Jeffrey L. Bennett, MD, PhD - University of Colorado Denver

Neuromyelits Optica (NMO): What You
Need To Know
Jeffrey L. Bennett, MD, PhD
Movement Disorders and MS 2012
University of Colorado School of Medicine

Disclosures
Consultant: Teva Neuroscience, EMD Serono,
Accorda Therapeutics, Novartis, Biogen-Idec,
Questcor
Intellectual property: Aquaporumab
No FDA approved treatments for NMO

Learning Objectives
Enumerate the diagnostic criteria for NMO.
Summarize cardinal features of the
pathophysiology of NMO.
Differentiate signs and symptoms of neuromyelitis
optica and multiple sclerosis.
Organize a diagnostic plan for the evaluation of a
patient with possible NMO.
Implement acute and chronic therapies for NMO
patients.

Neuromyelitis Optica
History
Clinical Clues
Imaging Clues
Laboratory Clues
Treatment
Future Therapies

History
Albutt (1870) “On the ophthalmoscopic signs
of spinal disease” Lancet 1:76.
Devic (1894) “Myélite subaiguë compliqué de
névrite optique” Bull méd 8: 1033.
Balser (1936) “Neuromyelitis Optica” Brain
59: 353
• Nosology: NMO vs MS, diffuse myelitis, & ADEM
• Clinical & Pathological Criteria
–Bilateral optic neuritis and myelitis
–Infiltrating demyelination
•Diffuse > Disseminated

Are MS and NMO Distinct or Related?
MS
NMO
MS NMO
OR MS OR
NMO
MS NMO

Clinical Criteria (Modern Era)
Absolute Criteria*
1. Optic Neuritis
2. Transverse Myelitis
3. No evidence of brainstem or cerebral
disease
* Strict – coincidental
Not strict – 2 nd event within 2 years
Wingerchuk et al. (1999). The clinical course of neuromyelitis
optica (Devic's syndrome). Neurology, 53(5), 1107–1114.

NMO: Index Symptoms & Recovery
Feature Monophasic NMO Recurrent NMO
Sex (F:M) 11:12 40:8
Median Age 29 (1-54) 39 (6-72)
Index Event (%)
Optic Neuritis (ON)
Myelitis
Bilateral ON
Myelitis + ON
Bilateral ON + myelitis
Index Event at
Recovery
Optic Neuritis
Myelitis
6 (26%)
5 (22)
4 (17)
1 (4)
7 (31)
Better than 20/30
MRC 3-4
23 (48%)
20 (42)
4 (8)
1 (2)
0
Better than 20/30
MRC 5- to 4+
Wingerchuk et al. (1999) Neurology 53:1107.

1999 NMO Imaging
Negative brain MRI (90%)
Non-specific lesions (43%)
Spinal MRI with lesion over
3 vertebral segments (91%)

Cerebrospinal Fluid in NMO
Parameter NMO MS
Pleocytosis (> 5 cells) 29.3% - 82% 24.6%
Differential Granulocytic Lymphocytic
Total Protein (mean) 75 mg/dl 38 mg/dl
OCB 23-35% 97%
McAlpine (1968); Wingerchuk (1999); Ghezzi (2004); Bergamashi (2004)

NMO-IgG
NMO Antibody
• IgG antibody
• Pial and microvessel
staining
• Target: Aquaporin-4 Water
Channel (AQP4)
• 73% Sensitive
• 91% Specific
High Risk Syndromes
Recurrent ON: 25% Sensitive
LETM: 50% Sensitive
Lennon et al. (2004) Lancet 364: 2106.
Lennon et al. (2005). JEM, 202:473.

EAE
AQP4 Antibodies Are Pathogenic
Anti-AQP4 rAb
Serum NMO-IgG
NMO
Kinoshita et al., Biochem Biophys
Res Comm, 2009
Bennett et al., Annal Neurol, 2009
Bradl et al., Annal Neurol, 2009
Complement +
Serum NMO-IgG
NMO
Saadoun et al., Brain, 2010
Ex Vivo Spinal Cord Explants
Zhang et al., Annal Neurol, 2011

NMO-IgG: A Specific Marker of NMO
Waters, P. J. et al. (2012). Neurology, 78(9): 665
Is seronegative NMO the same disease?
Takahashi et al. (2007) Brain 130:1235
Jarius et al. (2007) Neurology 68:1076
Waters et al. (2008), Arch Neurol 65:913
Kalluri et al. (2010), Arch Neurol, in press

Neuromyelitis Optica (NMO)
Revised Diagnostic Criteria
Major criteria:
1. Optic Neuritis
2. Acute Myelitis
2 of 3 minor criteria:
1. Contiguous spinal cord lesion
(≥ 3 segments)
2. Brain MRI not consistent with
MS
3. AQP4-IgG
*Wingerchuk et al. (2006) Neurology 55:1485
NMO IgG
• IgG antibody
against AQP4

NMO: Clinical Syndromes
Recurrent Optic Neuritis
Longitudinally-extensive Transverse Myelitis
NMO Spectrum Disease (+ AQP4-IgG)
Intractable hiccups
Intractable nausea-vomiting
Encephalopathy
Brainstem/Cerebellar symptoms
McKeon (2008). Neurology, 71(2), 93.
Pirko (2004). Arch Neurol, 61(9), 1401.
Popescu (2011). Neurology, 76(14), 1229.
Takahashi (2008). JNNP, 79(9), 1075.

Recurrent Optic Neuritis: NMO Risk?
5-year conversion rate:
• 12.5% NMO
• 14.4% MS
≥ 2 MRI lesions: increased risk of MS
No MRI lesions: NMO risk not increased
20-27% AQP4-IgG Seropositivity
Pirko et al. (2004) Arch Neurol 61:1401.
Matsushita et al. (2009) Multiple sclerosis 15:834.

Optic Neuritis and NMO: Clinical Pearls
Increased Suspicion
Severe vision loss (< 20/200)
Severe visual field loss (MD < -11 dB)
Poor visual recovery (< 20/60)
Posterior optic nerve involvement (MRI)
Optic chiasm involvement
Fernandes et al. (2012). J Neuro-Ophthalmol, 32:102.

MS and NMO: Ocular Coherence Tomography
15 mM RNFL loss with poor
visual recovery and atypical MRI
Ratchford et al. Neurology (2009) vol. 73: 302-8 Naismith et al. Neurology (2009) vol. 72: 1077-82

Imaging in NMO Patients
60% of NMO patients
10% with MS pattern lesions
•83% were NMO-IgG positive
•66% fulfilled Barkhof criteria
Pittock, S. J. et al. Arch Neurol 2006;63:390.

Unusual Brain MRI Lesions in NMO Patients
Pittock, S. J. et al. Arch Neurol 2006;63:964-968.

NMO: Laboratory Clues - Serum
Autoimmune Serology
ANA – 44%
SSA – 15.7%
Thyroid Abs – 16.7%
Acetylcholine Receptor Abs – 11%
Anti-Glutamic acid decarboxylase Abs – 15%
Pittock et al. (2008). Arch Neurol 65:78.
McKeon (2009). Muscle & nerve, 39:87–90.

NMO: Laboratory Clues - CSF
Pleocytosis > 50 cells/microliter
Elevated polymorphonuclear cells
Eosinophils
AQP4-IgG
Negative oligoclonal bands
Jarius et al. (2011) J Neurol Sci, 306:82.
Klawiter et al. (2009). Neurology, 72:1101.

NMO: To Treat or Not To Treat
AQP4-IgG Seropositivity
50% chance of relapse in 1 year
Visual Prognosis
•70% severe vision loss in one eye (8 yrs)
–MS Cohort: 8.5%
•Average time to severe vision loss
–Monocular: 2 ± 0.8 years
–Binocular: 13 ± 3 years
Ambulatory Prognosis
• Median time to EDSS 4: 7 years
• Median time to EDSS 6: 10 years Collongues, et al. (2010).
Neurology, 74:736.

NMO Therapy
Acute Exacerbations
Corticosteroids
Plasma exchange
Preventative Treatment
Azathioprine
Mycophenolate mofetil
Methotrexate
Rituximab
Corticosteroids
Mitoxantrone

NMO Treatment: Corticosteroids
Increased rate of recovery
Intravenous Methylprednisolone
1000 mg dosage
3-5 days
Role of steroid taper unknown
Incomplete recovery
Bridging therapy

NMO Treatment: Plasma Exchange
Administration
Concurrent or following IVMP
5 cycles: Daily or every other day
Improved Outcomes
Optic Neuritis
Visual acuity, visual fields, RNFL thickness
Transverse Myelitis
Faster improvement, improved EDSS
Bonnan et al. (2009). Multiple sclerosis 15(4):487.
Merle et al. (2012) Arch Ophthalmol 130:858.

NMO Treatment: Azathioprine
inhibits de novo purine synthesis; limits B and T cell
proliferation
Dosage: ≥ 2mg/kg daily
MCV increase of ≥ 5 points
Benefits: ARR reduced to 0.4-0.52; EDSS reduction
Adverse events: nausea, hepatotoxicity, leukopenia,
diarrhea, hair loss, bone marrow suppression, fatigue;
check thiopurine methyltransferase activity to avoid
drug toxicity
Costanzi et al. (2011). Neurology, 77:659.
Mandler et al. (1998). Neurology, 51:1219.
McKeon et al. (2008). Neurology, 71:93.

NMO Treatment: Mycophenolate Mofetil
hinders de novo synthesis of guanosine
nucleotides; limits B and T cell proliferation
Dosage: 1 gram twice daily
Benefits: ARR reduced to 0.2; EDSS
reduction
Adverse events: leukopenia, headache, hair
loss, diarrhea, skin malignancy, lymphoma,
PML
Jacob et al. (2009). Arch Neurol 66:1128.

NMO Treatment: Methotrexate
inhibitor of dihydrofolate reductase and
purine and thymidine synthesis
Dosage: 7.5 – 15 mg weekly
Benefits: Reduction or stabilization of ARR
and EDSS
Adverse events: leukopenia, stomatitis,
nausea, infection
Minagar A. Int J MS Care 2000;2:39.

NMO Treatment: Rituximab
anti-CD20 mAb that depletes B cells from pre-B
through memory lineages
Dosage: 1000 mg IV on days 0 and 15
Repeat every 6 months or if B cells > 5%
Benefits: ARR reduced to 0.0-0.3; EDSS
reduction
Adverse events: infusion reactions, infections,
PML.
McKeon et al. (2008). Neurology, 71:93.
Cree et al. (2005). Neurology, 64:1270.
Jacob et al. (2008). Arch Neurol 65:1443.
Kim et al. (2011). Arch Neurol 68:1412.

NMO Prevention: Methylprednisolone
binds to glucocorticoid receptor, induce gene
expression, and modulate immune function
Dosage: 2.5 mg/d to 25 mg/d
Benefits: ARR reduced to 0.49
Adverse events: insomnia, mood changes,
weight gain, glaucoma, osteoporosis,
diabetes, hypertension, and growth
impairment in children
Watanabe et al. (2007) Multiple sclerosis 13:968.

NMO Prevention: Mitoxantrone
intercalates DNA and inhibits topoisomerase
II, limits B and T cell proliferation
Dosage: 3 monthly cycles: 12 mg/m 2 ;
maintenance of 6-12 mg/m 2 every 3 months
Benefits: ARR reduced to 0.7; reduced EDSS
Adverse events: cardiotoxicity, leukemia,
hepatotoxicity, leukopenia
Weinstock-Guttman et al. (2006). Arch Neurol 63:957.
Kim et al. (2010). Arch Neurol 68:473.

NMO: Immunopathology
NMO-IgG
Anti-AQP4
Memory B Cells
Plasma Blasts

NMO: Etiology
Molecular Mimicry
Infection
Bystander Activation
NMO: HLA DRB1*03 (DR3) 1
OSMS: HLA DPB1*0501
(AQP4+) 2
Aquaporin-4
? Others
• MYCOBACTERIUM
• VARICELLA
ZOSTER
• MYCOPLASMA 3

TARGETS FOR NMO THERAPY
complement
astrocyte
Myelinolysis
Axonal transection
AQP4-IgG
cytokines
lymphocytes
eosinphils
ADCC, phagocytosis
neutrophils
macrophages
Inflammatory response

NMO: Th17 Immunopathology
Clinical Science (2012) 122, 487-511 - Shu
Zhu and Youcun Qian
*
Anti-AQP4
Wang, H. H. et al. (2011). J Clin
Neurosci 18(10), 1313–1317

NMO Pathogenesis: IL-6 and Interferon
Elevated IL-6 in NMO CSF 4
• Correlation with CSF Anti-AQP4 IgG Titer
Elevated peripheral blood plasma blasts 5
• IL-6 Anti-AQP4 IgG-expressing Cells
Elevated Type 1 interferon Signature 6
• IFN-b Exacerbates Disease Activity 7
Icoz et al., Int J Neurosci, 2010
Control
AQP4
Chihara et al., PNAS, 2011

Neutrophils Enhance NMO-IgG Mediated Pathology
Neutrophilia
Neutropenia
Neutrophil
Elastase
Inhibitor
Saadoun et al., Ann Neurol, 2012

ANTIGEN SPECIFIC NMO THERAPY
SMALL MOLECULE BLOCKERS
• Arbidol
• Berbamine
• Tamarixetin
Tradtrantip et al.,
FASEB J, 2012
NON-PATHOGENIC AQP4
BLOCKING ANTIBODIES
Tradtrantip et al..
Ann. Neurol., 2012