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Neuromyelitis Optica:Diagnosis and Treatment

http://www.nmoresearch.org1

Presented by: Maureen A. Mealy, RN, BSN, MSCN, CRND

2015 Annual Meeting of the Consortium of Multiple Sclerosis Centers

May 28, 2015

NMO Attacks: Blindness, Paralysis and Death

Repeated attacks leads to permanent damage of the nervous system

2002 2003 2006 2011

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PubMed search:Devic OR neuromyelitis

1870 1894 2004 2005

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100

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Public

atio

ns/y

ear

Antigen Specific DiseaseTarget: Aquaporin-4 (AQP4)

AQP4

Astrocytes

Myelin

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Outline

• Definition

• Science

• Epidemiology

• Diagnosis

• Treatments: Standards of care, acute treatment trials

What is NMO?

Multiple sclerosis

Neuromyelitis optica

Transversemyelitis

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What is NMO?

Recurren

ce rate

Humoral autoimmunity

Transversemyelitis

Rheumatologic diseases

Neuromyelitis optica

Multiple sclerosis

• Complement, IgG, IgM

• Granulocytes

• Responsive to plasma exchange

What is NMO?

Recurren

ce rate

Humoral autoimmunity

Transversemyelitis

Rheumatologic diseases

Neuromyelitis optica

Multiple sclerosis

• Complement, IgG, IgM

• Granulocytes

• Responsive to plasma exchange

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Definition of NMO:Revised criteria

1. Optic neuritis

2. Acute myelitis

3. At least 2 of the following 3 supportive criteria:

a. Longitudinally extensive spinal cord lesion

b. Non‐MS (multiple sclerosis) brain MRI

c. NMO‐IgG seropositivity

Wingerchuk et al. Neurology.  2006

Definition of NMO:NMO Spectrum

1. Optic neuritis or acute myelitis

2. NMO‐IgG seropositivity

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Definition of NMO:2015 Criteria

1. Seropositive

‐ Pretty much any lesion in the CNS

2. Seronegative

‐ Dissemination in time

‐ Dissemination in space

‐ Bad attacks, by MRI

‐ Not MS or other disease

Outline

• Definition

• Science

• Epidemiology

• Diagnosis

• Treatments: Standards of care, acute treatment trials

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The NMO‐IgG

Anti‐AQP4

Passive Transfer of NMO‐IgG

By itself, the NMO‐IgG was HARMLESS.• Intrathecal pathogenic anti‐aquaporin‐4 antibodies in early 

neuromyelitis optica. Ann Neurol. 2009 Nov;66(5):617‐29. doi: 10.1002/ana.21802.

• Neuromyelitis optica: Passive transfer to rats by human immunoglobulin. Biochem Biophys Res Commun. 2009 Sep 4;386(4):623‐7

• Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol. 2009 Nov;66(5):630‐43

• Passively transferred human NMO‐IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis. BMC Neurol. 2013 Aug 8;13:104. 

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Don’t forget the T cells!

Pep2

AQP4 -/-

AQP4 +/+

TT T

T

TT

Outline

• Definition

• Science

• Epidemiology

• Diagnosis

• Treatments: Standards of care, acute treatment trials

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Epidemiology of NMO:of all demyelinating diseases…

15%

27%

7-30%

36%

48%

6-23%

1.5%1.5%

NMO Consortium:Diagnosis, age and sex

Mealy MA. Arch Neurol. 2012 Sep;69(9):1176‐80.

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Effect of Age in NMO

Up To

10

10 T

o 15

15 T

o 20

20 T

o 25

25 T

o 30

30 T

o 35

35 T

o 40

40 T

o 45

45 T

o 50

50 T

o 55

55 T

o 60

60 T

o 65

65 T

o 70

70 T

o 75 75

+0

20

40

60

80TM

ON

Re

lap

se c

ou

nt

0 10 20 30 40 50 60 70 800

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40

60

80

100TM

ON

Age

Pe

rce

nt

of r

ela

pse

s

Unpublished data – Levy Lab

NMO Consortium:Diagnosis, age and sex

Mealy MA. Arch Neurol. 2012 Sep;69(9):1176‐80.

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NMO Consortium:Race

Mealy MA. Arch Neurol. 2012 Sep;69(9):1176‐80.

Effect of Race in NMO

PMC full text: Neurol Neuroimmunol Neuroinflamm. 2014 Jun; 1(1): e4.Published online 2014 Apr 24. doi: 10.1212/NXI.0000000000000004Copyright/License ► Request permission to reuse

Table 2

Adjusted risk and odds ratios for associations of demographic/clinical variables

Kimbrough DJ. Neurol Neuroimmunol Neuroinflamm. 2014 Apr 24;1(1):e4.

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Outline

• Definition

• Science

• Epidemiology

• Diagnosis

• Treatments: Standards of care, acute treatment trials

Definition of NMO:2015 Criteria

1. Seropositive

‐ Pretty much any lesion in the CNS

2. Seronegative

‐ Dissemination in time

‐ Dissemination in space

‐ Bad attacks, by MRI

‐ Not MS or other disease

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MRIs in NMO

MRIs in NMO

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MRIs in NMO

MRIs in NMO

> 17.6 mm

Sensitivity = 80.8%Specificity = 76.9%

Mealy, et al. JNS. In press

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Definition of NMO:2015 Criteria

1. Seropositive

‐ Pretty much any lesion in the CNS

2. Seronegative

‐ Dissemination in time

‐ Dissemination in space

‐ Bad attacks, by MRI

‐ Not MS or other disease

Diagnostic workup:Make sure it’s not MS

Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica

Ingo Kleiter, MD; Kerstin Hellwig, MD; Achim Berthele, MD; Tania Ku¨mpfel, MD; Ralf A. Linker, MD;  Hans‐Peter Hartung, MD; FriedemannPaul, MD; Orhan Aktas, MD; for the Neuromyelitis Optica Study Group

Development of extensive brain lesions following fingolimod(FTY720) treatment in a patient with neuromyelitis optica spectrum disorderJu-Hong Min, Byoung Joon Kim and Kwang Ho Lee

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Look for clues…

More common in NMO More common in MS

Longitudinally extensive TM Small, sensory, white matter TM

Permanent CNS destruction Recovers quickly

CSF WBC > 50/cc Oligoclonal bands

Other autoantibodies (e.g., SS-A) Normal labs

NMO-IgG seropositive NMO-IgG seronegative

MRI brain “non-symptomatic” Typical MS pattern

Outline

• Definition

• Science

• Epidemiology

• Diagnosis

• Treatments: Standards of care, acute treatment trials

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Comparison of Treatments:Preventive

Mealy MA. JAMA Neurol. 2014 Mar;71(3):324‐30

Three Phase III Trials in NMO!(All preventive)

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Acute Treatment of NMO

• Currently Available (off-label):– IV Methylprednisolone

– Plasma exchange

– Cyclophosphamide

• ASIA A

• systemic auto-immune disease

– IVIG???Greenberg, 2011

Acute Treatment of NMO

Treatment group At or below baseline EDSS at ≈1-year follow up

IVMP-only 6 (35%) IVMP + PLEX 33 (65%)

Abboud H. Multiple Sclerosis Journal. 2015 Apr 28.

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Acute Treatment of NMO:Block complement

Levy M. Neurol Neuroimmunol Neuroinflamm. 2014 Apr 24;1(1):e5.

Acute Treatment of NMO:Minimize BBB disruption

Basel

ine

Admis

sion

Disch

arge

Followup

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10*p=0.035

p=0.233

Exp

and

ed D

isab

ility

Sca

le S

core

(E

DS

S)

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Summary

• NMO is an antigen specific disease against AQP4• Definition: 2015 Criteria• Science: 

The NMO‐IgG is a highly specific biomarker The NMO‐IgG may make the pathology a little worse AQP4‐reactive T cells are necessary and sufficient to induce 

the disease• Epidemiology: Middle‐aged women of color: consider NMO• Diagnosis: Remember the MRIs• Preventive Treatment: Rituximab & mycophenolate are good, 

azathioprine is less so...• Acute Treatment: PLEX is good, we need better

Resources for NMO Patients

• Johns Hopkins Neuromyelitis Optica Clinic: http://www.nmoresearch.org/

• Johns Hopkins Transverse Myelitis Center: http://www.hopkinsmedicine.org/jhtmc

• Guthy Jackson Charitable Foundation: http://www.guthyjacksonfoundation.org/

• Transverse Myelitis Association:

http://myelitis.org/

• Consortium of MS Centers

http://www.mscare.org/

Johns HopkinsNeuromyelitis Optica Clinic

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Certification in Rare Neuroimmunologic Disorders

http://www.ptcny.com/clients/CRND/