Neuromyelitis Optica

Dean M. Wingerchuk, MD, MSc, FRCPCMayo Clinic College of Medicine

NMO: Outline• Historical concept• Definitions and diagnosis• Pathology• NMO-IgG• Use of NMO-IgG

• New diagnostic criteria• Prognosis

• Management• acute attacks• attack prevention

Neuromyelitis Optica (NMO)“Devic’s Syndrome/Disease”

• “Historical definition” – 19th century• Monophasic disorder• Fulminant bilateral optic neuritis

(ON) and myelitis occurring in close temporal association

Neuromyelitis Optica: History

• Case series• 1914-1990s• “Traditional” definition:

• Simultaneous bilateral ON and ATM• Variants:

• Unilateral ON• Relapsing course

• Similarity to Japanese optic-spinal MS• Debate: Is NMO a disease or severe

and topographically restricted MS?

NMO: The 1990s

• Case series:• Mandler et al 1993• O’Riordan et al 1996• Wingerchuk et al 1999

• Relapses• Severe course• Spinal cord MRI is distinctive• CSF may be helpful• Association with autoimmune d/o

Temporal Profile of Attacks

CSF Results

• > 50 WBC : 35%• > 5 neutrophils : 25%• Either : 39%

…within 4 weeks of myelitis

NMO: DefinitionsOld (Traditional)

• Bilateral ON• Myelitis• Short interattack interval• Monophasic

New (Evolving)• Unilateral or bilateral ON• Long. extensive myelitis• Monophasic or relapsing • Any interattack interval• MRI head normal• Autoimmunity

Diagnostic Criteria (1999)• Absolute criteria (all required):

1. Optic neuritis2. Acute myelitis3. Clinically restricted to optic nerve and spinal cord

• Supportive criteria:Either 1 Major

• MRI: brain negative at onset (25/58)• MRI: cord T2 lesion >3 segments (21/23)• CSF: >50 WBC/uL OR >5 PMN/uL (20/54)

Or 2 Minor• Bilateral optic neuritis (59/71)• Severe ON (VA <20/200 in 1 eye) (31/69)• Fixed, attack-related weakness (MRC<2) in >1 limb

(32/71)

Exceptions to NMO Diagnostic Criteria (we expected this…)

• Extra-optic-spinal symptoms/signs• Brain MRI lesions• Milder attacks

NMO Pathology

LFB-PAS (Myelin) KiM1P (Macrophage)

MOG Vascular HyalinizationLucchinetti et al, Brain, 2002

NMO Pathology

Eosinophils

ComplementIgG

Neutrophils

Lucchinetti et al, Brain, 2002

NMO Pathology Summary

• Destructive/necrotic lesions• Vascular changes (hyalinization)• Eosinophil and neutrophil infiltration• Perivascular Ig deposition (IgM>IgG) • Perivascular complement activation

• Humoral autoimmune mechanisms predominate

Recent Advances:A Serum NMO Biomarker

• Mayo Clinic Neuroimmunology Lab• Dr Vanda Lennon• Dr Sean Pittock

• Discovery of the novel serum autoantibody: NMO-IgG

Spinal CordSpinal Cord

Factor 8Factor 8

NMONMO

NMO-IgG+ by Clinical DiagnosisNMO-IgG+ by Clinical Diagnosis

Diagnosis Positive n (%)NMO 33/45 (73) *High risk 16/35 (46) *

Recurrent ON 3/8 (37)Single TM 7/16 (43)Recurrent TM 6/11 (67)

MS 2/21 (9)Other 0/8 (0)

Diagnosis Positive n (%)NMO 33/45 (73) *High risk 16/35 (46) *

Recurrent ON 3/8 (37)Single TM 7/16 (43)Recurrent TM 6/11 (67)

MS 2/21 (9)Other 0/8 (0)

p<0.01; * NMO vs MS; * HR vs MS

Differentiating NMO from MS

Pos 3333 22NMO-IgG

Neg 1212 2020

Sensitivity: 73% (60-86%)Specificity: 91% (79-100%)

NMO MS

Likelihood ratio + test = 8.1 (good); - test=0.30 (fair)

Opticospinal MS (Japan)

Pos 77 00NMO-IgG

Neg 55 1010

Sensitivity: 58%Specificity: 100%

OSMS MS

MRI, CSF and Autoimmunity (%)MRI, CSF and Autoimmunity (%)Diagnosis NMO High risk MSMRI head “neg” 85 85 62

MRI cord 3+ seg 95 76 14

OCB/IgG ind+ 6 6 33

CSF >5 PMNs 8 6 0

Autoimmune dis 23 27 0

AutoAb (ENA, ANA) 60 54 19

Diagnosis NMO High risk MSMRI head “neg” 85 85 62

MRI cord 3+ seg 95 76 14

OCB/IgG ind+ 6 6 33

CSF >5 PMNs 8 6 0

Autoimmune dis 23 27 0

AutoAb (ENA, ANA) 60 54 19

NMO-IgG: Conclusions

• NMO-IgG is highly specific for NMO, differentiating it from MS presenting with ON or myelitis

• NMO spectrum may be wider than previously suspected

• Recurrent isolated LETM• Single LETM• Recurrent isolated ON

NMO-IgG Antigen:Aquaporin-4 (AQP4)

NMO-IgG and AQP4-IgG colocalize

Evidence for Humoral Autoimmune Mechanisms

• Co-existing autoimmune disorders• Clinical disease or serologies

• Cord lesions:• Ig deposition• Complement activation

• Discovery of NMO-specific IgG autoantibody

• NMO = aquaporin channelopathy?

Diagnosis of NMO:

Incorporation of NMO-IgG

NMO-IgG Diagnostic Utility

• NMO-IgG alone• 75% sensitive• 90% specific• …when trying to differentiate NMO

from MS with ON/cord predominance

• Virtually never seen in ‘garden variety’ MS

NMO-IgG Diagnostic Utility

• Normal brain MRI plus NMO-IgG +• >94% sensitive• >90% specific• …for clinical diagnosis of NMO

• ***Brain MRI lesions make NMO less likely but do not rule it out

• Up to 60% will eventually have some white matter lesions

• …and up to 10% meet Barkhof MS criteria (Pittock et al, Arch Neurol 2006)

Pittock et al, Arch Neurol 2006

Revised NMO Diagnostic Criteria (2006)

• 99% sensitive• 90% specific• …in differentiating

NMO from MS with optic-spinal presentation

• Required elements:•Acute myelitis•Optic neuritis

• …And 2 of 3 supportive elements:

•Cord MRI: •Contiguous T2 lesion >3 vertebral segments

•Brain MRI: •Negative / not MS at onset

•Positive NMO-IgG serology

NMO-IgG Diagnostic Utility:Risk of Recurrence/NMO after LETM

• 23 pts• 9 NMO-IgG +

•2nd event: 5/9• 14 NMO-IgG –

•2nd event: 0/14

•…p=0.004

Weinshenker et al Ann Neurol 2006

Natural History of NMO:SP conversion is uncommon

• 91 cases ‘evaluable’• NMO cohort:

•Older (median 38y)•High relapsefrequency (med=5)

• Expected: 20 cases• Observed: 2 cases

•p < 3x10-5

•RR = 0.09Wingerchuk et al, AAN, 2006

Treatment Implications

• Earlier recognition of NMO• Earlier therapy should lead to reduced

disability• Relapsing NMO rarely becomes ‘SPNMO’

• Diagnosis of “high-risk” for NMO• LETM plus NMO-IgG +

• Initiate preventative treatment even after 1 attack

• Monitoring therapy• Uncertain if NMO-IgG status is associated

with outcome or treatment response

NMO: Treatment of Acute Exacerbations

• IVMP 1000 mg/d for 5-7 days• Plasmapheresis

• Weinshenker et al (Ann Neurol)• RCT of PLEX vs sham PLEX• 42% vs 11 % response• most improvement in NMO pts

• Retrospective observational experience consistent (Keegan et al)

NMO: Treatment Options for Attack Prevention

• Standard MS drugs: probably ineffective• Japanese βIFN-1b RCT not powered for this....

• General immunosuppression• Azathioprine (?mycophenolate) plus prednisone (Mandler et al)• Mitoxantrone or Cyclophosphamide

• B cell-directed therapies• IVIG• PLEX• Chlorambucil• Rituximab (Cree et al)

• All treatment decisions are based on clinical observation, not experiment

• There is no proof that one approach is “the best”

B cell-directed therapy

Summary• NMO can be distinguished from classical MS• NMO spectrum disorders include:

• (some) recurrent TM/LETM• (some) recurrent ON• (some) Japanese opticospinal MS

• NMO-IgG is a highly specific biomarker• Treatment: target humoral mechanisms