95% and Sens 91% by lesion • Disease course: ≈ ½ supratentorial > brainstem > 1/3 at distribution of MS cerebellum • Dawson’s fingers • Poorly demarcated, widespread lesions in younger children • Subcortical U fiber lesions, • Normal brain MRI in older children • Ovoid lesions adjacent to the body of LV No unique but typical/ suggestive of MOG associated diseases • T1 hypointense lesions • Fuffy lesions and ≤ 3 lesions • Large, confluent, poorly marginated MRI lesions (if clinically • Thalamus, pons more common in MOG presenting with ADEM) Ab-associated disorders • Brainstem (pons) and hypothalamic lesions • 16% cortical involvement • Leukodystrophy-like MRI pattern • 6% leptomeningeal enhancement • MRI is variable, depend on clinical presentation and age Optic MRI No unique but typical/suggestive of MOG associated diseases • Optic nerve head swelling • Contrast enhancement of the optic nerve • Some show perineural enhancement • 80% show >1/2 of the pre-chiasmic optic nerve lesion TM MRI No unique but typical/ suggestive of MOG associated diseases • Some reported conus medullaris LETM > sTM involvement Clinical Manifestation MOG associated disease Treatment No controlled treatment trials A favorable recovery in 70–90% of patients given IVMP Favored long-term steroid Rx over 6 months, given alongside other immunomodulatory or ISrugs PLEX, which is normally initiated if corticosteroid Rx is insufficient Only 40% received a long-term maintenance therapy AZA, rituximab, and mycophenolate, maintenance corticosteroids and rituximab being most effective in preventing disease activity IS/immunomodulation, including AZA, methotrexate, and RTX, on the risk of relapse and the ARR, in particular if Rx is maintained for > 3 months (1) Children benefit of IVIG on the ARR NTZ, IFN, and GA showed no Rx efficacy

(1) Jurynczyk M. Brain (2017) 140:3128–38 Brain MRI findings in Anti-MOG+ Syndrome

a-c: pontomedullary junction – C5 STIR

T1Gd+ Sato DK.et al. Neurology 2014;82:474-81 a: callosal lesions; diencephalon ->pons b: basal ganglia, juxtacortical, genu corporis

J-k: dorsal medullary, AP

Sato DK.et al. Neurology 2014;82:474-81 c: basal ganglia, periependymal areas d: leptomeningeal enhancement d-h: pons, midbrain, thalamus, basal ganglia, periependymal areas of the 3rd ventricles

e: callosal lesions f: callosal lesion g: large confluent lesions at temporal l-n: frontal&parietal subcortical WM, pontine tegmentum and cerebellar peduncles lobe Jarius et al. Journal of Neuroinflammation (2016) 13:280-281 Orbital MRI findings in Anti-MOG+ Syndrome STIR

a) swelling left optic n. b) GdE left optic n. Gd-enhanced peri-optic n. enhancement

(fat-suppressed): Longitudinal extensive Gd enhancement of the optic nerve

Swollen optic n., extensively optic nerve head edema e) longitudinally extensive BON from chiasm->the orbit

f-h) marked enhancement of the intraorbital optic n., perioptic nerve sheath

Biotti D. J Neurol (2017) 264:2173-5 Sato DK.et al. Neurology 2014;82:474-81

extending in the surrounding orbital fat i) Gd enhancement of right optic n.

J-k) bilateral lesions in the optic tract; j) at attack onset; k) f/up MRI 1 mo. later

Jarius et al. Journal of neuroinflammation (2016)13:280 Siritho et al. MSJ 1-5;DOI: 10.1177/1352458515614093 Nadja Borisow. Frontiers in Neurology | www.frontiersin.org 23 October 2018 | Volume 9 | Article 888 Extended spectrum of MOG-IgG Parameter MOG-associated disease AQP4-pos NMOSD F:M ratio F:M 1:1.6-1.3:1% F:M =7.2:1-10.1 Relapsing course Presence of MOG tend to relapse Relapsing 80-85% Mean age at onset (years) 27-37 40-46 Extraneural manifestations/rare Reversible paraspinal muscle hyperintensity Narcolepsy, acute diencephalic syndrome manifestation Combined central + peripheral demyelination or muscle affection syndromes Coexisting autoimmune disease 6-11% 16-45% (MG, coeliac disease, or Lower frequency paraneoplastic disorders (>50years), etc First attack with ON 33-64% 37-54% First attack with LETM 18-33% 30-47% Clinical Manifestations can affect optic nerve, spinal cord, and brainstem a more frequent occurrence of optic nerve head swelling and retrobulbar affection of the optic nerve in MOG-EM Simultaneous or rapidly sequential ON and Rare LETM Encephalitis and seizures Rare Mean EDSS at last F/U 0-1.5 4.0-5.8 Disability Lower disability outcomes, measured by the Higher disability EDSS Target Myelin-forming oligodendrocytes Water channels located on astrocytes Diagnosis Lab MOG-associated disease AQP4-pos NMOSD

Diagnosis criteria used No evidence based diagnostic criteria exist 2015 NMOSD diagnostic criteria Diagnostic test CBA targeting at full-length human MOG and the use CBA : sens 80-100% of IgG1-specific secondary antibodies is highly Spec 86-100% recommended to avoid cross-reactivity with IgM and ELISA –may cause false positive IgA Ab approx. 80% during acute attack AQP4- Abs usually stay detectable during remained positive during remission (Korean-50%) remission (low titer), and during acute MOG-Ab titers significantly higher during acute attack attacks Some Ab-titers associated with relapses and Rx status not predictive long term disease course not predictive response to immunoRX CSF-Ab MOG-Ab produced mainly extrathecally , serum>>CSF CSF  WBC in 25– 70%, no differentiation during acute  WBC elevated in up to 50% esp during attack and remission acute attack OCB detected in 10% OCB detected in 10%  CSF/serum albumin ratio in 32%  CSF/serum albumin ratio in 50% OCT RNFL and the GCL –equally damage? Localization of optic n. lesion Orbital, canalicular, intracranaial Orbital, chiasm Localization of cord lesion Thoracic, lumbar, conus Cervical, thoracic Localization of brain lesion More frequently ADEM like, deep gray matter, lesions More frequently lesions in medullar in pons, thalamus oblongata and AP Paraclinical Inx MOG-associated disease AQP4-pos NMOSD Spinal cord lesion 15% STM X-sectional cord :located centrally : Half of spinal cord x-section area : Bright spotty lesions : Microcystic defects of the spinal cord Brain lesion Abnormal in 58% Abnormal in 80% Supra- and infratentorial lesions in 40–50% Periependymal surfaces of the 3rd and 4th ventricle, area postrema, corpus callosum, hypothalamus or thalamus subcortical or deep WM lesions Meningeal enhancement been reported Orbital MRI Supra- and infratentorial MRI abnormalities in 40– Orbital MRI may show increased T2 50% signal and GE of the optic nerve A more frequent occurrence of optic nerve head Chiasmal involvement is more common swelling and retrobulbar affection of the optic nerve

MRI interval between clinical symptoms and the MRI is influencing the MRI presentation of LETM lesions. Brain imaging allows to distinguish MOG-EM from MS, but shows many overlaps with AQP4-Ab NMOSD Treatment MOG-associated disease AQP4-pos NMOSD Acute attacks Complete or almost complete recovery in IVMP led to complete recovery in 17–35% of the attacks 50% of IVMP treated MOG-EM attacks Prevention Less severe can be given subsequent to attack Rx with IVMP in relapse risk depends on Ab status decreasing dose levels and as co medication during the relapses during tapering or after cessation 1st months of AZA or MMF of subsequent OPN after IVMP attack Rx supports the beneficial effects of corticosteroid Rx (MOG—pos) Seroconversion Seroconversion to an Ab- negative status may occur during the disease course Treatment with Similar results were found in patients with IFN-, GA, FGM, ATZ, NTZ, and presumably also DMF is DMD used in MS MOG-EM known to have no or even harmful effects in NMOSD Effects of MTX or CyP in MOG-EM are CyP does not seem to be effective in NMOSD missing คณะแพทยศาสตร์ศิริราชพยาบาล มหาวิทยาลัยมหิดล Acknowledgements

Bumrungrad International Hospital Siriraj Neuroimmunology Center (SNIC)