Natural History of Optic Neuritis

Objective

The goals of this pilot study are:

1. To assess the degree to which subacute changes in clinical, electrophysiological, and
imaging measures can robustly predict retinal neuronal loss 12 months after acute optic
neuritis.

2. To construct a composite score that integrates these subacute changes, can itself
robustly predict retinal neuronal loss 12 months after acute optic neuritis, can be
validated in future trials, and is likely to be modulated by drugs that promote tissue
repair and neuroprotection in multiple sclerosis (MS).

3. To evaluate the usefulness of specialized magnetic resonance imaging (MRI) measures of
the optic nerve in future clinical trials of drugs designed to promote tissue repair and
neuroprotection. The primary hypothesis of the study is that peripapillary retinal nerve
fiber layer (RNFL) thickness, which is generally agreed to reflect the integrity of
optic nerve axons following optic neuritis, and which can be measured using
spectral-domain optical coherence tomography (OCT) in the affected eye 12 months
following optic neuritis, can be robustly predicted by changes in RNFL thickness between
1 and 3 months following symptom onset.

Study Population

The following cohorts will be recruited at each of the three study sites:

- Up to 30 participants with acute optic neuritis.

- Up to 15 healthy volunteers who are group-wise age- and sex-matched to the participants
with unilateral optic neuritis.

Design

This is a one-year, prospective, multi-cohort, multi-site, pilot natural history study. Data
obtained at NIH will be compared and aggregated with data obtained at other study sites,
specifically the University of Utah-Moran Eye Center (in Salt Lake City) and Hebrew
University-Hadassah Medical Center (in Jerusalem, Israel). Data will be gathered at baseline
(optional) and at 1, 3, 6, 9, and 12 months in the patient cohort, and at 1, 3, and 12 months
in the healthy volunteers.

Outcome Measures

The primary outcome measure is the RNFL thickness in the affected eye 12 months after optic
neuritis.

Secondary outcome measures, all measured at 12 months, include:

- Measures of optic nerve structure: mean cross-sectional optic-nerve area; mean,
parallel, and perpendicular diffusivity; and MTR all within the optic nerve lesion as
visualized at baseline.

- Measures of brain structure: ventricular volume; T2 lesion volume along the visual
pathway both sides considered together.

- Measures of retinal structure: ganglion cell layer + inner plexiform layer thickness in
the affected eye.

- Measures of visual function: low-contrast letter acuity; high-contrast letter acuity;
Pelli-Robson contrast sensitivity; object-from-motion detection; visual fields; and
critical flicker-fusion frequency all in the affected eye.

- Measures of visual physiology: VEP amplitude; VEP latency all in the effected eye.

- INCLUSION CRITERIA:

COHORT 1: Unilateral optic neuritis.

- Typical demyelinating optic neuritis based on the best clinical judgment of the
investigators.

- Symptom onset within 46 weeks of enrollment OR patients with history of optic neuritis
who were followed from symptom onset under a Neuroimmunology Branch natural history or
screening protocol.

- For women of childbearing potential, willing to use acceptable forms of contraception
(i.e. hormonal contraception (birth control pills, injected hormones, vaginal ring),
intrauterine device, barrier methods (condom or diaphragm) with spermicide or they
have undergone surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a
partner) for the study duration.

- Able to provide informed consent.

- Willing and able to participate in all aspects of the trial.

COHORT 2: Healthy volunteers.

- No medical history that would interfere with study result interpretation, in the best
clinical judgment of the investigators.

- Age greater than or equal to 18 years and less than or equal to 50 years.

- Able to provide informed consent.

- Willing and able to participate in all aspects of the trial.

EXCLUSION CRITERIA:

- History of signs or symptoms suspicious for MS, in the best clinical judgment of the
investigators.

- Pateints-Disease-modifying therapy for MS prior to the onset of the current episode of
optic neuritis (excludes oral or intravenous glucocorticoids: Healthy Volunteers -
Previous or current use of disease-modifying therapy for MS (excluding oral or
intravenous glucocorticoids.

- Previous history of clinical optic neuritis or a systemic disease associated with
optic neuritis (e.g. sarcoidosis, lymphoma).

- Current or prior optic neuropathy (e.g. trauma, ischemia, glaucoma, optic nerve
drusen).

- Previous history of a retinal disease (e.g. diabetic retinopathy, retinal drusen)
other than uveitis.

- Previous history of an ophthalmic disease that in the best judgment of the
investigator could affect ophthalmic imaging results.

- Previous history of a systemic disease that may mimic MS (e.g. neurosyphilis,
neurosarcoidosis, CNS ymphoma, Si(SqrRoot)(Delta)gren s syndrome).

- Previous history of a systemic disease that in the best judgment of the investigator
could confound study outcome.

- Current use of a TNF-alpha inhibitor (e.g. etanercept).

- Habitual use of illicit drugs that in the best judgment of the investigators could
confound study outcome.

- Pregnant or breast-feeding.

- Unwilling to co-enroll on a Neuroimmunology Branch natural history or screening
protocol currently 89-N-0045.

- Contraindication to MRI scanning.