Neuroretinitis in Patients with Multiple Sclerosis

McDonald criteria. One of the three patients underwent brain biopsy that further confirmed multiple sclerosis.

Neuroretinitis in the three patients occurred after the diagnosis of multiple sclerosis. All three patients with

multiple sclerosis had been treated with interferon

␤ before or concurrently with the development of

neuroreti-nitis.

Conclusions:

Neuroretinitis can be an associated manifestation of multiple sclerosis. The possible

associ-ation between neuroretinitis and interferon

␤ warrants further investigation. Ophthalmology 2004;111:335–341 ©

2004 by the American Academy of Ophthalmology.

In 1916, Theodor Leber described the syndrome of

neuro-retinitis, a disorder characterized by optic disc edema

ac-companied by macular exudates.

Although most cases are

thought to be the result of a nonspecific viral infection or

other immune-mediated process, various infectious agents

have been implicated, including syphilis, Lyme disease,

toxoplasmosis, and cat-scratch disease.

The symptoms of

unilateral decreased vision may be preceded by a virallike

prodrome.

Physical findings of recent onset neuroretinitis

typically include optic disc swelling and peripapillary

exu-dative detachment of the retina, followed by vitreous cells

and macular or peripapillary hard exudates.

The early stages of Leber’s neuroretinitis may seem

similar to demyelinating optic neuritis. However, optic disc

edema in optic neuritis is present only in one third of optic

neuritis cases, specifically the anterior variety, also known

as papillitis.

Other distinguishing features of neuroretinitis

are that eye pain and dramatic visual recovery are

uncom-mon.

Optic neuritis, in the setting of multiple sclerosis, is

not believed to be associated with macular star formation,

although 8 of the 448 patients (1.8%) in the Optic Neuritis

Treatment Trial had retinal exudates.

_Furthermore,

previ-ous case series found no increased risk of developing

mul-tiple sclerosis after an episode of neuroretinitis.

Conse-quently, we reviewed the records of our patients with

neuroretinitis to identify prior or subsequent diagnoses of

multiple sclerosis. Herein, we present three patients with

multiple sclerosis in association with neuroretinitis.

Patients and Methods

We reviewed the records of 35 consecutive patients with neuro-retinitis for evidence of multiple sclerosis. All subjects had been evaluated in a university-based practice over a 10-year period. The average follow-up time was 12 months, ranging from initial ex-amination to 38 months. Three patients met the McDonald criteria for diagnosis of multiple sclerosis. The McDonald criteria, a recently established international revision of the Poser and Schu-macher criteria, identify multiple sclerosis under the following conditions: (1) two or more attacks with clinical evidence of two or more neurologic lesions; (2) two or more clinical attacks with clinical evidence of one lesion and associated paraclinical evi-dence, defined as a positive magnetic resonance imaging (MRI) scan only, or combined positive cerebrospinal fluid oligoclonal bands (or increased immunoglobulin) with a positive MRI scan; or (3) one attack with one or more lesions, and paraclinical evi-dence.11

All three patients with multiple sclerosis, but none of the remaining 32 patients who did not have multiple sclerosis, were treated with a␤ interferon drug. The following is a summary of the three cases.

Case Reports

Patient 1. A 31-year-old woman with multiple sclerosis sought treatment for sudden vision loss of the right eye and pain with eye movement. During the previous 4 years, she experienced episodic dizziness, dysarthria, and right hand grip weakness. Past ocular history included two attacks of optic neuritis, including an episode of acute right eye superior visual field loss 2 years prior, and an episode of bitemporal vision loss with right optic disc edema 4

Originally received: September 10, 2002.

Accepted: February 21, 2003. Manuscript no. 220705. From the Neuro-Ophthalmology Unit, Mason Eye Institute, University of Missouri—Columbia, Columbia, Missouri.

Presented in part at the American Academy of Ophthalmology annual meeting, Orlando, Florida, October 2002.

Reprint requests to Lenworth N. Johnson, MD, Neuro-Ophthalmology Unit, Mason Eye Institute, University of Missouri—Columbia, Columbia, MO 65212. E-mail: [email protected].

Figure 1. Patient 1. Right fundus showing hemimacular “star” exudates.

Figure 2. A, T2weighted brain magnetic resonance imaging (MRI) scan of patient 2 showing the occipital region increased signal intensity (arrow) of tumefactive multiple sclerosis. B, T2weighted brain MRI scan 1 week later, and after intravenous corticosteroid treatment, showing regression of the hyperintensity.

Figure 3. A, Occipital brain lesion biopsy results of patient 2 showing

gray matter hypercellularity and perivascular lymphocytic infiltrate (inset) compatible with acute multiple sclerosis. B, White matter lymphocytic infiltrate and hypercellularity from the occipital lesion brain biopsy in patient 2.

Figure 4. Left fundus of patient 3 showing optic disc edema with

exuber-ant peripapillary and macular exudates.

Figure 5. Left fundus of patient 3 showing optic disc edema with

dorferi (Lyme antibody titer) test, Venereal Disease Research

Laboratories test, cryptococcus antigen test, rheumatoid factor test, antinuclear antibody test, and anticardiolipin immunoglobulin G test. Treatment with interferon ␤ 1A (Avonex, BIOGEN, Inc., Cambridge, MA) 30␮g intramuscularly once weekly was started for multiple sclerosis. On 1-month follow-up for this acute pre-sentation, her right eye visual acuity had improved to 20/80. The disc edema had resolved, but macular “star” exudate was now present, consistent with neuroretinitis (Fig 1).

Patient 2. A 32-year-old man was evaluated after a seizure characterized by “circling colors” in the left homonymous visual field. This lasted 3 to 4 minutes before he lost consciousness. He was diagnosed with multiple sclerosis 1 year before, after an identical episode. At that time, two lesions were seen on brain MRI scan (Fig 2), and a biopsy was performed on the occipital lesion. The biopsy showed gray and white matter hypercellularity and perivascular inflammation, compatible with tumefactive multiple sclerosis (Fig 3). Serum human immunodeficiency virus, reactive plasma reagent, and antinuclear antibody test results were normal. At that time, 1 year ago, he was treated with intravenous and oral corticosteroid. Subsequent MRI scans showed regression of the occipital lesions after 2 weeks and almost complete resolution by 6 months.

On examination of his current symptoms, visual acuity mea-sured 20/20 bilaterally. Confrontational visual field testing at bed-side showed an enlarged blind spot of the right eye. There was no afferent pupillary defect. There was optic disc hyperemia and edema bilaterally, being greater in the right eye. He received intravenous methylprednisolone for 5 days followed by oral pred-nisone taper then interferon␤ 1B (Betaseron, BERLEX Labora-tories, Montville, NJ) injections 250 ␮g subcutaneously every other day for optic neuritis and multiple sclerosis. Further inpatient evaluation included visual and auditory evoked potentials, human immunodeficiency virus testing, antinuclear antibody testing, uri-nalysis, reactive plasma reagent testing, Venereal Disease Re-search Laboratories testing, rheumatoid factor testing, coagulation studies, cryptococcal antigen testing, and cerebrospinal fluid stud-ies; all results were normal or negative.

At 1-month follow-up, his visual acuity and color vision were normal. Left optic disc edema was moderate and was associated with hemorrhage and exuberant peripapillary exudate (Fig 4) con-sistent with neuroretinitis. Tests for B. burgdorferi and B. henselae antibody were negative.

One year after initial ophthalmologic evaluation, the patient reported to our institution with 1 week of painless left eye vision loss. He had been taking interferon␤ 1B during the previous 12 months, having discontinued this medication 1 month before this visit. Visual acuity had decreased to 20/60 in the left eye. Auto-mated perimetry showed a left eye centrocecal visual field defect. There was no afferent pupillary defect. There was mild right optic

received Avonex injections 30␮g intramuscularly once weekly over the past year for treatment of multiple sclerosis.

Visual acuity measured 20/20 for the right eye and 20/50 for the left eye. She had a marked superior and inferior arcuate scotoma on automated perimetry of the left eye. Color vision of the left eye was diminished, identifying 13 of 17 color plates on pseudoisochromatic testing. There was a marked left afferent pu-pillary defect of 1.2 log units. The left optic disc showed diffuse optic atrophy with elevation.

One month after this initial visit, the patient returned, having experienced 2 weeks of severe worsening vision in the left eye, now measuring 2/200. Automated perimetry showed progression to a marked central scotoma. Funduscopic examination of the posterior pole revealed diffuse optic disc edema with macular “hemistar” exudate, compatible with neuroretinitis (Fig 5). There was perivenular sheathing in the peripheral retina of the left eye. A fluorescein angiogram showed diffuse leakage emanating from the left optic disc. The leakage was progressive from early to late frames (Fig 6). Laboratory analysis included blood count, sedi-mentation rate, B. burgdorferi testing, B. henselae testing, purified protein derivative skin testing for tuberculosis, fluorescent trepo-nemal antibody testing, reactive plasma reagent testing, Brucella titer, Mantoux skin test, toxoplasmosis titer, angiotensin convert-ing enzyme testconvert-ing, tularemia testconvert-ing, and serum protein electro-phoresis, all of which had normal or negative results. A chest radiograph and chest computed tomography scan showed no signs of sarcoidosis. Pulmonary function tests from a previous hospital-ization the same year were normal.

Treatment was initiated with systemic corticosteroid. The ret-initis and subretinal transudation improved over the following months. However, there was minimal improvement in her vision.

Discussion

Although optic neuritis and neuroretinitis are considered

separate entities, their separation is partly based on the

understanding that neuroretinitis does not predispose one to

multiple sclerosis.

The Optic Neuritis Treatment Trial

(ONTT) elucidated the increased risk of developing

demy-elinating disease after optic neuritis.

The results of the

ONTT showed that the cumulative risk of developing

clin-ically definite multiple sclerosis for all enrolled patients was

14% in 2 years and 30% within 5 years after a first episode

of optic neuritis.

This risk of conversion to multiple

scle-rosis at 5 years seemed lower for patients with optic disc

edema (papillitis)—particularly when the disc swelling was

severe— but this was not statistically significant.

In the

largest case series of patients with neuroretinitis, none of the

40 patients reviewed retrospectively for a mean follow-up

of 8 years and none of the 10 others followed up

prospec-tively for 1 to 2 years experienced multiple sclerosis.

Note, however, if one superimposed the results of the

ONTT (i.e., 14% incidence of multiple sclerosis in 2 years)

to this study of neuroretinitis patients, then we may expect

none to only one of the prospectively followed up patients

with neuroretinitis to be diagnosed with multiple sclerosis

within 1 to 2 years. It is more difficult to apply the ONTT

results to the retrospective group of patients with

neuroreti-nitis, because retrospective patient analyses have high rates

of missed diagnoses.

In the study of Parmley et al,

of

the 40 retrospectively studied patients with neuroretinitis,

30% were contacted by telephone. It is possible that some of

these patients may have experienced symptoms of multiple

sclerosis, but this was not uncovered in this retrospective

analysis. In the ONTT, 341 of 388 patients who completed

the study underwent annual, standardized neurologic

exam-ination by board-certified neurologists. Parmley et al did not

use this rigorous practice in the series of patients with

neuroretinitis. By incorporating a longer prospective

fol-low-up period and rigorous neurologic examination,

multi-ple sclerosis might have been identified in patients who had

neuroretinitis.

We identified three patients with neuroretinitis that

oc-curred 4, 1, and 10 years, respectively, after the initial

manifestation of multiple sclerosis. Consequently,

neuro-retinitis may not be an initial manifestation of multiple

sclerosis, but rather a late finding. Two of our three patients

had positive MRI scan results compatible with multiple

sclerosis, whereas one patient (patient 1) underwent two

MRI scans with normal results. The McDonald criteria

suggest that multiple sclerosis remains largely a clinical

diagnosis.

Radiographic evidence of demyelinating

cen-tral nervous system lesions alone is insufficient for

diagno-sis. However, MRI scan is a vital test to support the

diag-nosis of multiple sclerosis, with the positive predictive

value of MRI for diagnosing multiple sclerosis being 23%

to 65%.

All three patients in our case series had clinically

definite multiple sclerosis, and two of the three had evidence

of brain lesions on MRI scan at the time of diagnosis of

neuroretinitis. Again, using the ONTT as a model, without

a history or clinical signs of multiple sclerosis, only 42%

(150) of 352 patients had at least one brain lesion on MRI

scan at the onset of optic neuritis.

Of patients already

diagnosed with clinically definite or probable multiple

scle-rosis on entry, 10% (6 of 60) had normal brain MRI scan

results.

The ONTT, therefore, may reflect the MRI

find-ings in our three patients, where only two of the three

patients had brain lesions on MRI scan. In patient 2, the

diagnosis of multiple sclerosis was supported further by

brain biopsy. The lesions showed hypercellularity with

gemistocytes and perivascular lymphocytic infiltrate, the

earliest abnormalities in acute multiple sclerosis.

The

lack of demyelination is not unusual in such early lesions

because the biopsy was taken within the first 2 weeks of

clinical presentation. Demyelination may not appear until

after months or years of illness.

Our case series may not contradict previous reports of

the absence of increased risk of multiple sclerosis after

onset of neuroretinitis, because for all of our patients, the

diagnosis of multiple sclerosis was made before the

occur-rence of neuroretinitis.

In our small series of 35 patients,

fully 8.6% (three patients) of patients with neuroretinitis had

multiple sclerosis. The 8.6% prevalence is much higher than

the prevalence of multiple sclerosis in the general

popula-tion—approximately 0.1%.

Neuroretinitis has been associated with infections

agents such as cat-scratch disease, and noninfectious

illnesses such as arteriovenous malformation, malignant

hypertension, polyarteritis nodosa, inflammatory bowel

disease, optic disc melanocytoma, pseudotumor cerebri,

and sarcoidosis.

Unlike direct infections of the

ret-ina or choroid, infectious organisms rarely are isolated

from vitreous or ocular tissues in neuroretinitis.

Labo-ratory and radiographic evidence likewise supports no

other systemic diagnosis in our patient, particularly

sar-coidosis and cat-scratch disease. Neuroretinitis may

re-cur, as noted in one of our three patients with multiple

sclerosis, and recurrence has been reported in the

litera-ture on neuroretinitis.

A subset of patients

the retina. As the transudate is resorbed, lipids precipitate to

form the stellate pattern within Henle’s layer of the macula.

Damaged capillaries, rather than a persistent immune

re-sponse, are believed to account for the prolonged leakage,

even after removing the causative agent.

If a particular

vulnerability does exist at the delicate junction between the

optic nerve and retina, it appears to be exploited rarely by

many disease entities.

It is noteworthy that two of our patients (patients 2 and

3) had been treated with interferon

␤ (Betaseron, Avonex)

for approximately 1 year before the diagnosis of

neuroreti-nitis. The third patient (patient 1) began interferon

␤

(Avonex) treatment concurrently with the appearance of a

macular star exudate on funduscopic examination. The

clin-ical juxtaposition of neuroretinitis while taking Avonex or

Betaseron suggests that interferon

␤ treatment could have

contributed to the neuroretinitis in these patients. To our

knowledge, this association between neuroretinitis and

these two recombinant DNA products (i.e., Avonex from

mammalian Chinese hamster ovarian cells and Betaseron

from Escherichia coli bacteria) previously has not been

identified or reported, and hence deserves further

investiga-tion.

In conclusion, multiple sclerosis can be associated

with neuroretinitis. In all three patients, neuroretinitis

occurred after the diagnosis of multiple sclerosis and

after previous episodes of optic neuritis. This may

sug-gest that neuroretinitis is a late finding in multiple

scle-rosis, rather than an initial presenting event. It is of

interest to note that 8 of the 448 patients (1.8%) enrolled

in the ONTT had evidence of retinal exudates at the time

of presentation, suggesting neuroretinitis could be an

early manifestation.

A confounder is that 59 of the initial

448 patients in the ONTT had probable multiple sclerosis

at the time of enrollment, and we are unaware if these

were the individuals who displayed neuroretinitis.

Fi-nally, two of our patients were treated with interferon

␤

during the months preceding neuroretinitis, and the third

patient was started on interferon

␤ concurrently with the

appearance of neuroretinitis. This raises questions as to

whether interferon

␤ may be a causative agent of

neuro-retinitis in our patients. We suggest special attention be

given to patients treated with interferon

␤ to assess for

the development of neuroretinitis.

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Discussion

by

Steven A. Newman, MD

cataract owes its origin to the similarity in appearance between the lens and the waterfalls of the Nile River in Upper Egypt. As medical observation became more sophisticated, presumed disease pathologic features were described by a combination of symptoms and signs. Multiple abnormalities were grouped together as a “syndrome.” To keep these straight, physicians adopted several ploys. In the absence of an understanding of pathophysiology, Jonathan Hutchinson, an English surgeon, naturalist, scientist, and ophthalmologist in the latter portion of the nineteenth century, described disease processes by the name of the patient afflicted. Pity poor Sarah if “Sarah’s disease” was his original description of syphilis. This practice was not widely accepted. Most doctors chose (albeit perhaps with some ego) to name the syndromic findings after the first physician who described it or who brought it to public attention by presentation or within the literature. This was neither the first nor last example of the importance of a publicist. These eponyms have remained with us into the twentieth and even the twenty-first century. The chief reason for their lon-gevity has been our lack of understanding of the true pathophys-iologic process behind even common disease processes.

Over the last two centuries, better understanding of inflamma-tory, infectious, vascular, metabolic, and hereditary causes of disease has led to a natural tendency to abandon eponyms as soon as a pathophysiologic explanation could be advanced. In these days of molecular genetics, we often are able to identify specific gene defects primarily responsible for disease or at least respon-sible for increasing the risk of some pathologic process. Even as we identify specific molecular abnormalities, the true mechanism of disease often remains obscure.

It has also become apparent that multiple genetic abnormalities may produce very similar symptoms and signs. This disparity between genotype and phenotype is an important concept in

anal-ysis of disease processes even today. The final common pathway may end up seeming similar despite an initiation by multiple processes.

In 1916, Theodore Leber described the syndrome of decreased vision associated with optic disc edema and macular exudates. This has become known as Leber’s neuroretinitis. The most char-acteristic feature of the macular exudates has been the apparent star pattern. Initially this pattern was believed to be secondary to nonspecific viral papillitis. More recently, it has been recognized that specific inflammatory and infectious agents may be at work. In particular, this clinical syndrome is often seen after infection with

Bartonella henselae, responsible for cat-scratch disease. A very

similar picture has been described related to toxoplasmosis, syph-ilis, and Lyme disease, among others.

Although acute visual loss in young patients brings to mind optic neuritis secondary to demyelinating disease, the clinical findings in neuroretinitis specifically have been believed not to be associated with multiple sclerosis. Up to one third of patients with demyelinating optic neuritis may have disc edema, but to date the finding of a macular star was believed to indicate that there was some other cause.

In this retrospective study of 35 consecutive patients with the clinical syndrome of neuroretinitis, three were found to have evidence supportive of demyelinating disease. All three cases of demyelinating disease were diagnosed before the advent of the clinical picture of neuroretinitis. In one case, there was brain biopsy evidence of demyelination, and in the other two cases, the clinical findings strongly supported the presence of demyelinating disease.

It is certainly true that having multiple sclerosis does not protect you from other disease processes that may cause inflam-matory disc swelling associated with a macular star, but a least two of the three patients were screened for cat-scratch disease, and all three were evaluated for other possible causes of optic neuritis.

Perhaps a more likely scenario relates to the genotype and phenotype questions. The presumed mechanism of macular star formation in patients with neuroretinitis is accumulation of fluid within Henle’s layer, overwhelming the ability of the retina–retinal pigment epithelium complex to drain it. Although this most

com-From the Neuro-ophthalmology Division, Department of Ophthmology, University of Virginia, Charlottesville, Virginia.

Correspondence to Steven A. Newman, MD, Department of Ophthalmol-ogy, University of Virginia, P.O. Box 800715, Charlottesville VA 22908. E-mail: [email protected].