Neuroretinitis in Patients with Multiple Sclerosis Kyle E. Williams, MD, Lenworth N. Johnson, MD Purpose: To present a case series of three patients with neuroretinitis associated with multiple sclerosis. Design: Retrospective, noncomparative, consecutive, interventional case series. Participants: Thirty-five consecutive patients with neuroretinitis. Methods: The records of 35 consecutive patients with neuroretinitis were reviewed for prior, concurrent, or subsequent development of multiple sclerosis. Main Outcome Measures: Presentation, clinical course, and diagnosis of multiple sclerosis. Results: Three of 35 patients (8.6%) with neuroretinitis were diagnosed with multiple sclerosis by the 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 neuroretinitis. Conclusions: Neuroretinitis can be an associated manifestation of multiple sclerosis. The possible association 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 neuroretinitis, a disorder characterized by optic disc edema accompanied by macular exudates.1 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.1– 4 The symptoms of unilateral decreased vision may be preceded by a virallike prodrome.1 Physical findings of recent onset neuroretinitis typically include optic disc swelling and peripapillary exudative detachment of the retina, followed by vitreous cells and macular or peripapillary hard exudates.5–7 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.8 Other distinguishing features of neuroretinitis are that eye pain and dramatic visual recovery are uncommon.9 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.7,8 Furthermore, previous case series found no increased risk of developing multiple sclerosis after an episode of neuroretinitis.9,10 ConseOriginally 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]. © 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
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 neuroretinitis 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 examination 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 Schumacher 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 evidence, 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 evidence.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 ISSN 0161-6420/04/$–see front matter doi:10.1016/S0161-6420(03)00663-8
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Figure 1. Patient 1. Right fundus showing hemimacular “star” exudates.
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 2. A, T2 weighted brain magnetic resonance imaging (MRI) scan of patient 2 showing the occipital region increased signal intensity (arrow) of tumefactive multiple sclerosis. B, T2 weighted brain MRI scan 1 week later, and after intravenous corticosteroid treatment, showing regression of the hyperintensity.
Figure 4. Left fundus of patient 3 showing optic disc edema with exuberant peripapillary and macular exudates.
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Figure 5. Left fundus of patient 3 showing optic disc edema with peripapillary exudates and macular “star” exudates.
Williams and Johnson 䡠 Neuroretinitis in Patients with Multiple Sclerosis years prior. A previous MRI scan of the brain and spinal cord showed normal results, as did cerebrospinal fluid studies. There was no oligoclonal banding. A previous visual evoked response documented prolonged P100 for the right side. Her history was otherwise normal except for a fall at age 2 years, when she sustained facial fractures and a concussion, and frequent holocranial headache since she was 15 years of age. On examination, her visual acuity was severely reduced to 2/200 in the right eye and mildly reduced to 20/40 in the left eye. There was a marked (1.2 log unit) right afferent pupillary defect, right eye superior altitudinal visual field defect, and right optic disc edema. Optic neuritis was diagnosed, and she was admitted for intravenous methylprednisolone. A repeat brain MRI scan showed normal results. Further evaluation showed normal results, including a chest radiograph, Bartonella henselae (cat-scratch disease) immunoglobulin G and immunoglobulin M tests, Borrelia burgdorferi (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 presentation, 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 measured 20/20 bilaterally. Confrontational visual field testing at bedside 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 prednisone taper then interferon  1B (Betaseron, BERLEX Laboratories, 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, urinalysis, reactive plasma reagent testing, Venereal Disease Research Laboratories testing, rheumatoid factor testing, coagulation studies, cryptococcal antigen testing, and cerebrospinal fluid studies; 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) consistent 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. Automated perimetry showed a left eye centrocecal visual field defect. There was no afferent pupillary defect. There was mild right optic
disc edema and moderate left optic disc edema with optic nerve pallor. The peripapillary exudate seen on examination 1 year previously was notably absent. Two months later, the left eye vision had improved to 20/30, and marked peripapillary and macular exudate was seen surrounding the edematous left optic disc. This was consistent with recurrent neuroretinitis. The right optic disc was flat. The patient had recently restarted interferon  1B 250 g subcutaneously every other day for multiple sclerosis. Patient 3. A 44-year-old woman with multiple sclerosis was evaluated for progressive vision loss of the left eye. Ten years earlier, she experienced left eye vision loss associated with optic disc edema. An MRI scan at that time showed demyelinating lesions compatible with multiple sclerosis. Her other chronic symptoms included numbness and paresthesias of the hand, pain in the lower extremities, and common migraine headache. She had 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 pupillary 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, sedimentation rate, B. burgdorferi testing, B. henselae testing, purified protein derivative skin testing for tuberculosis, fluorescent treponemal antibody testing, reactive plasma reagent testing, Brucella titer, Mantoux skin test, toxoplasmosis titer, angiotensin converting enzyme testing, tularemia testing, and serum protein electrophoresis, 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 hospitalization the same year were normal. Treatment was initiated with systemic corticosteroid. The retinitis 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.12 The Optic Neuritis Treatment Trial (ONTT) elucidated the increased risk of developing demyelinating disease after optic neuritis.13 The results of the ONTT showed that the cumulative risk of developing clinically definite multiple sclerosis for all enrolled patients was 14% in 2 years and 30% within 5 years after a first episode of optic neuritis.14 This risk of conversion to multiple sclerosis 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.14 In the
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Figure 6. Patient 3. Left fundus fluorescein angiogram showing diffuse disc leakage in early (A) and late (B) frames.
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 prospectively for 1 to 2 years experienced multiple sclerosis.10 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 neuroretinitis, because retrospective patient analyses have high rates of missed diagnoses.15,16 In the study of Parmley et al,10 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 examination 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 follow-up period and rigorous neurologic examination, multiple sclerosis might have been identified in patients who had neuroretinitis. We identified three patients with neuroretinitis that occurred 4, 1, and 10 years, respectively, after the initial manifestation of multiple sclerosis. Consequently, neuroretinitis 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.11 Radiographic evidence of demyelinating central nervous system lesions alone is insufficient for diagnosis. However, MRI scan is a vital test to support the diagnosis of multiple sclerosis, with the positive predictive value of MRI for diagnosing multiple sclerosis being 23% to 65%.17 All three patients in our case series had clinically definite multiple sclerosis, and two of the three had evidence
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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.18 Of patients already diagnosed with clinically definite or probable multiple sclerosis on entry, 10% (6 of 60) had normal brain MRI scan results.19 The ONTT, therefore, may reflect the MRI findings 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.20,21 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.22 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 occurrence of neuroretinitis.9,10 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 population—approximately 0.1%.23 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.24 –30 Unlike direct infections of the retina or choroid, infectious organisms rarely are isolated from vitreous or ocular tissues in neuroretinitis.25 Laboratory and radiographic evidence likewise supports no other systemic diagnosis in our patient, particularly sarcoidosis and cat-scratch disease. Neuroretinitis may recur, as noted in one of our three patients with multiple sclerosis, and recurrence has been reported in the literature on neuroretinitis.31 A subset of patients demonstrat-
Williams and Johnson 䡠 Neuroretinitis in Patients with Multiple Sclerosis ing retinal vasculitis with aneurysms and neuroretinitis was previously described in a series of 10 patients.32 In patient 3 of our series, our patient had retinal periphlebitis, but unlike the patients with retinal vasculitis with aneurysms and neuroretinitis (IRVAN), she had no retinal aneurysms or evidence of capillary nonperfusion. Periphlebitis, as in our patient with peripheral venous sheathing, is present in as much as 11.5% to 18% of patients with multiple sclerosis.33–37 There is a lack of a clearly identifiable pathophysiologic process regarding the location and nature of injury in neuroretinitis. Dreyer et al1 and Gass6 suggested that vascular damage results in leakage of proteinaceous fluid, which spreads from the optic disc into the outer plexiform layer of 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 response, are believed to account for the prolonged leakage, even after removing the causative agent.38,39 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 neuroretinitis. The third patient (patient 1) began interferon  (Avonex) treatment concurrently with the appearance of a macular star exudate on funduscopic examination. The clinical 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 investigation. 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 suggest that neuroretinitis is a late finding in multiple sclerosis, 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.8 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. Finally, 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 neuroretinitis 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 The earliest recognition of disease was descriptive. The word for 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 longevity has been our lack of understanding of the true pathophysiologic process behind even common disease processes. Over the last two centuries, better understanding of inflammatory, 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 responsible 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 analFrom the Neuro-ophthalmology Division, Department of Ophthmology, University of Virginia, Charlottesville, Virginia. Correspondence to Steven A. Newman, MD, Department of Ophthalmology, University of Virginia, P.O. Box 800715, Charlottesville VA 22908. E-mail:
[email protected].
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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 characteristic 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, syphilis, 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 inflammatory 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-
