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Neuromyelitis Optica:

Progress in Diagnosisand Management

Dean M. Wingerchuk, MD, MSc, FRCPC

Mayo Clinic

Scottsdale, AZ

Case Presentation

21M African-American

Age 7 Cervical complete ATM

CSF: pleocytosis - ? differential

Lyme titer (CSF) = 1:128

Diagnosis: ? Lyme myelitis

Rx: PCN, IVMP

Partial recovery

Case Presentation

Ages 7-15

5 myelitis attacks

1995: CSF during acute myelitis WBC 92 (58% L / 22% P / 20% M)

Protein 198, negative OCB

Ages 15-18

Prednisone 5-10 mg/d

No attacks

Case Presentation

Age 18-21

Off prednisone2 myelitis attacks per year

Treatment: Oral cytoxan for 1 year

(1 attack) Oral methotrexate for 6 months

(2 attacks)

then no treatment

Case Presentation

Nov 2003 Bilateral ON (first ON attacks)

IVMP, then PLEX complete recovery

Began IV Cytoxan

Feb 2004

Bilateral ON (NLP ; 20/100)

Exam

Triplegic (LUE relatively spared)

Va: NLP; 20/100

Labs

ANA positive: 1.1 U

ACLA IgM positive: 14.0 U

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Imaging

Prior MRI spinal cord:

Longitudinally extensive myelitis1995, 1998

T2-T6, T9-conus

MRI brain

MRI spinal cord

Upper Cervical Cord

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Lower Cervical Cord Upper Thoracic Cord

Lower Thoracic Cord Case Presentation

Diagnosis: Relapsing NMO

Treatment:

IVMP X 4 days

PLEX X 7

Partial visual recovery

Neuromyelitis Optica (NMO)Devics Syndrome/Disease

Historical definition

Monophasic disorder consistingof fulminant bilateral ON andmyelitis occurring in closetemporal association

NMO Case Series:Mayo Clinic (1999)

71 patients (1950-1998)

Established:

Many had unilateral ON

Time between index events varied

Monophasic or relapsing

Natural history was dismal

Respiratory failure

Death

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Diagnostic Criteria (1999)

Absolute crit eria (all required):1. Optic neuritis

2. Acute myelitis

3. Clinical ly restricted to optic nerve and spinal cord

Supportive criteria:

Ei ther 1 Majo r

MRI: brain negative at onset

MRI : cord T2 lesion >3 segments

CSF: >50 WBC/ uL OR>5 PMN/ uL

Or 2 Minor

Bilateral optic neuritis

Severe ON (VA 3 vert segments: 88%

Gad enhancement: 64%

Cord swelling: 50%

Atrophy 22%

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CSF Results*

> 50 WBC : 35%

> 5 neutrophils : 25%

Either : 39%

*acute CSF (within 4 weeks of myelitis)

NMO: DefinitionsOld (Historical)

Bilateral ON

Myelitis

Monophasic

Short interattack interval

New (Evolving)

Unilateral or bilateral ON

Long. extensive myelitis

Monophasic or relapsing

Any interattack interval

MRI head normal

Autoimmunity

NMO Pathology

Severe inflammatory/necrotic lesionsEosinophil & neutrophil infiltrationVascular hyalinization

Perivascular Ig reactivity (IgM>IgG)

Perivascular complement activation

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Evidence for Autoimmunity

Co-existing autoimmune disorders

Analogy with MOG-EAE

IgG and activated complement inspinal cord lesions

Excellent response to PLEX

NMO-specific IgG autoantibody

Recent Advances:A Serum Marker of NMO

Mayo Clinic Neuroimmunology Lab Dr Vanda Lennon

Discovery of a novel serumautoantibody: NMO-IgG

Diagnoses of 12 IncidentalNMO-IgG Positive Patients

Diagnosis No.

NMO

Definite 2

Long extensive myelitis 4

Recurrent optic neuritis 2

Other

New onset myelopathy 1Inflammatory CNS disorder 1

Unknown 2

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

Diagnosis Positive n (%)

NMO 32/47 (68) *

High risk 15/33 (45) *

Recurrent ON 3/8 (37)

Single TM 6/16 (37)

Recurrent TM 4/9 (44)

MS 2/21 (9)

Other 0/8 (0)

Diagnosis Positive n (%)

NMO 32/47 (68) *

High risk 15/33 (45) *

Recurrent ON 3/8 (37)

Single TM 6/16 (37)

Recurrent TM 4/9 (44)

MS 2/21 (9)

Other 0/8 (0)

p70%or cord presentation

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Why Diagnose Early?

Severe morbidity

Therapeutic decisions:

Early immunosuppressant therapy

Standard MS-modifying therapiesmay not be effective

NMO: Treatment of AcuteExacerbations

IVMP 1000 mg/d for 5-7 days

If no improvement: PLEX, ~55ml/Kg per exchange 7 exchanges, done every 2nd day Evidence:

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

NMO: Treatment Optionsfor Attack Prevention

Standard MS therapies: ? ineffective

Azathioprine plus prednisone

Usual first-line Rx (Mandler et al) Azathioprine target 3mg/kg/d

Prednisone 1 mg/kg/d

Slow taper to QOD dosing Very slow taper to d/c

Other Therapies

Mitoxantrone or Cyclophosphamide

IVIG

PLEX B cell-directed therapies

Chlorambucil

Rituximab

Case Presentation

Age 6: Neck pain, meningismus

Within 4 d severe R hemiparesis

Diagnosis: stroke

No CSF exam

Partial recovery

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Case Presentation

Diagnosis: Relapsing NMO

Initial Treatment: IVMP X 4 days

PLEX X 7

Partial visual recovery

Treatment for Attack Prevention:

IV rituximab

1000 mg day 0 and day 14

Receiving out-of-state

Revised Diagnostic Criteria Absolute cri teri a (al l required):

1. Two attacks consisting of either optic neuritis OR acutemyelitis

2. M RI: cord T2-weighted cord lesion >3 segments inpatients with myelitis

Support ive cri teria:

Either 1 Major

Clinically restricted to optic nerves and spinal cord

Brain MRI negative at onset

CSF: >50 WBC/uL OR >5 PMN/uL

Posit ive test for NMO-IgG autoantibody

Or 2 Minor Bilateral optic neuritis

Severe ON (fixed VA