International Journal of Neuroscience, 2014; Early Online: 1–8 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.896912


White matter involvement beyond the optic nerves in CRION as assessed by diffusion tensor imaging Ayse Ilksen Colpak,1 Asli Tuncer Kurne,2 Kader Karli Oguz,3 Arzu Ceylan Has,5 Anil Dolgun,4 and Tulay Kansu3 Int J Neurosci Downloaded from by Washington University Library on 05/26/14 For personal use only.


Institute of Neurological Sciences and Psychiatry; 2 Departments of Neurology; 3 Radiology, and; 4 Biostatistics, Hacettepe University, Sihhiye, Ankara, Turkey, and; 5 Bilkent University, National Magnetic Resonance Research Center, Bilkent, Ankara, Turkey Background: Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory optic neuropathy, characterized by relapses and remissions in patients with normal brain and spinal magnetic resonance imaging (MRI). Discrepancy from other demyelinating diseases is important, and it is still uncertain whether CRION is restricted to the optic pathways or it affects other brain white matter (WM) structures. Objective: To assess WM structure in patients with CRION by using diffusion tensor imaging (DTI). Methods: DTI was performed in six CRION patients and six age- and sex-matched healthy controls on a 3 T scanner. Tract-based spatial statistics (TBSS) was used for voxelwise statistical analysis of DTI data. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) measures were obtained. Results: TBSS analysis revealed two different patterns of WM alterations in patients with CRION. The optic chiasm and connected structures had significantly higher FA and lower RD, AD and MD in the patients than in the healthy controls. On the other hand, anterior frontal bundles of inferior fronto-occipital tracts, left uncinate fascicule and internal capsule showed decreased FA and increased RD. No correlation was found between the clinical variables and diffusion measures. Conclusion: WM appearing normal on brain MRI shows widespread abnormalities in a cohort of CRION patients as assessed by DTI. KEYWORDS: optic neuropathy, multiple sclerosis, neuromyelitis optica, diffusion tensor imaging, white matter diseases, recurrent

Introduction Optic neuritis, most common form of optic neuropathy, is defined as inflammatory and demyelinating involvement of the optic nerves. In the majority of cases, optic neuritis is associated with multiple sclerosis (MS) and is a familiar presenting symptom of the disease. Another, but distinct demyelinating disease of the central nervous system (CNS) is neuromyelitis optica (NMO) in which there is a preferential involvement of the optic nerves and spinal cord. The onset of optic neuritis and myelitis may be coincident or separated by several months. Although once considered a subtype of MS, NMO has been recognized as a distinct disease since the discovery of NMO-IgG (immunoglobulin G) [1–3]. Received 29 January 2013; revised 31 January 2014; accepted 18 February 2014. Correspondence: Dr. Ayse Ilksen Colpak, M.D., Institute of Neurological Sciences and Psychiatry, Hacettepe University, Sihhiye, Ankara, 06100 Turkey. E-mail: [email protected]

Magnetic resonance imaging (MRI) of the brain and orbits with gadolinium-based contrast material has become the keystone of evaluation in patients with optic neuritis. However, a small group of patients with relapsing and remitting inflammatory optic neuropathy was shown to have no lesion on brain MRI and defined as chronic relapsing inflammatory optic neuropathy (CRION) [4]. Patients with CRION may present with frequent relapses, at least one of which may be extremely severe. Most of these patients become steroiddependent. Immunosuppressive treatment allows discontinuation of steroids and can prevent or reduce further relapses in CRION, which is dissimilar to MS with respect to clinical characteristics and natural history [4, 5]. The diagnosis of CRION is based on the presence of the seronegativity for NMO-IgG and exclusion of other causes of inflammatory optic neuritis such as sarcoidosis, collagenous tissue disorders [4–7]. Brain and spinal MRI with no demyelinating or inflammatory lesion also help in the differential diagnosis of CRION. Altogether, 1

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A. I. Colpak et al.

CRION could be entirely separate entity from MS and NMO. Determination of this discrepancy from MS or NMO provides physicians to predict the prognosis and to decide the long-term treatment, accurately. Diffusion tensor imaging (DTI) is an advanced MRI technique that gives the opportunity to evaluate the tissue integrity, mainly the white matter (WM). Region-ofinterest (ROI) based DTI studies have the disadvantage of lack of reproducibility due to accurate positioning, compared to tract-based spatial statistics-DTI (TBSSDTI). TBSS, a part of the FSL 4.0 software package (Centre for functional MR imaging of the Brain, Oxford University, Oxford, UK), enables assessment of voxelwise statistical diffusion tensor analysis of the whole brain. It is an established and widely accepted voxelbased analytic approach and useful when evaluating the WM changes in a particular disease in comparison to a group of either healthy controls or patients with another disease [8]. A number of DTI studies demonstrated mean diffusivity (MD) and fractional anisotropy (FA) alterations of normal-appearing white matter (NAWM) of MS and NMO patients [9–16]. In this study, our purpose was to test the hypothesis that brain WM alterations occur in CRION as assessed by DTI. We also aimed to explore whether the WM alterations occur mainly due to Wallerian degeneration of the optic nerve involvement or demyelination also contributes to it.

Materials and methods Subjects This prospective study was approved by the local institutional review board. A written informed consent was obtained from all the participants. The patients were retrieved from our neuro-ophthalmology and neuro-immunology clinical database. Among 598 patients with optic neuritis, 16 patients (2.6%) were diagnosed as CRION, and we focused on six of whom fulfilled the inclusion criteria and accepted to participate in the study. For patients, inclusion criteria of this study were (1) well-established clinical diagnosis of CRION with recurrent, unilateral, sequential, painful, central vision loss attacks with response to steroids, relapse upon withdrawal of steroids and a follow-up period of more than 3 years [4]; (2) no acute relapse of optic neuritis or corticosteroid use within the last 2 months of imaging study; (3) absence of WM and/or cortical lesions in brain parenchyma on brain and spinal MRI and (4) normal cerebrospinal fluid (CSF) findings with seronegativity of NMO-IgG and no oligoclonal bands. Exclusion criteria were presence of lesions on brain and spinal MRI and associated neuropsychiatric or systemic illness like sarcoidosis,

collagenous tissue disorders, diabetes mellitus and hypertension with a potential neurologic effect. Although we did not perform specific tests on hand dominance, our patients and controls had a preference of right hand as ascertained by hand preference (more skillful hand) in special tasks such as handwriting, cutting something. Healthy control subjects were volunteers with no neuropsychological or systemic disease, and all of them had normal brain MRI.

Methods A neuroradiologist (KKO) with an experience of over 15 years evaluated structural MRI studies and assessed eligibility of the patients and control subjects for the study.

Image acquisition All imaging studies were performed on a 3 T MR scanner (Magnetom, Trio TIM system, Siemens, Germany) equipped with an eight-channel phase-array head coil. Structural brain MR pulse sequences were axial T1W SE (TR/TE, 500/20 ms), coronal T2W fast SE (TR/TE, 4500/100 ms) and axial fast FLAIR (TR/TE/TI, 9500/100/2100 ms) with a slice thickness of 5 mm and 10% interslice distance. No contrast media were administered to patients. DTI of the entire brain applied single-shot echoplanar imaging sequence and was performed in the axial plane, parallel to the anterior-posterior commissures (TR/TE: 8020 /83 ms, maximum b factor: 1000 s/mm2 , 60 independent directions, field of view: 23 cm, matrix: 128 × 128, 64 sections with 2-mm thickness without intersection gap, voxel size: 2 mm × 2 mm × 2 mm).

Clinical evaluation Six patients with CRION and six age- and gendermatched healthy control subjects were included in the study. All patients underwent a detailed neuroophthalmological and neurological examination, including visual acuity (Snellen visual acuity chart), color vision, eye movements, relative afferent pupillary defect, fundus examination and automatic visual field analysis. Age at disease onset, the number of relapses, duration of disease, final visual acuity and response to steroid therapy and other immunosuppressive treatment were reviewed. Blood pressure measurement was done. Laboratory tests included blood glucose level, total blood count, renal and liver function test, serologic markers such as antinuclear antibodies, anti-SS-A antibody, anti-SS-B antibody, anti-cardiolipin anti-body, antiphospholipid antibodies IgM and IgG, anti-ds DNA, lupus anticoagulant, erythrocyte sedimentation rate, International Journal of Neuroscience

Diffusion tensor imaging in CRION 3

angiotensin-converting enzyme and C-reactive protein. CSF was analyzed for protein, glucose, oligoclonal bands and cell content. Patients were screened for NMO-IgG and were shown to be seronegative.

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Data processing and analyses We used TBSS for voxelwise statistical analysis of DTI data. After preprocessing of the diffusion-weighted data, including head motion and eddy current correction, diffusion tensor fitting (FSL DTIFit), FA, MD, axial diffusivity (AD), radial diffusivity (RD) were computed. FA maps were registered and aligned to the average space as input for TBSS, and the thinned mean FA skeleton was computed. Permutation-based inference with 500 permutations was performed for voxelwise statistics. Resulting threshold-free cluster enhancement output was corrected for multiple comparisons, and family wise error-corrected maps were obtained with p values less than 0.05. Standard cluster-based thresholding corrected for multiple comparisons, comprising Gaussian-smoothing, thresholding of the smoothed data at a cluster-forming t threshold of two and finally, formation of the contiguous clusters of supra-threshold voxels (using 26-neighbor connectivity) were done. The total number of voxels with significant changes in diffusion metrics in FSL was calculated, by separating these clusters into each hemisphere using freeview (http:// WM clusters with significant change of FA, MD, AD and RD on the corrected threshold-cluster extend voxel maps were delineated as ROIs and registered to Montreal Neurological Institute (MNI) anatomical template. Using Johns Hopkins University WM tractography and the International Consortium for Brain Mapping DTI81 WM atlases included in FSL, those ROIs were named, and the mean values of FA, MD, AD and RD of the ROIs were calculated for each subject and groups. Statistical analyses were done using the software SPSS for Windows, version 17.0 (SPSS, Chicago, IL). Mann-Whitney U test and chi-square test were used to test group differences in terms of age, gender, handedness, age at disease onset, disease duration and the number of relapses. p Values < 0.05 were considered significant. For correlation between the duration of disease, the number of optic neuritis relapses, visual acuity and diffusion metrics, Spearman correlation coefficient was used.

Results Patients and controls were similar in distributions of age, gender and handedness statistically (all p > 0.05). Demographic and clinical features of the patients are  C

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summarized in Table 1. The mean age of patients was 40.2 (range, 27–56 ±10.2) years, and five of six patients were female. Mean total duration of the disease was 124 (range, 36–276 ± 98.3) months, median number of optic neuritis relapses per patient was eight (range, 4–17 ± 5.1) and the median visual acuity of the worst eye was 0.06 (range, 0.001–0.3). The patients had been treated with methylprednisolone pulse therapy (1 g intravenous3 days) for each episode of optic neuritis, and at the time of scan all patients had been taking methotrexate for at least 6 months.

Diffusion tensor imaging The total number of voxels with significant change compared to the controls is given in Table 2 for each diffusion metrics. Both regions of a significant increase and decrease in FA and diffusivity components were found; however FA increase, RD decrease and AD increase were dominant and concordant with each other. This dominance was not observed in MD. These changes were observed bilaterally, as also assessed by low asymmetry index. TBSS analysis (Figure 1) revealed that optic chiasm of the patients had higher FA and lower RD, AD and MD than the healthy controls. The cerebellum, right superior cerebellar peduncle, optic chiasm, body and splenium of the corpus callosum (CC), left thalamus, posterior cingulum and bilateral posterior bundles of inferior fronto-occipital tracts, inferior longitudinal fasciculi were affected by increased FA, decreased RD, MD. Anterior frontal bundles of inferior fronto-occipital tracts, left uncinate fascicule and left internal capsule showed decreased FA and increased RD. Mean values of significant clusters, their x, y and z coordinates according to MNI atlas and corresponding WM structures according to the WM atlases are given in Table 3.

Correlation with clinical variables None of the clinical variables showed a correlation with DTI measures (p > 0.05).

Discussion Although some authors have regarded CRION as a subtype of NMO or MS, it presents a distinct clinical course with recurrent optic neuropathy episodes as the sole manifestation and reveals no abnormality on brain and spinal MRI. With DTI that is extremely sensitive to WM pathology, we inquired whether CRION is a disorder of mainly optic pathways or rather a disease of WM with clinical manifestations of the most prominently affected structure, the optic nerves. Our data suggest WM, which






Pt 4

Pt 5

Pt 6





OD: 0/12 OS: 1/12

OD: 20/20 OS: HM

OD: 20/50 OS: 20/70

OD: 11/12 OS: 0/12

OD: 0/12 OS: 0/12

OD: NLP OD: 0/12 OS: 20/200 OS: 11/12

OD: CF OS: 20/50

OD: 20/70 OD: 11/12 OS: 20/200 OS: 5/12

OD: marked constriction OS: marked constriction OD: full OS: marked constriction

OD: nasal constriction OS: marked constriction OD: central scotoma OS: mild constriction OD: NA OS: full

OD: full OS: central scotoma

Left (+)


Right (+)

Right (+)

Left (+)

Left (+)

OD: temporal pallor OS: optic atrophy OD: temporal pallor OS: optic atrophy OD: optic atrophy OS: optic atrophy OD: optic atrophy OS: normal OD: optic atrophy OS: optic atrophy OD: temporal pallor OS: optic atrophy Negative

C5–6 bulging disc Negative




C4–5 bulging disc





Cervical spine MRI


Steroid response









ANA: 1/100 (+)


ANA: 1/320 (+)



Other serologic markersc




Azathioprine Methotrexate

Azathioprine Methotrexate


Immune suppressive treatment

CF: counting fingers, EOM: extraocular movements, HM: hand motion, NA: not applicable, NLP: no light perception, OD: occulus dexter, OS: occulus sinister, Pt: patient, RAPD: relative afferent pupillary defect. a By Snellen chart. b Visual acuity of Pts 2 and 5 is improved after treatment. c Antinuclear antibodies (ANA), anti-SS-A antibody, anti-SS-B antibody, anti-cardiolipin anti-body (aCL), anti-phospholipid antibodies (aPL) IgM and IgG, anti-ds DNA, lupus anticoagulant, erythrocyte sedimentation rate (ESR), angiotensin-converting enzyme (ACE) and C-reactive protein (CRP).

11 (5/6)

4 (2/2)

7 (1/6)

5 (1/4)


OD: 12/12 OS: 0/12


Pt 3

4 (2/2)

OD: 20/20 OS: HM




Visual field

Pt 2

17 (7/10)

Color vision


Visual acuitya,b

Pt 1

Follow-up duration (year)

Current age/sex/ age of onset

Patient number

Number of ON attacks Total (R/L)

Patients with the diagnosis of chronic relapsing inflammatory optic neuritis (CRION) (n = 6).

Table 1.

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Diffusion tensor imaging in CRION 5 Table 2.

Number of voxels with significant differences in diffusion metrics in patients CRION compared to healthy control subjects.

Number of voxels

FAp > FAc

FAp < FAc

MDp > MDc

MDp < MDc

ADp > ADc

ADp < ADc

RDp > RDc

RDp < RDc









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AD: axial diffusivity, c: controls, FA: Fractional anisotropy, MD: mean diffusivity, p: patients, RD: radial diffusivity.

appears normal on brain MRI, shows alterations in a cohort of CRION patients. In this study, we investigated individual diffusivities (RD, AD) along with FA, and MD, which have been most commonly used diffusion parameters. The main reason for that was to avoid missing WM alterations in which FA is unchanged due to proportional changes in other diffusion components [17]. FA, which is accepted as a measure of WM integrity, is closely related with axonal caliber and surrounding myelin. Thus, an increase in FA may reflect either increased axonal caliber, myelin thickness and fiber coherence in a given direction or a combination of these pathological processes [18,19]. While AD and RD measure the diffusion of water parallel and perpendicular to WM fibers respectively, MD gives a measure of the aver-

age molecular motion independent of the constraints of tissue boundaries. Rather, cellular size, compartmental fluid imbalance and degradation products affect MD [20]. In our patient group, the dominant DTI finding in the target WM structure, namely the optic chiasm was the increase of FA, decrease of RD and MD. Changes in posterior inferior fronto-occipital tracts and CC showed similar DTI abnormalities, suggestive of concordant histopathological changes in WM connections related to optic pathways. Increased intracellular water resulting in cellular swelling, fiber reorganization or remyelination can account for an increase in FA and decrease in RD and MD. Reduction in FA is usually accompanied by RD increase, and these changes could reflect a de/dysmyelinating process [21]. This was the situation with anterior frontal bundles of

Figure 1. TBSS (FWE-corrected) maps show significant clusters with increased (red) and decreased (blue) FA (A), RD (B), AD (C) and MD (D) compared to healthy control subjects at p < 0.05. FA skeleton projected on mean FA map is shown in green.  C

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A. I. Colpak et al.

Table 3. Mean values of significant clusters, their X, Y, Z coordinates according to Montreal Neurological Institute atlas, corresponding white matter structures according to the white matter atlases.

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WM structure R superior cerebellar peduncle L cerebellum Optic chiasm L IFOF R IFOF L uncinate fasciculus L cingulum R cingulum L acoustic radiation R acoustic radiation L anterior thalamic radiation L optic radiation R optic radiation L SLF R SLF Splenium of CC Body of CC R inferior parietal lobule L visual cortex




FAp /FAc

MDp /MDc (×10−3 )

ADp /ADc (×10−3 )

RDp /RDc (×10−3 )

82 108 87 125 54 114 112 79 143 43 109 112 62 125 41 83 86 30 105

76 51 126 119 113 138 80 73 110 108 96 51 58 86 83 91 97 97 76

43 48 58 63 63 61 68 94 78 75 88 94 94 98 64 92 96 84 68

0.36/0.31 0.25/0.21 0.15/0.11 0.57/0.47 0.54/0.43 0.40/0.32 0.39/0.28 0.39/0.27 0.27/0.19 0.34/0.32 0.39/0.33 0.35/0.24 0.51/0.28 0.47/0.44 0.43/0.35 0.83/0.78 0.74/0.72 0.30/0.24 0.23/0.19

1.27/1.49 0.70/0.71 1.09/1.71 0.75/0.85 0.81/0.85 0.80/0.85 0.73/0.77 0.79/0.80 0.78/0.90 0.70/0.73 1.14/1.18 0.82/0.87 0.78/0.83 0.77/0.78 0.73/0.75 0.72/0.76 1.04/0.88 0.77/0.81 1.41/1.51

1.57/1.77 0.91/0.86 1.20/1.82 1.24/1.31 1.27/1.28 1.23/1.10 1.01/0.95 1.10/1.04 1.03/1.08 1.23/1.01 1.65/1.46 1.12/1.11 1.21/1.16 1.20/1.12 0.94/1.04 1.65/1.70 2.01/1.73 1.03/1.02 1.68/1.44

1.30/1.05 0.62/0.66 1.10/1.70 0.49/0.62 0.65/0.67 0.59/0.69 0.61/0.64 0.64/0.65 0.63/0.80 0.89/0.61 0.95/1.02 0.62/0.75 0.55/0.64 0.57/0.59 0.60/0.61 0.26/0.29 0.56/0.43 0.64/0.69 1.2/0.99

AD: axial diffusivity, c: controls, CC: corpus callosum, FA: fractional anisotropy, IFOF: inferior fronto-occipital fasciculus, L: left, MD: mean diffusivity, p: patients, R: right, RD: radial diffusivity, SLF: superior longitudinal fasciculus.

inferior fronto-occipital tracts, left uncinate fascicule and left internal capsule in our patient group. We also found abnormalities in the WM fibers with which the optic radiation mingles with such as the inferior occipitofrontal fasciculus and the superior longitudinal fasciculus, as well as the visual cortex. A more heterogeneous and complicated pathological processes, rather than uniform demyelination or axonal degeneration, may explain these profound and complicated DTI changes in the WM of the brain in our patients with CRION. DTI has been widely used in studies conducted to understand the pathogenesis of CNS demyelinating diseases, mainly MS. DTI studies in MS patients have demonstrated that a decrease in FA and increase in MD values is more widespread than T2/FLAIR hyperintense lesions that have commonly been used as a major follow-up parameter of MS [10, 11]. Despite variations depending on the clinical subtype of MS, chronic T2-hyperintense lesions have lower FA than NAWM and acute lesions have even significantly lower FA than chronic lesions, which may reflect axonal loss [11, 22, 23]. Our findings, predominantly increased FA and decreased RD in the WM do not agree with those previous DTI changes in NAWM or demyelinating lesions of MS. However, similar to our results, T1-hyperintense lesions in the brain tissue affected by MS showed decreased MD and increased FA compared to T1-hypo- or isointense lesions in one study, and the authors attributed these findings to the presence of remyelination confirming hyperintensity on T1-weighted imaging [24].

On the contrary to previous MS studies revealing a high correlation between DTI values and clinical disability in MS patients [11, 22, 25], we failed to find such a correlation with clinical measures, including the severity of vision loss in patients with CRION. This might have resulted from the limited number of patients in our cohort. Advanced MRI studies on NMO are less than those on MS. Based on the presence of WM alterations outside the T2 hyperintense lesions in MS patients, microscopic changes in NMO patients have been investigated by DTI. A previous study reported an increase in MD in normal-appearing grey matter (NAGM), with no change in NAWM of NMO patients compared to healthy control subjects [14]. Yu et al. [15] found that abnormal diffusion in WM was limited to the tracts connected with optic nerves and found a correlation between diffusion indices of corticospinal tract-optic radiation and clinical measures. In another study, NAWM showed no difference in MD and FA values, despite a significant difference in FA of NAGM connected with motor and visual systems. On the other hand, voxelwise analysis showed a reduced FA in bilateral optic pathways involving the lateral geniculate nuclei, which might suggest a secondary anterograde axonal degeneration in NMO [16]. Although TBSS is a well-established technique for assessment of whole-brain changes, most peripheral WM alterations may not be well displayed due to restriction of calculations to the FA skeleton. Additionally, our highresolution images without a gap between slices (2 mm × International Journal of Neuroscience

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Diffusion tensor imaging in CRION 7

2 mm × 2 mm voxel size) enabled us to evaluate the optic chiasm; however, we were not able to detect changes in intraorbital segments of the optic nerves due to potentially high partial volume effects and possibly atrophic optic nerves. Main limitation of our study is scarce number of our patients. However, given the rarity of the disease and applicability of this technique to six or more subjects, we believe that our study provides invaluable insight into WM alterations occurring in CRION. Another limitation is the effect of methotrexate on WM integrity due to methionine depletion and demyelination [26]. Methotrexate is one of the commonly used agents in childhood cancers. DTI study in childhood cancer survivors treated with high-dose methotrexate showed that white matter FA is decreased in the right inferior frontooccipital tracts, genu and body of CC [27]. Contrarily, in our study, FA is increased in these areas, suggesting that it is over than drug-related changes. And also, in the clinical setting, it would be inaccurate to leave the patients without such chemotherapy.

Conclusion To conclude, TBSS was able to show that not only optic chiasm, but also additional WM structures in the brain were affected in patients with CRION. Increased FA and decreased RD, AD and MD along with less-pronounced and more-limited contrast findings were observed. This may reflect a more complex combination of pathological processes, rather than solely demyelination or axonal degeneration occurring in the cerebral WM, in this particular disease. Our findings may support that CRION is a distinct entity from primary demyelinating disease, such as MS or NMO.

Declaration of Interest The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of this paper.

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International Journal of Neuroscience

White matter involvement beyond the optic nerves in CRION as assessed by diffusion tensor imaging.

Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory optic neuropathy, characterized by relapses and remissions in patients with...
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