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Autoimmune Diseases of the CNS: Optic Neuritis and Myelitis Michael J. Bradshaw, MD

Rosalind Franklin University of Medicine and Science

Billings Clinic Neurology

Disclosures/Off-Label Use

No financial conflicts of interest

Off-label treatment of neuromyelitis optica spectrum disorders is discussed

Goals

Recognize and understand diagnostic evaluation of two common presentations of autoimmune CNS disease:

Optic Neuritis

Myelitis

Review the neuromyelitis optica spectrum disorders

Case 1

46 year old woman with no medical history reports two days progressive vision loss in the left eye. Her vision started out “cloudy” and has been getting progressively worse. She noticed that while driving, it looked like cars were swerving toward her. She also has mild retro-orbital discomfort.

Optic Neuritis: Typical Symptoms

Subacute, progressive monocular vision loss

Decreased visual acuity

Dyschromatopsia

Variably accompanied by retro-orbital pain

Mayoclinic.org

Optic Neuritis: Unusual Symptoms

Phosphenes: light flashes with eye mvmt

Photisms: light induced by noise, taste or touch

Pulfrich effect: false perception of depth in lateral motion

“What is out of the common is usually

a guide rather than a hindrance.”

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Pulfrich Effect

https://www.youtube.com/watch?v=1mnWI_u_zBg

Watch with dark sunglasses blocking the left eye only and the image will appear three-dimensional due to the Pulfricheffect

Patient’s view

Neurology July 19, 2016, 87:3 338-339.

Localization: surface of the eye to the optic chiasm (on the left)

Baehr M, Frotscher M. Duus’ topical diagnosis in neurology. Thieme.

Mayoclinic.org

Case 1

Physical exam: visual acuity 20/80 OS, 20/20 OD, left eye red desaturation, and a

relative afferent pupillary defect in the left eye. No disc edema.

aapos.org

Optic Nerve Lesion:Physical exam

Decreased visual acuity (especially to low contrast chart)

Color desaturation

Relative afferent pupillary defect

May not have optic disc edema

Lancet Neurol 2014; 13: 83–99.

Relative Afferent Pupillary Defect

https://www.youtube.com/watch?v=soiKbngQxgw

Normal: 1:20 min

Right eye relative afferent pupillary defect: 2:10 min

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DDx

Lancet Neurol 2014; 13: 83–99.

Immune-mediated CIS/MS

NMOSD

ANCA-associated vasculitis

Neurosarcoidosis

Paraneoplastic(e.g. CRMP5)

Infectious Neuroretinitis (viral, toxo,

bartonella)

Syphilis

Lyme disease (rare)

Vascular Nonarteritic ischemic optic

neuropathy

Giant cell arteritis

Retinal hemorrhage

Mass Glioma, meningioma

Toxic/metabolic B12/folate deficiency

Drugs

Genetic (rare) Leber hereditary optic

neuropathy

Kjer-type autosomal dominant optic atrophy

Inflammatory Non-Inflammatory

Case 1: Next step?

Diagnostic Evaluation

Serum:

ANA, SSA/B, ANCAs, ESR/CRP, AQP4/MOG, B12/Folate

CSF: Cell count/diff, glucose, protein, OCBs, IgG index, VDRL (others)

Imaging:

MRI orbits w/wo contrast

AQP4 = Aquaporin-4

MOG = myelin oligodendrocyte glycoprotein Axial T1 Postcontrast

Optic Neuritis:

MRI

MRI orbit w/wocontrast (includes brain)

T2 hyperintensityand contrast enhancement of the affected optic nerve

Coronal T1 Postcontrast

Ann Neurol 2011;69:292-302.

Visual evoked potentials

Diagnosis: Optic Neuritis/RRMS

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Optic Neuritis: Treatment

1 g IV methylprednisolone daily x 3-5 days

Some give an oral prednisone taper

Oral prednisone 1250 mg/day (=25 pills!) x 3-5 days

Oral methylpred (1g; 1:1 oral availability)x 3-5 days

N Engl J Med. 1992 Feb 27;326(9):581-8.

PO Steroids: Non-Inferior to IV in the Short-Term

COPOUSEP trial: 1 g IVMP vs 1 g POMP

JAMA Study: 1g IVMP vs 1.25 g PO prednisone

Both demonstrated non-inferiority in short term

Decrease risk to MS conversion with IV?

Reserve PO route for relapses with special circumstances, rather than initial presentation

JAMA Neurol. 2018 Jun 1;75(6):690-696.

Lancet. 2015 Sep 5;386(9997):974-81.

Optic Neuritis: Prognostication

Long term risk of conversion to clinically definite MS

Additional lesions: ~80%

No lesions, +OCBs: ~23%

No lesions: ~20%

No lesions and no OCBs: ~4%

Arch Neurol. 2008;65:727–32. Brain. 2008;131(Pt 3):808–17. Neurology.

2006;67:968–72. Mult Scler. 2011;17:312–8. Neurology. 2008; 70:1079–83.

Case 2

A three year old girl is brought to the emergency department for vision changes.

Four days ago, she reported “seeing water” on the floor, then over the next few days seemed to have difficulty seeing objects, such as a toy held out to her. Today, she started walking into walls, saying she couldn’t see them.

Physical exam: no central vision in either eye (light perception only), but some preserved peripheral vision. There is no relative afferent pupillary defect. Left Babinski.

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Optic Neuritis: RED FLAG Features

Severe visual deficits

Bilateral optic neuritis

Involvement of the chiasm on MRI

Longitudinally extensive optic neuritis (>1/2 length of the ON)

Concerning for neuromyelitis optica spectrum disorders

Poor recovery from attacks; emergent

treatment indicated

CSF: 0 WBC, normal glucose, normal protein, no oligoclonal bands, elevated IgG index

Treated with emergent IVMP and PLEX- vision fully recovered

Serum AQP4 IgG positive, MOG negative

Diagnosis: AQP4+ neuromyelitis optica spectrum disorder (AKA “Devic’s disease”)

Maintenance therapy with rituximab q3 months

Case 2

Neuromyelitis Optica Spectrum Disorders

Divided into three groups:

Aquaporin 4+

Aquaporin 4-, MOG +

Aquaporin 4-, MOG-

Relapsing myelitis, relapsing optic neuritis, etc.

MOG = myelin oligodendrocyte glycoprotein

AQP4+ NMOSD

Relapsing autoimmune astrocytopathy

AKA Devic’s disease

Episodes resemble demyelinating events

Predominant optic neuritis and myelitis

Once thought to be a

form of MS

Eugène Devic, 1894

NMOSD: Core Clinical Features

Optic neuritis

Bilateral, severe, poor recovery, longer lesions/chiasm

Myelitis

>3 segments, extensive, swelling, central cord

Area postrema syndrome

Intractable hiccups, nausea, vomiting

Brainstem syndrome

Symptomatic narcolepsy/diencephalicsyndrome

Cerebral syndromeContinuum (Minneap Minn) 2016;22(3):864–896. Bradshaw MJ, Kimbrough DK. Practical Neurology 2/2019;76-89.

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AQP4+ NMOSD

AQP4 is a water channel heavily expressed on optic nerves, brainstem, spinal cord

Aquaporin-4 IgG are pathogenic

Fix complement: kills the astrocyte Neuronal death

J Exp Med 2005;202(4):473-477. Neurology. 2013 Oct;81(14):1197-204.

NMOSD Acute Treatment

All disability accumulates during relapses

Relapses should be treated aggressively

IVMP and early plasma exchange

Area postrema syndrome generally responds to steroids alone

NMOSD Maintenance Treatment

Eculizumab (C5 complement inhibitor; FDA approved)

Rituximab (CD20 Ab)

Mycophenolate mofetil, azathioprine

Clinical trials:

Tocilizumab/satralizumab (IL-6R antagonist)

Inebilizumab (CD19 Ab)

Case 427 yoF presents to her PCP after she developed paresthesias in the hands and feet over the course of a few days. Several days later, she noted sensory loss/paresthesias from the nipple line down.

She had an episode of optic neuritis 12 years ago.

Next step?

Case 2: Next steps?

Ascending sensory

pathways

Descending motor

pathways

Fine touch, vibration, proprioception

(ipsilateral)ARM LEG

Motor control

extremities(ispilateral)

Motor control

trunk (bilateral)

Crude touch,

temperature, pinprick(contralateral)

VENTRAL

DORSAL

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Myelopathy

Spinal cord dysfunction from any cause

Compression, immune-mediated,

infectious, spinal cord infarct,

toxic/metabolic

Myelitis is spinal cord dysfunction with evidence of inflammation

MRI or CSF

A Systematic Approach to MyelopathyClinical evidence of spinal cord

dysfunction

MRI spine w/wo contrast Extrinsic compression NSGY

CSF analysis

Cord pathology?

Evidence of Inflammation?

Myelitis

- Immune-mediated- Infectious

- Malignant

Cord inflammation

Myelopathy

- Compressive- Toxic/Metabolic

- Vascular

Cord pathology

No inflammation

Consider myelopathy

- MRI/CSF too early?- Not myelopathy?

No cord pathology

No inflammation

Image the suspected

localization AND more Rostrally

e.g. sx from

T4 down- include C spine MRI

T2 T1-Post T2 T1-Post

Longitudinally extensive transverse myelitis (LETM): Spinal cord lesion > 3 spinal segments suggests against MS

Bradshaw MJ, et al. Neuro Board Rev, 6/2018.

Spinal cord lesion typical of MS: short segment, dorsal cord

T2 T1 Post T1 Post

T2

Baehr M, Frotscher M. Duus’ topical diagnosis in neurology. Thieme.

ArmLegs

Arm

C3

NORMAL T2 T1 post-contrast

Spinal cord lesion typical of NMOSD: Longitudinally extensive, grey matter/ventral cord

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West Nile Myelitis: Grey matter lesion with flaccid paralysis

Baehr M, Frotscher M. Duus’ topical diagnosis in neurology. Thieme.

T2 T1 Post T1 PostNeurosarcoidosis: nodular meningeal enhancement and

LETM (wide range possible)

Case 4

Brain MRI normal; spine with LETM

CSF: 23 (89%lymph, 10%mono), normal glucose, protein, no OCBs

Serum: MOG IgG positive 1:1000

AQP4 IgG neg

MOG + NMOSD

Neuromyelitis optica

spectrum disorder with

IgG antibodies against

MOG

Myelin oligodendrocyte

glycoprotein

Expressed on outer

surface of myelin sheath,

involved in cell

adhesion/microtubule

stability

MOG+ NMOSD

Optic neuritis, myelitis, brainstem encephalitis, ADEM

~25-33% of AQP4 negative NMOSD patients have MOG IgG

Treatment is similar to AQP4+NMOSD, but still being defined

MMF, rituximab, IVIg

Generally carries better prognosis than AQP4+ NMOSD

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Questions?

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