Variation in Evolving Optic Neuritis

The typical natural history of optic neuritis is subjected to important exceptions. Recognition of these exceptions has led to valuable insights regarding specific etiologies of optic neuritis. Exceptions to the natural history of recovering optic neuritis are well-defined (e.g., chronic relapsing inflammatory optic neuropathy), but exceptions to the natural history of evolving optic neuritis are less so.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Variation in Evolving Optic Neuritis Marc A. Bouffard, MD, Robert M. Mallery, MD, Yaping J. Liao, MD, PhD, Nurhan Torun, MD Background: The typical natural history of optic neuritis is subjected to important exceptions. Recognition of these exceptions has led to valuable insights regarding specific etiologies of optic neuritis. Exceptions to the natural history of recovering optic neuritis are well-defined (e.g., chronic relapsing inflammatory optic neuropathy), but exceptions to the natural history of evolving optic neuritis are less so. Methods: Medical records of patients illustrating an atypical course of evolving optic neuritis were reviewed in a retrospective manner. Each patient was treated by at least one of the authors. Results: Four patients were identified who illustrated an atypical natural history of incipient optic neuritis. Diagnoses included idiopathic optic neuritis, seropositive neuromyelitis optica spectrum disease, anti-myelin oligodendrocyte glycoprotein antibody disease, and multiple sclerosis in 1 patient each. Features of interest included an atypical temporal relationship between development of pain and onset of clinical optic neuropathy, an unusually protracted duration of pain, and an unusually long duration of worsening optic neuropathy before stabilization. Conclusions: This case series illustrates the substantial clinical heterogeneity which may be observed in the evolution of optic neuritis. The temporal relationship between development of pain and onset of clinical optic neuropathy, the duration of pain, and duration of worsening optic neuropathy before stabilization are all subjected to significant variability. Although most patients with optic neuritis present with painful vision loss which progresses over 1 week or less, careful attention to the exceptions described herein may facilitate earlier recognition of diagnostically challenging cases. Journal of Neuro-Ophthalmology 2021;41:476–479 doi: 10.1097/WNO.0000000000001310 © 2021 by North American Neuro-Ophthalmology Society Department of Neurology, Beth Israel Deaconess Medical Center (MAB), Harvard Medical School, Boston, Massachusetts; Department of Surgery, Division of Ophthalmology (NT), Harvard Medical School, Boston, Massachusetts; Department of Neurology (RMM), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Ophthalmology (YJL), Byers Eye Institute, Stanford University, Palo Alto, California The authors report no conflicts of interest. Address correspondence to Marc A. Bouffard, MD, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215; E-mail: [e-mail] 476 BACKGROUND T he landmark Optic Neuritis Treatment Trial established much of the natural history of optic neuritis, which typically entails painful, progressive vision loss over an interval of several days followed by a period of stably poor vision for several weeks and gradual improvement over several months (1–3). Vision loss which is painless, painful for over a week, or progresses for over a week is unusual and should prompt consideration of alternate diagnoses (1). Identification of exceptions to the typical natural history of optic neuritis has done much to enhance the understanding and treatment of optic neuritis. Recognition of unusual phenotypes of optic neuritis (e.g., severe vision loss, bilateral onset, and disc edema) or exceptions to its typical natural history (e.g., very poor recovery, very rapid recovery, or a chronic relapsing course) enables rapid identification of important and distinct etiologies of optic neuritis, including anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, anti-aquaporin-4 (AQP4) antibodies, and sarcoidosis (4–8). Prompt recognition of these etiologies permits optimization of type and timing of treatment, mitigating unnecessary vision loss (e.g., early plasma exchange in cases of neuromyelitis optica spectrum disease (NMOSD)-associated optic neuritis) and avoiding unnecessary iatrogenic harm (e.g., low likelihood of requiring plasma exchange in anti-MOG–associated optic neuritis to achieve a good visual outcome) (4,9,10). In contrast to the well-described natural history of recovering optic neuritis, the natural history of early, evolving optic neuritis is less well-defined. Although we agree with the statement made by the authors of the Optic Neuritis Study Group 30 years ago that vision loss which is painless or continues to progress for over 1 week should raise suspicion for an alternate diagnosis, we report here 4 patients whose early evolution of optic neuritis deviated from the expected natural history, posing diagnostic and therapeutic challenges (1). Fostering a better understanding of heterogeneity in the onset of optic neuritis may mitigate diagnostic confusion and facilitate timely treatment in a challenging patient population. Bouffard et al: J Neuro-Ophthalmol 2021; 41: 476-479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution METHODS Patients illustrating an atypical course of incipient optic neuritis were identified by fellowship-trained neuroophthalmologists in the course of routine clinical care. Medical records were subsequently reviewed in a retrospective manner by the examining physician and the first author to exclude diagnoses other than optic neuritis. Each patient was treated by at least one of the authors. All available ancillary testing, laboratory results, and neuroimaging studies were reviewed independently by the first author. RESULTS/CASE SERIES Patient 1 A 48-year-old woman with a history of systemic lupus erythematosus on hydroxychloroquine and mycophenolate mofetil, marginal cell lymphoma of the left parotid metastatic to the right lacrimal gland on ibrutinib status-post rituximab, and remote isolated transverse myelitis without subsequent demyelinating disease for over 30 years was incidentally found to have fullness of the right optic nerve without pain or vision loss. MRI orbit with gadolinium revealed right optic nerve enhancement, initially believed to reflect infiltrative disease from marginal cell lymphoma, which involved the ipsilateral lacrimal gland. There was no other clinical or radiographic suggestion of CNS metastatic disease. Serum anti-AQP4 antibody was positive at a low titer (1:2). Over the following 2 years (during which she continued B-cell targeted treatment for lymphoma and hydroxychloroquine and mycophenolate mofetil for lupus), she remained visually asymptomatic with unchanged serial examinations (fullappearing optic nerves with visual acuity 20/20–20/30 and variable peripheral arcuate visual field loss in the right eye) and fluctuating optic nerve enhancement on serial MRIs of the orbit with contrast. Five years after recognition of disc edema in the right eye, she developed her first typical attack of optic neuritis with subacute, painful vision loss in the right eye to a nadir acuity of count fingers at 39 , mild disc edema in the right eye, and right optic nerve enhancement from the globe to the ipsilateral optic tract on MRI orbit with gadolinium (Fig. 1). Serum AQP4 returned positive at a titer of .1:10,000. Lumbar puncture revealed 3–5 white blood cells (WBCs) (74% lymphocytes), 0 red blood cells (RBC), glucose 51, and protein 39) without evidence of marginal cell lymphoma. Treatment included 5 days of intravenous methylprednisolone at a dose of 1 gm/day, 5 sessions of plasma exchange, and increase in mycophenolate dose. Within 2 months, the visual acuity improved from count fingers at 39 to 20/100 in the right eye (from a premorbid baseline of 20/80, attributable to a macular hole). The blossoming AQP4 titer, classic neuroimaging findings for AQP4-associated optic neuritis, absence of Bouffard et al: J Neuro-Ophthalmol 2021; 41: 476-479 FIG. 1. MRI orbit with gadolinium demonstrates abnormal enhancement of the intraorbital right optic nerve (A), the intracanalicular right optic nerve (B), the right optic chiasm (C), and the right optic tract (D). discernible lymphomatous invasion of the CNS, lack of conspicuous lacrimal gland enlargement, response to intravenous methylprednisolone and plasma exchange, and lack of recurrence after steroid cessation favored a diagnosis of anti-AQP4–related optic neuritis rather than lymphomatous infiltrative optic neuropathy. Patient 2 A 30-year-old woman, 2 weeks postpartum, presented with 1 week of headache and blurred vision in the left eye. Visual acuities were 20/20 in each eyes with intact color vision and a subtle relative afferent pupillary defect (rAPD) in the left eye. Funduscopy revealed mild 270° disc edema in the right eye and conspicuous disc edema with peripapillary heme in the left eye. Automated perimetry (Humphrey visual field 30–2) was normal in the right eye and revealed inferior defects in the left eye. MRI brain without contrast and MRV head were normal; dedicated orbital sequences were not obtained because of initial suspicion for intracranial hypertension rather than optic neuritis. Lumbar puncture revealed 1 WBCs, 1 RBC, protein 27, glucose 61, and an opening pressure of 14 cm H2O. Serum FTA, RPR, Lyme, Bartonella, ANCA, and ACE were unrevealing. ANA was positive at a titer of 1:40. Painful eye movements and red desaturation in the left eye developed 2 weeks after disc edema was noted; reexamination revealed red desaturation in the left eye, a nowconspicuous rAPD in the left eye, and resolution of peripapillary heme in the left eye. Pain elicited by eye movement in the left eye persisted for approximately 2 weeks before subsiding. The patient was unable to undergo dedicated MRI of the orbit after the development of pain elicited by eye movement. She did not receive corticosteroid treatment. One month after her initial examination, the patient’s painful eye movements had completely resolved with improvement in red desaturation and visual field as well as resolution of disc edema in both eyes. At follow-up 6 years later, the visual acuity remained 20/20 in both eyes with normal color vision in both eyes, a subtle rAPD in the left eye, and mild optic nerve pallor in the left eye. In retrospect, this patient with transient, painful, bilateral optic neuropathy with disc edema and peripapillary heme may have had anti-MOG antibody disease; at that time, no commercially available assay was available. 477 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Patient 3 A 28-year-old previously healthy woman presented with 6 weeks of severe pain in the left eye before developing blurred vision. Initial examination 1 day after the onset of blurred vision revealed acuities of 20/25+2 in the right eye and 20/2521 in the left eye, normal color vision, no rAPD, and symmetric optic disc edema in both eyes. Automated perimetry (Humphrey 30-2 fast) revealed generalized depression in the right eye and an inferior arcuate defect in the left eye. An MRI brain with gadolinium and lumbar puncture were normal. Approximately 8 weeks after onset of eye pain, the patient reported worsening vision. Reexamination revealed acuities of 20/5022 in the right eye and count fingers at 19 in the left eye with a rAPD in the left eye and resolution of prior disc edema. MRI orbit performed at the time of worsened afferent visual function, revealed optic nerve enhancement in both eyes. Anti-MOG antibody returned positive at a titer of 1:40. and sheath with extension of the previous bilateral prechiasmatic optic nerve enhancement to include the optic chiasm. MRI brain and cervical spine redemonstrated new, enhancing lesions consistent with multiple sclerosis. Because of the unusual, progressive course of vision loss, PET-CT skull base to midthigh was performed but did not reveal evidence of sarcoidosis, systemic vasculitis, or malignancy. Brain biopsy was deferred given the potential morbidity posed by the locations of the active lesions. She underwent 5 sessions of plasma exchange and another 5 days of IV methylprednisolone followed by a slow oral prednisone taper. Two weeks later (7 weeks after onset of vision loss), the visual acuity had improved to 20/400 in the right eye but worsened to 20/400 in the left eye. Goldmann perimetry revealed a large central scotoma in both eyes. Rituximab was initiated. At follow-up 2 weeks later (9 weeks after onset of vision loss), visual acuities had improved to 20/40 in the right eye and 20/200 in the left eye with profound dyschromatopsia and mild optic disc pallor in both eyes. Patient 4 A 42-year-old woman with a history of recently diagnosed multiple sclerosis presented for 3 weeks of progressive, painless vision loss in both eyes which began contemporaneously with 3 days of IV methylprednisolone for an attack of transverse myelitis. At the time of initial examination 3 weeks after onset of vision loss, visual acuities were 20/200 in the right eye and 20/30 + 1 in the left eye with dyschromatopsia and rAPD in the right eye. Both optic nerves appeared normal on funduscopic examination, and peripapillary RNFL values on OCT were within the normal range (mean peripapillary RNFL 89 mm in the right eye and 94 mm in the left eye). Automated perimetry (Humphrey 24-2 fast) revealed generalized depression on total deviation with a dense inferior altitudinal defect on pattern deviation in the right eye and generalized depression sparing the superonasal quadrant in the left eye. Serum AQP4 and MOG antibodies returned negative. MRI orbit revealed short patches of abnormal enhancement affecting both prechiasmatic optic nerves and the intraorbital portion of the left optic nerve. MRI brain demonstrated an increased number of enhancing and nonenhancing lesions compared with a study 3 months prior. Lumbar puncture revealed 0 WBCs, 0 RBC, a protein of 25, a glucose of 64, and 8 oligoclonal bands unique to the cerebrospinal fluid. Further steroids were deferred given the diagnosis of MS, 3 week interval between onset of vision loss and examination, and recent administration of IV methylprednisolone administered at outset for vision loss (although given for transverse myelitis). At follow-up 2 weeks later (5 weeks after onset of vision loss), visual acuities continued to worsen to count fingers at 39 in the right eye and 20/200 in the left eye with dyschromatopsia in the left eye. Repeat MRI orbit revealed increased enhancement of the left intraorbital optic nerve 478 CONCLUSIONS This case series illustrates the substantial clinical heterogeneity which may be observed in the evolution of early optic neuritis. The temporal relationship between development of pain and onset of clinical optic neuropathy, the duration of pain, and duration of worsening optic neuropathy before stabilization are all subjected to significant variability. Although the observations made by the Optic Neuritis Study Group are undoubtedly correct in most cases, careful attention to these exceptions may facilitate earlier recognition of diagnostically challenging cases. The potential for unusually slow, progressive vision loss is illustrated by Patients 2, 3, and 4 (1,3). Patient 3 did not develop profound vision loss until 8 weeks after onset of eye pain and mild afferent visual dysfunction. Vision loss in patient 4 began contemporaneous with intravenous methylprednisolone administration for transverse myelitis and progressed both clinically and radiographically for up to 7 weeks. The duration of progressive vision loss in each of these patients exceeded the point of time by which most patients with idiopathic or multiple sclerosis–associated optic neuritis begin to exhibit some recovery (3). Dissociation of radiographic findings from subclinical or pauci-clinical disease for long periods of time is illustrated by Patient 1, whose AQP4 antibody titer increased from 1:2 to .1:10,000 over a period of 2 years. Optic neuritis in patients with AQP4 seropositivity typically involves discrete, fulminant attacks of optic neuritis, between which there is no ongoing damage to the optic nerve as demonstrated by stable peripapillary RNFL thickness on OCT (11). We hypothesize that this patient’s immunosuppression led to this unusual state of radiographic optic nerve inflammation with minimal clinical manifestations. The long quiescent period between transverse myelitis and Bouffard et al: J Neuro-Ophthalmol 2021; 41: 476-479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution recognition of incipient optic neuritis approximately 30 years later might suggest a case of NMOSD more indolent than is typical (12,13). Atypically indolent lymphomatous infiltration cannot be definitively excluded without biopsy of the optic nerve; however, the eventual typical attack of NMOSD-like optic neuritis (both clinically and radiographically), blossoming anit-AQP4 titer, lack of evidence of marginal cell lymphoma on lumbar puncture, lack of radiographic evolution consistent with worsening lymphoma, and recovery with corticosteroids and plasma exchange favors an unusual presentation of AQP4-associated optic neuritis rather than the coincidence of an unusual presentation of two diseases rather than one. Pain with eye movement typically accompanies or precedes vision loss by several days, resolving in less than a week (1). However, Patients 2 and 3 demonstrate an unusual temporal relationship between pain and the onset of optic disc edema or vision loss. Patient 2 developed pain late in the course (2 weeks after onset of optic neuropathy) which persisted for an unusually protracted duration (2 weeks). Conversely, Patient 3, subsequently diagnosed with MOGAD, reported eye pain for over 6 weeks before developing a conspicuous optic neuropathy. These patients embody important caveats to the natural history of optic neuritis, which apply to idiopathic optic neuritis (Patient 2), seropositive NMOSD (Patient 1), MOGAD (Patient 3), and multiple sclerosis (Patient 4). Recognition of the clinical heterogeneity in the onset of optic neuritis can expedite diagnosis and facilitate early and appropriate treatment, limiting visual morbidity. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. A. Bouffard, N. Torun, R. M. Mallery, and Y. J. Liao; b. Acquisition of data: M. A. Bouffard, N. Torun, R. M. Mallery, and Y. J. Liao; c. Analysis and interpretation of data: M. A. Bouffard, N. Torun, R. M. Mallery, and Y. J. Liao. Category 2: a. Drafting the manuscript: M. A. Bouffard, N. Torun, R. M. Mallery, and Y. J. Liao; b. Revising it for intellectual content: M. A. Bouffard, N. Torun, R. M. Mallery, and Y. J. Liao. Category 3: a. Final approval of the completed manuscript: M. A. Bouffard, N. Torun, R. M. Mallery, and Y. J. Liao. Bouffard et al: J Neuro-Ophthalmol 2021; 41: 476-479 REFERENCES 1. Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol. 1991;109:1673–1678. 2. Beck RW, Cleary PA, Anderson MM, Keltner JL, Shults WT, Kaufman DI, Buckley EG, Corbett JJ, Kupersmith MJ, Miller NR, Savino PJ, Guy JR, Trobe JD, McCrary JA, Smith CH, Chrousos GA, Thompson SH, Katz BJ, Brodsky MC, Goodwin JA, Atwell CW; Optic Neuritis Study Group. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326:581–588. 3. Beck RW, Cleary PA, Backlung JC; The Optic Neuritis Study Group. The course of visual recovery after optic neuritis. Ophthalmol. 1994;101:1771–1778. 4. 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