neuroimaging to guide diagnosis, prognosis and treatment

Suzana Zorca, HMS IIIGillian Lieberman, MD

Optic Neuritis Neuroimaging to guide Diagnosis,

Prognosis and Treatment

Suzana Zorca, Harvard Medical School Year IIIGillian Lieberman, MD

January 2007

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Agenda

Patient J.K.: Introduction to the clinical presentation of optic

neuritis.

Differential diagnosis for focal lesions of the optic nerve.

Diagnosis: Imaging the intra-orbital optic nerve.

Prognosis: Predicting outcome for optic neuritis patients.

Therapy: Neuroimaging to guide Rx with immunomodulatory agents.

Emerging modalities: DT-MRI and OCT.

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A 24 year old woman p/w acute vision loss and pain in her left eye.

Vision “blurry”

upon awakening the previous day; deteriorated since.

No systemic symptoms. Denies accidental trauma to the eye.

No past medical or surgical history. On no medications except OCPs.

Ophthalmologic examination: visual acuity OD 20/20, OS 20/200. Fundus exam shows mild optic nerve head swelling OS. Ishahara

color plate testing 10/10 OD, 0/10 OS. Left RAPD, and a central field defect on visual field testing.

Further neurological and general physical exam is unremarkable.

Patient J.K.: 24 y.o. woman w/acute vision loss OS

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Focal optic nerve lesions

Tumor (meningioma, glioma, lymphoma, leukemia, mets)

Trauma (foreign body, retinal detachment, traumatic hemorrhage)

Infection (viral, Lyme, Toxoplasmosis, Bartonella, syphilis).

Infarction/Vascular (GCA and NAION, CRAO/CRVO, aneurysms).

Others: ***Inflammation/Idiopathic demyelinating optic neuritis; genetic: LHON; optic nerve head drusen, drug-induced.

T T i i… !

Casper et al. Orbital Disease: Imaging and Analysis. 1st ed. Stuttgart: Thieme,1993

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Menu of tests: Imaging the optic nerve

CT = 1o imaging modality if trauma

history

is unclear (e.g. kids). 1. orbital fractures2. metallic foreign body3. intraocular air/blood/hemorrhage4. nerve sheath hematoma5. calcifications

Courtesy of Dr. Jeffrey VelezCT head w/o Contrast

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U/S = useful if limited fundoscopic exam or if one cannot dilate the pupil. Can help clarify diagnosis of:

1. globe rupture2. lens dislocation3. retinal detachment4. suprachoroidal hemorrhage5. optic nerve head drusen


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MRI = best modality for evaluating orbital soft tissues.1. vascular injury2. aneurysms3. inflammatory lesions4. demyelinating lesions5. tumors

*NB: Contrast (Gd)-enhancement especially helpful in the acute phase of inflammation or demyelination, when the BBB is compromised.

Challenges:1.

Orbit: small area, packed with intraconal fat –

must ↓

fat signal!

2.

Optic nerve surrounded by CSF within dural sheath –

must ↓

CSF signal!

3.

Motion artifact common.

4.

Anatomic variation in optic nerve length, diameter and tortuosity.

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Advantages of different MRI modalities

T1 –

great for imaging orbital anatomy:

STIR (Short Tau Inversion Recovery)

Allows better characterization of fat-filled structures.

T2 –

images inflammation and demyelination better:

FLAIR (Fluid Attenuated Inversion Recovery)

Edema and gliosis are hyperintense.

Heavily T2 weighted, CSF signal is nulled

by sampling the MR image at an appropriate time after magnetization inversion, when longitudinal magnetization of CSF is zero.

Similar to STIR, except used for CSF instead of fat.

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Companion Patient # 1: Optic nerve tumors (Axial T2WI FSE)

optic nerve glioma axial T2WI FSE

Courtesy of Dr. Andrew Hines-Peralta and Dr. Moritz Kircher

normal optic nerve anatomy axial T2WI FSE

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Companion Patient #1 (cont.) Optic nerve glioma: Sagittal T2WI


sag T2WI sag T2WI

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cor T2 FLAIR cor T2 FLAIR

Companion Patient #1 (cont.) Optic nerve glioma: Coronal T2WI FLAIR

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Companion Patients 2 and 3: More Compressive optic nerve lesions

Aneurysmal Bone Cyst

Rhabdomyo-sarcoma

Axial SE-T1 weighted MRI Coronal FSE T2-weighted MRI

Sagittal T1 Sagittal T2

(L) Shingleton

BJ and O’Donoghue MW. Blurred Vision. NEJM 2000: 343:8. 556-62.(R) Mashima

Y, Oshitari

K, Imamura Y et al. High-resolution Magnetic Resonance Imaging of the Intraorbital Optic Nerve and Subarachnoid Space in Patients with

Papilledema and Optic Atrophy. Arch Opthalmol 1996; 114. 1197-1203.

in upper retro-bulbar musclespace abuttingthe optic nerve

a well-circum-scribed, L-sided multi-cystic orbital lesion. Cavities are filled with hyper-intensehemorrhagicfluid (met-hemoglobin).

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PACS, BIDMC

Companion Patient #4: Optic Nerve Meningioma (Coronal T1WI)

Meningioma: selectively enhances the CN II nerve sheath (T1WI post-Gd FS)

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Orbital lymphoma infiltrating the optic nerve and the surrounding muscles (superior and medial rectus involvement observed)

PACS, BIDMC

Companion Patient #5: Infiltrative process (Coronal STIR)

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Back to our Patient: Axial T1WI findings

PACS, BIDMC

Axial T1WI: enhancement of L. optic nerve, post-Gd views necessary to confirm finding.

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Three sequential coronal STIR images show L optic nerve sheath enhancement.

These findings, in conjunction with the typical clinical presentation and the absence of other symptoms, lead to the diagnosis of acute optic neuritis.

PACS, BIDMC

Our Patient J.K.: Coronal STIR images

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Optic neuritis: recap of J.K.’s presentation

3. pain

with eye movement

Typical presentation: optic neuritis (ON) usually affects young patients: ages 20-40, but can also present in infancy and later adulthood.

Diagnostic triad: 1. monocular vision loss

(hours to days)

2. dyschromatopsia*Drawings by a British artist diagnosed with optic neuritis, who

attempted to portray his visual deficits.

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Visual prognosis: deficits remit spontaneously over weeks ↔ months.

Variants: insidious (typical onset is sudden!), chronically progressive, irreversible vision loss (typically resolves!), or unaccompanied

by pain (typically painful with eye movements!)

Bilateral attacks: rare in adults, more frequent in children.

Recurrences in the affected eye or the fellow eye: 10-34%

Largest trial is the ONTT, the Optic Neuritis Treatment Trial –

available 10 year follow-up data on 455 patients, completed in 2004.

Optic neuritis: primer continued…

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1. Visual Prognosis-

Visual acuity or extent of CN II lesion on MRI not predictive of speed or extent of recovery.

-

Prognosis excellent: >93% of patients improve by 5 weeks.

2. Neurologic

prognosis: ON as “harbinger of MS”-

Baseline brain MRI is a strong predictor of risk of CDMS in patients with monosymptomatic optic neuritis.

-

Do not want to commit our patient to a lifetime on immunomodulatory therapy unless @ high risk.

-

However, these drugs have been shown to reduce risk of disability in MS patients so want to start early if risk is high.

Imaging to inform Prognosis

Smith, CH. Optic Neuritis. Clinical Neuro-ophthalmology. 2005; Ch.6: 293-347.

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Relationship to MS

MRI = used to stratify risk of developing MS

Baseline brain MRI: estimate # of white matter lesions during first ON attack.

Number of white matter lesions correlate with risk of further demyelination.

2 randomized, placebo-controlled studies have found that patients w/clinically isolated demyelinating syndromes, such as optic neuritis, at high risk for MS may benefit from the early institution of disease modifying agents. (Chen L et al. Ocular Manifestations of

Multiple Sclerosis. Contemporary Opthalmology. 4:24. 2005. 1-6)

Conclusions: Baseline brain MRI has a robust predictive value due to its ability to reveal an underlying vulnerability to axonal damage that predisposes optic neuritis patients to recurrent demyelinating injury.

Patients with one or more lesions on baseline MRI are at increased risk (P<0.001).

Optic Neuritis Study Group Data: High-

and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: the experience of the optic neuritis treatment trial: Arch Ophthalmol

2003; 121:944-9.

~20%

~55-60%

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Our Patient: Multiple lesions on FLAIR MRI (Baseline scan)

Axial FLAIR T2W PACS, BIDMC

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Axial FSE T2W PACS, BIDMC

J.K.’s Baseline Brain MRI (Axial T2W FSE)

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Detailed questioning revealed that J.K. experienced 1 month of trigeminal neuralgia in the year prior.

She also noted paresthesias and tingling during trip to Iceland in 2005. Diagnosed with Raynaud’s by PCP but no imaging work-up until later.

Underwent brain MRI after her episode of optic neuritis.

As discussed, MRI is sensitive for detecting demyelinating MS lesions.

However, there is a “window of opportunity”

to image: the acute and chronic MS lesions give abnormal MRI signals due to different reasons: edema in the

acute flares, gliosis in chronic lesions.

During the time window between the two, when the edema has mostly resorbed and gliosis has not yet occurred, MRI may not detect these lesions.

Follow-up for our patient J.K.

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Axonal loss due to transection, not only demyelination, has been

shown in histopathological and immunocytochemical studies of acute MS lesions.

This leads to retrograde (Wallerian) degeneration over time.

Recent studies demonstrated that axonal damage, originally thought to occur only late in MS, actually occurs quite early, even at the time of first demyelinating episode such as optic neuritis.

Unfortunately, MRI-FLAIR cannot discern in fine detail the ongoing damage or subtle improvement in the optic nerve. Therefore, need new imaging modalities!

Diffusion Tensor-MRI may provide in vivo information about CNII pathology (it monitors ↑

in mean diffusivity and ↓fractional anisotropy, which have been found to correlate with axonal disruption).

Emerging Modalities: DT-MRI

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-

non-invasive, non-contact, performed in short-time frame.

-

perfect for monitoring (with histological accuracy) axonal loss

over time and correlating axonal loss with drug therapy.

-

initially used in glaucoma to provide images of the macula with

histological accuracy and to measure the retinal nerve fiber layer thickness.

-

Retinal nerve fiber layer (RNFL) imaging and other methods have

confirmed that axon transaction occurs in optic neuritis plaques.

-

OCT has a new application in optic neuritis and MS, as patients

with optic neuritis have been shown to have decreased thickness of peripapillary RNFL compared to controls.

-

as a result, there is enthusiasm about generating specific guidelines for OCT use to assess axonal preservation/protection in clinical trials of ON and MS (Sergott

et al. 2006)

Emerging Modalities: Optical Coherence Tomography (OCT)

Rebolleda

G, Munoz-Negrete

FJ, Noval

S et al. New Ways to Look at an Old Problem. Survey of Ophthalmology 2006: 51(2). 169-73

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Conclusions:

Idiopathic optic neuritis

manifests with sudden, reversible loss of vision (TRIAD: decreased visual acuity, color washout, and pain w/eye movement!)

MRI of orbit: rules out compressive and traumatic injuries.

Baseline brain MRI: detects areas of demyelination and informs prognosis.

Corticosteroids

accelerate visual recovery, no effect on final visual outcome.

Recent research on MRI-DT and OCT/RNFLI

in ON patients suggests benefit for earlier therapeutic intervention with immunomodulatory agents.

*** In order to use these emerging imaging techniques in clinical trials of immuno-

modulatory agents, reliable end-points are needed to ensure uniformity of clinical trials!

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Many thanks to…

Gillian Lieberman, MD

Pamela Lepkowski

Andrew Hines-Peralta, MD

Jeffrey Velez, MD

Moritz Kircher, MD

Larry Barbaras, Webmaster

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References

Smith, CH. Optic Neuritis. Clinical Neuro-ophthalmology. 2005; Ch.6: 293-347.

Hess RF, Plant GT. Optic Neuritis. 1985: Cambridge Univ. Press. 1-85.

Chen L and Gordon LK. Ocular Manifestations of Multiple Sclerosis. Contemporary Opthalmology. 4:24. 12/1/2005. 1-6.

Shingleton

BJ and O’Donoghue MW. Blurred Vision. NEJM 2000: 343:8. 556-62.

Wilejto

M, Shroff

M, Buncic

JR et al. The clinical features, MRI findings, and outcome of optic neuritis in children. Neurology 2006; 67. 258-62.

Miller DH, Newton MR, van der Poel

JC et al. Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology 1988; 38. 175-79.

Kaufman DI, Trobe JD, Eggenberger

ER and Whitaker JN. Practice Parameter: The role of corticosteroids in the management of acute monosymptomatic optic neuritis. Neurology 2000; 54. 2039-44.

Hickman SJ, Brex

PA, Brierley

CMH et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using fat-saturated short-echo fast FLAIR sequence. Neuroradiology 2001; 43. 123-28.

Onofri

M, Tartaro

A, Gambi

D et al. Long echo time STIR sequence MRI of optic nerves in optic neuritis. Neuroradiology 1996. 38:. 66-69.

Dunker S. and Wiegand

W. Prognostic value of MRI in Monosymptomatic Optic Neuritis. Ophthalmology 1996; 103. 1768-73.

Mashima

Y, Oshitari

K, Imamura Y et al. High-resolution Magnetic Resonance Imaging of the Intraorbital Optic Nerve and Subarachnoid Space in Patients with Papilledema and Optic Atrophy. Arch Opthalmol 1996; 114. 1197-1203.

Guy J, Mao J, Bidgood

WD et al. Enhancement and Demyelination of the Intraorbital Optic Nerve. Opthalmology 1992; 99. 713-25.

Guy J, Mancuso A, Quisling R et al. Gadolinium-DTPA-enhanced Magnetic Resonance Imaging in Optic Neuropathies. Opthalmology 1990; 97. 592-600.

Rebolleda

G, Munoz-Negrete

FJ, Noval

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73.

Ciccarelli

O, Toosy

AT, Hickman SJ et al. Optic Radiation Changes after Optic Neuritis Detected by Tractography-Based Group Mapping. Human Brain Mapping 2005; 25. 308-16.

Optic Neuritis Study Group. Long-term Brain Magnetic Resonance Imaging Changes after Optic Neuritis in Patients without Clinically Definite Multiple Sclerosis. Arch Neurology 2004; 61. 1538-41.

Trip SA, Schlottmann

PG, Jones SJ et al. Optic nerve atrophy and retinal nerve fibre

layer thinning following optic neurits: Evidence that axonal loss is a substrate of MRI-detected atrophy. NeuroImage 2006; 31. 286-93.

Trip SA, Wheeler-Kingshott

C, Jones SJ et al. Optic nerve diffusion tensor imaging in optic neuritis. NeuroImage 2006; 31. 498-505.

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