Neuroophthalmological evaluation in primary inflammatory demyelinating diseases with special reference to optic neuritis: A prospective study

ABSTRACT

Introduction:

The involvement of ocular system especially optic neuritis (ON) is an important clinical aspect of inflammatory demyelinating disease (IDD) of the central nervous system. The primary IDD spectrum includes neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein-associated diseases (MOGAD), multiple sclerosis (MS), and clinically isolated syndrome (CIS). The clinical presentation of ON varies according to disease pathophysiology.

Aim:

We aimed to determine the clinical characteristics of treatment-naïve ON at baseline and on the 6-month follow-up and assessed the predictors of visual outcome.

Methods:

A prospective study of patients with treatment-naïve ON was performed with structural and functional ophthalmological evaluation. Univariate and multivariate logistic regression analyses were used to determine the predictive factors of visual outcome.

Results:

Out of 46 patients of IDD, ON occurred in 30 patients. The etiological subtyping included NMOSD (10), CIS (8), MOGAD (7), and MS (5) patients in our study. The ON group showed female preponderance, greater delay in diagnosis, and significant relapsing course. Bilaterality occurred predominantly in NMOSD followed by MOGAD. Optical coherence tomography analysis showed predominant thinning of superior and inferior quadrants in retinal nerve fiber layer (RNFL) and global thinning of Ganglion cell inner plexiform layer (GC-IPL) in NMOSD, but the values were not statistically significant. Univariate analysis for predictors of visual outcome showed age at onset, delay in diagnosis, NMOSD, longitudinally extensive ON (LEON) and chiasmal lesions were associated with poor outcome, while multivariate analysis showed statistical association of NMOSD and LEON with poor outcome.

Conclusion:

NMOSD and longitudinally extensive optic neuritis showed poor ophthalmological outcome and optical coherence tomography was unyielding.

Introduction

Optic neuritis (ON) is a commonly encountered clinical entity of multiple aetiologies. Neuro-ophthalmological aspects of demyelinating disorders can have prominent effects if undiagnosed or improperly treated. Early diagnosis and proper treatment can give a better outcome, otherwise, it might lead to permanent blindness. These are treatable disorders, not to be missed. Inflammatory demyelinating diseases (IDDs) are a significant contributor to inflammatory and neurodegenerative damage in the central nervous system (CNS) among young adults.[1] These diseases are categorized into two groups: secondary demyelination, caused by known factors such as infections, deficiencies, intoxication, and malnutrition; and primary where demyelination itself is the primary manifestation and mechanism.[2] The primary demyelinating spectrum disorders, include multiple sclerosis (MS), myelin oligodendrocyte glycoprotein-associated diseases (MOGAD), neuromyelitis optica spectrum disorders (NMOSD) and clinically isolated syndrome (CIS). Primary demyelination exhibits a wide range of clinical and pathological phenotypes, and in certain cases, specific biomarkers are associated with it.[3] Clinical differentiation among demyelinating diseases relies on factors such as lesion topography, disease course, and the presence of specific biomarkers.

A lot of ambiguity exists regarding ophthalmological manifestations in IDD, with sparse literature. In this study, we aimed to explore the spectrum of ophthalmological manifestations in primary demyelinating disorders with special reference to ON, and correlate with radiological and electrophysiological findings.

Material and Methods

This study was a prospective-cohort study, conducted from December 2021 to May 2023, in the Department of Neurology, King George’s Medical University, Lucknow, India. Prior ethical approval was obtained from the Institutional Ethics Committee. A written informed consent was taken, either from the patients or their legal guardians.

All patients aged >12 years, with suspected with acute event of naïve primary demyelinating disorder were included in this study. Patients satisfying 2017 revisions of the McDonald criteria for MS, International Panel for NMO diagnosis-2015 criteria for NMOSD and/or fulfilling the diagnostic criteria for MOGAD with anti-MOG antibody positivity.[4,5,6] Patients with diagnosis of primary demyelinating illness under immune therapy; patients who get established with alternative diagnosis (infectious, metabolic, vascular); conjunctivitis, iritis, endophthalmitis, cataract, glaucoma, retinal detachment, scleritis; patients who do not consent to be part of the study and pregnant ladies were excluded.

The primary objective were to study ophthalmological manifestations in primary demyelinating disorders of central nervous system; and study clinico-radiological and electrophysiological correlation of ophthalmic manifestations. The secondary objective was to assess the prognosis of ophthalmological features and its relationship with visual outcome at six-months.

A detailed history, neurological examination including higher mental functions, cranial nerve, motor system, sensory system, and ophthalmic evaluation was carried out in all the patients.

The work-up included complete blood count, erythrocyte sedimentation rate, blood glucose, kidney function tests, liver function tests, serum electrolytes, vitamin-B12 levels, chest X-ray and enzyme-linked immunosorbent assay for human immunodeficiency virus (HIV). Cerebrospinal fluid (CSF) biochemical and microscopic examination, including India-ink preparation, were performed. CSF Oligoclonal band (OCB) was done wherever required. Serum Anti-AQP4 antibody (Ab) and Anti MOG-antibody was done by cell-based, immunofluorescence assay method. Antinuclear antibody (ANA) test by indirect immunofluorescence method and extractable nuclear antigen (ENA) test by immunoblot method and Myeloperoxidase (MPO) and Proteinase-3 (PR-3) antibody test by ELISA method was done in all patients. Visual evoked potential (VEP) was done using checkerboard method in NIHON-KOHDEN machine. Fundus photograph of each eye was taken in VISUCAM 524 machine. Optical coherence tomography (OCT) was done with CIRRUS HD-OCT MODEL 5000 machine for evaluating retinal nerve fibre layer (RNFL) and Ganglion cell layer-Inner plexiform layer (GC-IPL) with the help of two protocols were used in both eyes; the macular map allowing fast macular scan for ganglion cell complex measurements and the peripapillary RNFL protocol measuring RNFL thickness around the optic nerve head.

At baseline, all the patients underwent gadolinium contrast enhancing magnetic resonance imaging (MRI) of the brain, spine and orbit using Signa Excite 1.5 Tesla instrument (General Electric Medical Systems, Milwaukee, WI, USA). Longitudinally extensive optic neuritis (LEON) was defined as contiguous involvement in at least 2 of 4 segments of the optic nerve.[7] At baseline, all patients underwent visual charting (Snellen’s charting and Ishihara charting), VEP, fundus photography, OCT for RNFL and GC-IPL analysis, intra ocular pressure monitoring and repeated at six-months of follow-up. Ophthalmic, radiological and statistical assessment were done by independent assessors with blinding.

All patients presenting with index event of primary cns demyelinating event and relapse of demyelinating event was given pulse therapy of injection methyl prednisolone 30 mg/kg body weight/day (maximum dose 1000 mg/day) for 5 days and were later on taken to targeted therapy according to their respective management guideline. Symptomatic treatment was given, wherever indicated. All of the patients were monitored for 5 months. Patients were advised to return to the neurology outpatient department on a monthly basis after discharge for the study. Patients were examined and Expanded Disability Status Scale (EDSS), Modified Rankin Score (mRS), Visual Function Severity Score (VFSS) of 0-4 was applied on admission and on follow-up at six months for visual outcome. Score 0 (no vision impairment/visual acuity <6/12), score 1 (mild vision impairment/visual acuity 6/12-6/18), score 2 (moderate vision impairment/visual acuity 6/18-6/60), score 3 (severe vision impairment/visual acuity 6/60-3/60), and score 4 (blindness/visual acuity <3/60). Poor visual outcome was taken as best corrected visual acuity (BCVA) <6/18, or VFSS >2 and good outcome was taken as BCVA >6/18 and VFSS of 0-2.[8,9]

IBM SPSS (statistical package for social sciences) version 24.0 was used for statistical analysis. Continuous variables were reported as mean, standard deviation, and median (interquartile range), whereas categorical variables were expressed as percentages. The Chi-square/Fisher-exact test was used to compare categorical variables. Independent t-test was used to analyze the mean comparison of two independent groups. Kruskal-Wallis test was applied for matching the medians of >2 groups. The P value <0.05 was considered significant. For univariate analysis, Chi Square/Fisher Exact test were done for qualitative variables and Mann-Whitney test was done for quantitative variables. For multivariate analysis, binary logistic regression was performed to see the impact of individual predictors of outcome for dependent variables. Backward logistic regression method was selected for determination of multivariate analysis of independent variables [all the factors with P value of <0.05 on univariate analysis].

Result

The baseline characteristics in the study is shown in Table 1 and Figure 1. A total of 46 patients were included which comprised of 17 NMOSD (15 Anti AQP4 Ab+), 16 MOGAD, 8 CIS and 5 MS patients. The median age was 24 years (12-70 years) with majority among 11-30 years group and the sex ratio showed female preponderance (65.22%). The clinical spectrum of events at onset showed predominant isolated ON (19,41.30%), isolated TM (15,32.61%), ON + B (4,8.6%), ON + TM (3,6.52%), TN + B (3,6.52%) and ON + TM + B (2,4.34%) as shown in Figure 2. Abnormality of fundus, VEP and OCT was observed in 18 (39.13%), 28 (60.87%) and 19 (41.30%) patients respectively, with thinning being the most prevalent finding.

Table 1.

Baseline clinical characteristics of demyelinating disorders (n=46)

Study variables	Values number (percentage%)
Age of onset (years): Mean±Standard deviation, Median (Range)	26.32±12.67, 24 (12-70)
Mean Delay in diagnosis (months)	18.27±29.74
Gender: Male, Female	16 (34.78%), 30 (65.22%)
Initial clinical presentation
Isolated optic neuritis	19 (41.30%)
Isolated myelitis	15 (32.61%)
Optic neuritis + brain	4 (8.60%)
Optic neuritis + transverse myelitis	3 (6.52%)
Transverse myelitis + brain	3 (6.52%)
Optic neuritis + transverse myelitis + brain	2 (4.33%)
Isolated Brain involvement	0
Acute transverse myelitis	23 (50.00%)
Symmetric, Asymmetric	18 (78.26%), 5 (21.74%)
Paraparesis, Quadriparesis	20 (86.96%), 3 (13.04%)
Co-existing autoimmune disease	5 (10.87%)
(Systemic Lupus Erythematosus, Rheumatoid Arthritis)	3 (60%), 2 (40%)
Ocular Signs
Relative Afferent Pupillary Defect	8 (17.39%)
Internuclear ophthalmoplegia	5 (10.87%)
Nystagmus	5 (10.87%)
Visual acuity: Abnormal	26 (56.52%)
Unilateral, Bilateral	10 (38.46%), 16 (61.54%)
Fundus: Abnormal	18 (39.13%)
Unilateral, Bilateral	7 (38.89%), 11 (61.11%)
Disc edema, Atrophy	6 (33.33%), 12 (66.67%)
Visual Evoked Potential: Abnormal	28 (60.87%)
Unilateral, Bilateral	6 (21.43%), 22 (78.57%)
Increased P-100 latency, Nonrecordable	14 (50%), 10 (35.71%)
Increased P-100 latency and Nonrecordable (opposite eye)	4 (14.29%)
Optical Coherence Tomography Retinal Nerve Fibre Layer: Abnormal	19 (41.30%)
Unilateral, Bilateral	7 (36.84%), 12 (63.16%)
Thickening, Thinning	6 (31.58%), 13 (68.42%)
Cerebrospinal Fluid
Elevated protein (>45 milligram/deciLitre)	26 (56.52%)
Pleocytosis (>5 cells/cubic millimeter)	17 (36.96%)
OligoClonal Band	03 (6.52%)
Antiaquaporin-4 Antibody	15 (32.61%)
Antimyelin Oligodendrocyte Glycoprotein Antibody	16 (34.78%)
Mean Expanded Disease Severity Scale (EDSS)±Standard Deviation	5.38±2.77
Mean Modified Rankin Score (mRS)±Standard Deviation	3.41±1.38
Mortality	0
Magnetic resonance imaging of Orbit: Abnormal	18 (39.13%)
Unilateral, Bilateral	04 (22.22%), 14 (77.78%)
Intraorbital, Intracanalicular	11 (61.11%), 10 (55.56%)
Intracranial, Chiasmal	11 (61.11%), 08 (44.44%)
Longitudinally extensive optic neuritis	8 (44.44%)
Contrast enhancement	14 (77.78%)
Magnetic resonance imaging of Brain: Abnormal	14 (30.43%)
Subcortical white matter, Juxtacortical	11 (78.57%), 09 (64.29%)
Periventricular white matter, Corona radiata	06 (42.86%), 11 (78.57%)
Corpus callosum, Area postrema	04 (28.57%), 05 (35.71%)
Peri-ependymal, Brainstem	06 (42.86%), 09 (64.29%)
Cerebellum	06 (42.86%)
Contrast enhancing	07 (50%)
Magnetic resonance imaging of Spinal Cord: Abnormal	23 (50.00%)
Short segment, Long segment, Both long and short segment	3 (13.04%), 18 (78.26%), 2 (8.69%)
Isolated Cervical, Isolated Dorsal, Cervicodorsal	7 (30.43%),4 (17.39%),12 (52.17%)
Contrast enhancing	15 (65.22%)

Figure 1.

Flowchart of study

Figure 2.

Clinical spectrum of involvement in the study

Relapsing course was observed in 19 (41.3%) patients. The relapsing spectrum showed. TM in 11, isolated brain involvement in 5, isolated ON in 2, and transverse myelitis with brain involvement in 1 patient. At follow-up, visual-acuity remained abnormal in 18 (39.13%) cases, with fundus abnormalities persisting in 22 (47.83%), abnormal VEP in 20 (43.48%) and abnormal OCT RNFL in 22 (47.83%) cases [Table 2]. Bottom of Form A total of 30 (28 on baseline and 2 in follow-up) (65.21%) cases of ON was observed in the study.

Table 2.

Follow-up study characteristics at 6 months (n=46)

Variables	Number (percentage %)
Relapses	19 (41.30%)
Isolated Optic neuritis	2 (10.52%)
Isolated transverse myelitis	11 (57.89%)
Optic neuritis + brain	0
Optic neuritis + transverse myelitis	0
Transverse myelitis + brain	1 (5.26%)
Optic neuritis + transverse myelitis + brain	0
Isolated Brain involvement	5 (26.32%)
Visual Acuity: Abnormality	18 (39.13%)
Unilateral, Bilateral	5 (27.77%), 13 (72.22%)
Fundus: Abnormality	22 (47.83%)
Unilateral, Bilateral	3 (13.64%), 19 (86.36%)
Atrophy	22 (100%)
Visual Evoked Potential : Abnormality	20 (43.48%)
Unilateral, Bilateral	2 (10%), 18 (90%)
Increased P-100 latency, Nonrecordable	15 (75%), 5 (25%)
Optical Coherence Tomography Retinal Nerve Fibre Layer: Abnormality	22 (47.83%)
Unilateral, Bilateral	3 (13.64%), 19 (86.36%)
Thinning	22 (100%)
Mean EDSS±Standard Deviation	1.90±1.81
Mean mRS±Standard Deviation	0.15±0.36
MRI of Orbit: Abnormal	2 (10.52%)
Unilateral, Bilateral	0, 2 (100%)
Intraorbital, Intracanalicular	2 (100%),2 (100%)
Intracranial, Chiasmal	0,0
LEON	2 (100%)
Contrast enhancing lesion	2 (100%)
MRI of brain: Abnormal	15 (32.61%)
Subcortical white matter, Juxtacortical	7 (46.67%), 6 (40%)
Periventricular white matter, Corona radiata	8 (53.33%), 8 (53.33%)
Corpus callosum, Area postrema	5 (33.33%), 4 (26.67%)
Peri-ependymal, Brainstem	10 (66.66%), 11 (73.33%)
Cerebellum, Contrast enhancing lesions	5 (33.33%), 4 (26.67%)
MRI of spinal cord: Abnormal	12 (26.09%)
Short segment, Long segment, both	4 (33.33%), 8 (66.67%), 0
Cervical, Dorsal, Cervicodorsal	6 (50%),4 (33.33%),2 (16.67%)
Contrast enhancing lesion	4 (33.33%)

n=number, %=percentage, EDSS=Expanded Disease Severity Scale, mRS=modified Rankin Score, MRI=Magnetic resonance imaging, LEON=Longitudinally extensive optic neuritis

We further classified the 46 patients into two groups: ON+ (30 patients) and ON- (16 patients). The clinical characteristics and subtyping of ON+ group is shown in Table 3. The ON+ group showed 70% female preponderance, experienced a delay in diagnosis, and most of them had a significant relapsing course. CSF pleocytosis was more prominent in the ON- group. On admission, the ON- group had a higher EDSS and mRS scores as compared with the ON+ group, indicating more disability. At follow-up, the ON- group showed a greater improvement in EDSS and mRS scores compared with the ON+ group.

Table 3.

Comparison of Optic Neuritis (ON+) vs Nonoptic Neuritis (ON-) patients

Variables		ON- (n=16)		ON+ (n=30)		P
		Mean	Standard deviation	Mean	Standard deviation
Age at onset (years)		24.19	11.36	27.47	13.36	0.387
Age at presentation (years)		24.19	11.36	29.17	13.25	0.190
Delay in diagnosis (months)		0	0	18.27	29.74	NA
Number of relapses		0.19	0.40	1.40	1.91	0.016
EDSS (baseline)		7.75	1.81	4.12	2.33	<0.001
EDSS (follow-up)		1.56	1.90	2.08	1.77	0.371
mRS (baseline)		4.50	0.82	2.83	1.26	<0.001
mRS (follow-up)		1.00	1.37	1.367	1.33	0.388
		n	%	n	%
Sex	Female	9	56.3	21	70	0.351
	Male	7	43.7	9	30
	Total	16	100	30	100
Relapsing course	No	13	81.3	14	46.7	0.031
	Yes	3	18.7	16	53.3
	Total	16	100	30	100
Co-existing autoimmunity	No	14	87.5	27	90	1.000
	Yes	2	12.5	3	10
	Total	16	100	30	100
Clinical brain involvement	No	10	62.5	17	56.7	0.702
	Yes	6	37.5	13	43.3
	Total	16	100	30	100
Clinical spinal cord involvement	No	0	0	12	40	NA
	Yes	16	100	18	60
	Total	16	100	30	100
Brain MRI abnormality	No	7	43.7	13	43.3	0.983
	Yes	9	56.3	17	56.7
	Total	16	100	30	100
Spinal cord MRI abnormality	No	0	0	12	40	NA
	Yes	16	100	18	60
	Total	16	100	30	100
CSF pleocytosis	Absent	4	25	25	83.3	<0.001
	Present	12	75	5	16.7
	Total	16	100	30	100
CSF protein	Normal	4	25	16	53.5	0.117
	Elevated	12	75	14	46.7
	Total	16	100	30	100

ON=Optic neuritis, P=Probability, EDSS=Expanded disease severity scale, mRS=Modified Ranking Score, NA=Not-applicable, n=number, %=Percentage; MRI=magnetic resonance imaging, CSF=Cerebrospinal fluid, <=less than

In the ON+ group (n = 30), the etiological subtyping included 10 (33.33%) NMOSD, 8 (26.67%) CIS, 7 (23.33%) MOGAD and 5 (16.67%) MS patients. NMOSD and CIS had a female preponderance. The median age of onset were 20.5 years in NMOSD, 25 years in MS and CIS, and 28 years in MOGAD. Median age of presentation was 24.5 years in NMOSD, 25.5 years in CIS, 28 years in MOGAD and 32 years in MS. MS and NMOSD had a median delay in diagnosis of 18 months. The laterality of ON was predominantly unilateral in MS and CIS groups, while bilateral ON occurred in 8 (80%) NMOSD and 5 (71.43%) MOGAD patients [Table 4].

Table 4.

Comparison of optic neuritis (n=30) in NMOSD, MOGAD, MULTIPLE SCLEROSIS, and CLINICALLY ISOLATED SYNDROME

Variables	Group 1 (n=8) CIS-ON	Group 2 (n=7) MOGAD-ON	Group 3 (n=5) MS-ON	Group 4 (n=10) NMOSD-ON	P*
Sex
Male (n,%)	2 (6.7)	3 (10)	3 (10)	1 (3.3)	0.196
Female (n,%)	6 (20)	4 (13.3)	2 (6.7)	9 (30)
Age at onset (years)
Mean±SD	32±18.52	29.86±12.92	28.6±12.38	21.6±8.21	0.384
Median (IQR)	25 (21)	28 (20)	25 (22)	20.5 (8)
Age at presentation (years)
Mean±SD	32.5±18.24	29.86±12.92	31.8±10.55	24.7±10.49	0.611
Median (IQR)	25.5 (19)	28 (20)	32 (19)	24.5 (12)
Delay in diagnosis (months)
Mean±SD	6.25±16.88	0.43±1.13	24±24.37	37.5±39.48	0.009
Median (IQR)	0 (1)	0 (0)	18 (45)	18 (76)
Relapsing course	2 (6.7%)	1 (3.3%)	5 (16.7%)	8 (26.7%)	0.003
Median number of relapses (Range)	0 (1-3)	0 (1)	2 (1-4)	2 (1-8)	NA
Autoimmune disease (SLE, RA)	0	1 (33.33%), 1 (33.33%)	0	1 (33.33%), 0	NA
Clinical features:
Isolated ON	8 (26.67%)	5 (16.67%)	1 (3.33%)	5 (16.67%)
ON + ATM	0	2 (6.67%)	1 (3.33%)	2 (6.67%)	NA
ON + Brain	0	0	2 (6.67%)	2 (6.67%)
ON + Brain + ATM	0	0	1 (3.33%)	1 (3.33%)
Optic neuritis (n=30)
Unilateral	5 (62.5%)	2 (28.57%)	5 (100%)	2 (20%)	NA
Bilateral	3 (37.5%)	5 (71.43%)	0	8 (80%)
MRI Optic Nerve (n=19)
Abnormal	7 (36.84%)	3 (15.78%)	1 (5.26%)	8 (42.10%)	0.036
Intraorbital	6 (31.57%)	3 (15.78%)	1 (5.26%)	0	NA
Intracanalicular	4 (21.05%)	0	0	6 (31.57%)	NA
Intracranial	3 (15.78%)	0	0	8 (42.10%)	NA
Chiasmal	1 (5.26%)	0	0	8 (42.10%)	NA
LEON	2 (20%)	0	0	8 (80%)	NA
Gd enhancement	7 (100.0%)	1 (14.28%)	0	8 (100%)	NA
MRI Brain abnormal
Corona radiata	1 (3.3%)	1 (3.3%)	4 (13.3%)	3 (10%)	NA
Corpus callosum	0	0	4 (13.3%)	1 (3.3%)
Periventricular W M	0	0	4 (13.3%)	4 (13.3%)
Brain stem	0	1 (3.3%)	5 (16.7%)	6 (20.0%)
Periependymal	0	1 (3.3%)	2 (6.67%)	8 (26.67%)
Area Postrema	0	0	0	9 (30.0%)
Cerebellum	0	0	4 (13.3%)	1 (3.3%)
Contrast enhancement	0	2 (18.18%)	5 (45.45%)	4 (36.36%)
MRI Spinal Cord
Abnormal	0	3 (16.7%)	5 (27.8%)	10 (55.6%)	NA
Short segment	0	1 (3.33%)	5 (16.67%)	0
Long segment	0	2 (6.67%)	2 (6.67%)	10 (33.33%)
Cervical	0	2 (6.67%)	4 (13.33%)	9 (30.0%)
Dorsal	0	2 (6.67%)	3 (10.0%)	7 (23.33%)
CSF Pleocytosis	0	0	0	5 (100.0%)	NA
CSF Elevated Protein	0	4 (28.57%)	2 (14.29%)	8 (57.14%)	NA
Fundus examination
Admission: Abnormal	5 (27.8%)	7 (38.9%)	2 (11.1%)	4 (22.2%)	0.362
Disc edema	2 (11.1%)	4 (22.2%)	0	0	NA
Disc Atrophy	3 (16.7%)	3 (16.7%)	2 (11.1%)	4 (22.2%)	0.998
At follow-up Atrophy	5 (22.7%)	4 (18.2%)	3 (13.6%)	10 (45.5%)	0.138
Visual evoked potential examination:
Admission: Abnormal	8 (32%)	7 (28%)	3 (12%)	7 (28%)	0.100
Follow-up: Abnormal	4 (20%)	3 (15%)	3 (15%)	10 (50%)	0.058
Median EDSS
Admission	2	2	3.5	6.75	0.348
Follow-up	1	1	2	3
Median mRS
Admission	1	3	3	4	NA
Follow-up	0	0	0	0
Abnormal Visual Acuity
Baseline	8 (32%)	7 (28%)	1 (4%)	9 (36%)	<0.001
Follow-up	4 (22.2%)	3 (16.6%)	1 (5.6%)	10 (55.6%)	0.011
Visual Acuity Grading (VFSS) (Admission)
Grade 0	0	0	4 (13.33%)	1 (3.33%)
Grade 1	0	0	0	2 (6.67%)	0.004
Grade 2	0	0	0	2 (6.67%)
Grade 3	1 (3.33%)	0	0	0
Grade 4	7 (23.33%)	7 (23.33%)	1 (3.33%)	5 (16.67%)
Visual Acuity Grading (VFSS) (Follow-up)
Grade 0	4 (13.33%)	4 (13.33%)	4 (13.33%)	0
Grade 1	0	2 (6.67%)	0	3 (10.0%)	0.100
Grade 2	3 (10.0%)	0	0	2 (6.67%)
Grade 3	0	0	0	1 (3.33%)
Grade 4	1 (3.33%)	1 (3.33%)	1 (3.33%)	4 (13.33%)

*Calculated by Kruskal–Wallis test; ON=Optic neuritis, CIS=Clinically isolated syndrome, MOGAD=Myelin oligodendrocyte glycoprotein associated disorder, NMOSD=Neuromyelitis optica spectrum disorder, MS=Multiple Sclerosis, n=number, %=Percentage, P=Probability value, SD=Standard deviation, IQR=Inter-quartile ratio, NA=Nonapplicable, ATM=Acute transverse myelitis, +=Present, MRI=Magnetic resonance imaging, Gd=Gadolinium, WM=White matter, CSF=Cerebrospinal fluid, EDSS=Expanded disease severity scale, mRS=modified Ranking Score, VFSS=Visual function severity score; SLE=Systemic lupus erythematosus, RA=rheumatoid arthritis

Median EDSS at admission was 2 in CIS and MOGAD, 3.5 in MS, and 6.75 in NMOSD. Median EDSS at 6-months was 1 in CIS and MOGAD, 2 in MS, and 3 in NMOSD [Table 4]. At admission, a relatively preserved global RNFL thickness was demonstrated in MOGAD, CIS and MS group, while thinning was observed in NMOSD group. At six-months of follow-up, NMOSD patients exhibited greater RNFL thinning than others, superior and inferior quadrants being most affected, but the values were not statistically significant [Table 5]. The global GCIPL thickness which was initially preserved in all the patients, became thin in NMOSD at 6-months [Table 5]. On univariate analysis, age-of-onset, delay in diagnosis, NMOSD, LEON and chiasmal lesions were found to be associated with poor outcome. However, on multivariate analysis, only NMOSD and LEON were significantly associated with poor outcome [Table 6].

Table 5.

Optical coherence tomography RNFL and gcipl analysis in optic neuritis (n=30)

OCT RNFL ANALYSIS (At admission)		Group 1 (n=8) CIS	Group 2 (n=7) MOGAD-ON	Group 3 (n=5) MS-ON	Group 4 (n=10) NMOSD-ON	P*
Abnormal		5 (26.31%)	7 (36.84%)	2 (10.53%)	5 (26.31%)	0.112
Right eye Global (mm)	Mean±SD	95.88±36.65	131.71±62.35	76±13.10	78.10±17.00	0.098
	Median (IQR)	94.5 (56)	129 (80)	79 (23)	81 (33)
Right eye Superior (mm)	Mean±SD	119.13±51.60	160.4±86.31	91.80±26.86	96.50±26.40	0.124
	Median (IQR)	118.50 (82)	160 (59)	96 (44)	102.5 (44)
Right eye Inferior (mm)	Mean±SD	126.75±53.75	163.14±79.03	96.40±18.74	99.90±31.60	0.131
	Median (IQR)	125.50 (59)	140 (121)	93 (36)	112 (58)
Right eye Nasal (mm)	Mean±SD	77.88±32.46	133.43±79.35	71±7.84	63.20±9.90	0.093
	Median (IQR)	71 (50)	117 (143)	73 (12)	62 (12)
Right eye Temporal (mm)	Mean±SD	63.88±7.18	62.29±11.47	44.60±9.84	52.20±6.11	0.004
	Median (IQR)	64 (13)	63 (18)	49 (19)	52.50 (9)
Left eye Global (mm)	Mean±SD	92.25±34.04	106.57±51.91	72±14.51	75.50±18.70	0.447
	Median (IQR)	98.5 (34.04)	119 (93)	76 (26)	77 (38)
Left eye Superior (mm)	Mean±SD	116.25±52.06	129.29±75.16	91.20±26.86	90±30.45	0.516
	Median (IQR)	125.50 (104)	128 (120)	93 (46)	88 (54)
Left eye Inferior (mm)	Mean±SD	123.50±59.97	134.14±80.12	88.20±23.04	93.60±33.43	0.519
	Median (IQR)	136 (123)	150 (142)	90 (42)	95 (70)
Left eye Nasal (mm)	Mean±SD	75.50±17.46	93.57±37.62	61.40±8.62	61.50±10.60	0.208
	Median (IQR)	73.50 (28)	98 (79)	60 (15)	62.50 (17)
Left eye Temporal (mm)	Mean±SD	54±12.01	62.86±9.08	44±9.67	51.80±8.24	0.220
	Median (IQR)	52.50 (21)	64 (25)	42 (19)	51 (10)
OCT RNFL Analysis (At Follow-Up)
Abnormal		5 (22.72%)	4 (18.18%)	3 (16.67%)	10 (45.45%)	0.138
Right eye Global (mm)	Mean±SD	79.50±26.65	75.57±19.06	68.80±12.52	57.40+5.93	0.107
	Median (IQR)	78.50 (38)	78 (40)	63 (24)	55 (3)
Right eye Superior (mm)	Mean±SD	91.75±35.37	85.57±20.06	87.20±20.41	66.10+10.13	0.154
	Median (IQR)	84.50 (59)	90 (41)	81 (38)	62.50 (13)
Right eye Inferior (mm)	Mean±SD	100.13±39.64	94.43±29.95	84.20±21.22	62.30+9.98	0.056
	Median (IQR)	107.50 (69)	103 (55)	80 (36)	60 (11)
Right eye Nasal (mm)	Mean±SD	65.75±18.17	71.14±17.45	67.60±10.07	53+5.85	0.080
	Median (IQR)	60.50 (26)	75 (36)	70 (14)	53 (7)
Right eye	Mean±SD	58.25±16.77	46.43±9.00	48.60±9.56	43.50+6.85	0.090
Temporal (mm)	Median (IQR)	54 (16)	46 (19)	50 (17)	46 (6)
Left eye Global (mm)	Mean±SD	78.38±22.40	71.29±22.78	69.00±13.44	58.10±6.42	0.180
	Median (IQR)	79 (40)	58 (43)	65 (26)	54 (11)
Left eye Superior (mm)	Mean±SD	96.75±33.79	84.00±28.51	88.80±24.35	65.50±14.57	0.081
	Median (IQR)	95.50 (66)	69 (42)	82 (44)	60.50 (15)
Left eye Inferior (mm)	Mean±SD	99.75±38.86	84.86±34.62	82.00±20.45	63.90±15.20	0.195
	Median (IQR)	111 (80)	64 (59)	84 (37)	59.50 (21)
Left eye Nasal (mm)	Mean±SD	66.38±14.53	64.14±18.12	60.60±9.40	51.40±6.10	0.126
	Median (IQR)	67.50 (22)	69 (27)	65 (18)	51 (9)
Left eye Temporal (mm)	Mean±SD	47.25±9.66	48.14±13.11	51.00±10.51	40.40±5.95	0.222
	Median (IQR)	47 (15)	49 (25)	52 (18)	40.50 (8)
OCT GC IPL ANALYSIS (At admission)
Right eye	Mean±SD	76.88±13.03	78.71±10.89	75.20±12.64	70.40±11.83	0.167
	Median (IQR)	81 (24)	82 (6)	80 (21)	71.50 (24)
Left eye	Mean±SD	76.75±11.85	78.14±11.63	74.80±12.68	68.90±12.78	0.130
	Median (IQR)	81.50 (19)	83 (13)	81 (21)	71.50 (24)
Follow-Up
Right eye	Mean±SD	69.25±12.97	68.14±16.18	68.80±12.60	59.60±13.46	0.213
	Median (IQR)	74 (23)	68 (31)	71 (23)	56.50 (24)
Left eye	Mean±SD	70.75±12.27	63.57±14.12	69.40±12.22	59.40±9.89	0.163
	Median (IQR)	75 (23)	63 (22)	75 (21)	54.50 (14)

*Calculated by Kruskal–Wallis test. n=Number, ON=Optic neuritis, NMOSD=Neuromyelitis optica spectrum disorder, MOGAD=Myelin oligodendrocyte glycoprotein associated disorder, MS=Multiple sclerosis, CIS=Clinically isolated syndrome, OCT=Optical coherence tomography, RNFL=Retinal nerve fibre layer, GCIPL=Ganglion cell-inner plexiform layer; SD=Standard deviation, IQR=Interquartile ratio, mm=Micrometer, P=Probability value

Table 6.

Predictive factor analysis for poor visual outcome in Optic neuritis

Predictive factors	Final BCVA >6/18 (Good Outcome) n=15	Final BCVA <6/18 (Poor Outcome) n=15	Univariate Analysis		Multivariate Analysis
			ODDS Ratio (95% CI)	P	ODDS Ratio (95% CI)	P
Age of onset (y)	32.20±14.83	23.20±0.02	NA	0.048		0.623
Delay in diagnosis (m)	6.87±17.37	29.67±35.38	NA	0.004		0.296
Sex:
Male: Female	6:9	3:12	2.67 (0.52-13.66)	0.427		NA
Bilaterality (Optic nerve)	5	11	4.33 (0.96-3.48)	0.215		NA
Abnormal optic disc	9	10	1.33 (0.30-5.91)	0.705		NA
Initial BCVA <6/18	11	12	1.45 (0.26-8.00)	1.000		NA
NMOSD	1	9	21.00 (2.15-204.61)	0.002	28.03 (2.20-358.04)	0.010
MOGAD	6	1	0.11 (0.01-1.04)	0.080		NA
CIS	4	4	1.00 (0.20-5.01)	1.000		NA
MS	4	1	0.19 (0.01-2.01)	0.330		NA
Abnormal OCT RNFL	10	9	0.75 (0.17-3.32)	0.705		NA
Abnormal OCT GCIPL	2	7	5.68 (0.93-34.45)	0.109		NA
LEON	2	8	9.75 (1.59-39.69)	0.021	13.41 (1.51-119.57)	0.020
Chiasmal lesion	1	8	16.00 (1.65-154.59)	0.014		0.557
Abnormal VEP	12	13	1.00 (0.12-8.21)	1.000		NA
Elevated CSF protein	5	9	3.00 (0.67-13.30)	0.140		NA
CSF pleocytosis	0	5	NA	0.042		NA
Concurrent involvement of spinal cord	6	11	1.75 (0.40-7.66)	0.456		NA
Concurrent involvement of brain	6	11	4.12 (0.88-19.27)	0.139		NA

BCVA=Best corrected visual acuity, y=Years, m=Months; P=Probability value, CI=confidence interval, NA=Not-applicable, NMOSD=Neuromyelitis optica spectrum disorder, MOGAD=Myelin oligodendrocyte glycoprotein associated disorder, MS=Multiple sclerosis, CIS=Clinically isolated syndrome, OCT=Optical coherence tomography, RNFL=Retinal nerve fibre layer, GCIPL=Ganglion cell inner plexiform layer, LEON=Longitudinally extensive optic neuritis, VEP=Visual evoked protein, CSF=Cerebrospinal fluid, NA=Not-applicable

Discussion

In our study, we enumerated the spectrum of IDD (n = 46) and compared patients with and without ON. We further subdivided ON (n = 30) patients into MS, NMOSD, MOGAD and CIS, to assess the predictors of visual outcome. We observed a higher involvement of the optic nerve (65.21%) in our study, which was comparable to study by Gangopadhyay et al.[10] (71%), Manisha et al.[11] (59.57%), and Jena et al.[12] (58.6%). We observed bilateral ON in MOGAD (71.43%) and NMOSD (80%), similar to study by Ramanathan et al.,[13] where bilaterality occurred more in MOGAD and NMOSD (84% and 82%). Bilateral ON was commonly observed in MOGAD in Chinese cohort by Ying Zhao et al.[14] There was a considerable delay in diagnosing ON, with a mean delay of 18.27 ± 29.17 months in our study, which was similar to finding by Dhar et al.[15] This may be explained due to delayed presentation, sub-clinical course, self-remitting course, or referral delay to tertiary centre.

Visual-acuity at-presentation was poor across all the groups, except for MS. However, upon follow-up, it became evident that the NMOSD had a poor visual recovery compared with others, which was similar to study by Ambika et al.[16] In terms of visual acuity after treatment, the MOGAD exhibited a favorable response to treatment, as demonstrated by Zhao et al.[14] and Ishikawa et al.[17] Moreover, Jitprapaikulsan et al.[18] found that both pretreatment and posttreatment visual acuity were poor in NMOSD, while visual outcomes were favorable in MOGAD-ON.

Disc edema was found in 57% MOGAD patients and 25% CIS patients in our study. In the ONTT report, disc swelling was associated with a significantly lower likelihood of developing MS.[19] Optic disc pallor was noted in 40% of MS patients on admission, probably due to chronic presentation, subclinical ON, or recurrent neuritis as shown in study by Ambika et al.[16]

Orbital MRI findings revealed various patterns of optic nerve involvement in different subgroups, with 87.5% in CIS and 20% in MS patients. Optic nerve lesions in MS are typically short segments and anteriorly located in the study. 80% NMOSD patients exhibited abnormality in orbital imaging. This aligns with a similar study by Siegel et al.,[20] which reported a 72% abnormality. Chiasmal involvement was particularly prominent (70%) in NMOSD. In our study, 80% NMOSD and 25% CIS patients showed LEON, which was similar to a study by Kezuka et al.[21] Patients with LEON were associated with poor visual outcome (P value = 0.021). MRI showed abnormality in 43% MOGAD patients with involvement of anterior segment in all the cases. These findings are consistent with the study by Pandit et al.[22] and Pedapati et al.[23]

During the acute phase of MOGAD-ON, we observed thickening of the RNFL, as evidenced by OCT measurements compare to NMOSD group. This thickening likely represents edema and inflammation in the optic nerve.[24] However, in the chronic phase, we found that thinning of the superior (pRNFL-S) and inferior (pRNFL-I) quadrants were observed in NMOSD, but the values were not statistically significant. This suggests that the extent of thinning in these specific areas might reflect permanent damage to the optic nerve and subsequent visual loss. On the other hand, the thickness of the nasal (pRNFL-N) and temporal (pRNFL-T) quadrants was less in all the four groups. It is possible that the baseline thickness of these quadrants was already relatively thin, explaining the lack of correlation with visual outcomes. This pattern might point towards vascular compromise as a mechanism of optic nerve injury in NMOSD. Notably, retinal vascular alterations have been reported in vivo in NMOSD and pathologic studies have identified prominent vascular fibrosis and hyalinization in NMO lesions. MOGAD patients experience less retinal neuronal loss than NMOSD despite severe optic nerve swelling. In addition, a floor effect exists for OCT measures, where a single attack of ON can lead to significant atrophy, potentially limiting the sensitivity of subsequent changes in inner retinal layer thicknesses to worsening visual function.[25] Based on these findings, it is crucial to focus on preventing the thinning of the pRNFL-S and pRNFL-I in patients with NMOSD. Preserving the thickness of these quadrants could potentially help to minimize irreversible visual impairment. Severe thinning of these layers often occurs in MOGAD after recurrent attacks, while NMOSD tends to cause significant thinning after single attack. In a large initial OCT study, it was demonstrated that RNFL thinning < 75 μm was associated with poor visual outcome in ON.[26] However, patients can have significant pRNFL and GCIPL thinning with good visual function, especially observed in MOGAD patients.[27] In contrast, NMOSD patients show severe visual loss with similar thinning in OCT.[28] This discrepancy could be related to astrocytopathy-induced retinal injury in NMOSD.[29] Another possibility could be the “bottom-out” phenomenon of the RNFL and GCIPL at around 50-60 μm, and therefore OCT may not capture the greater extent of optic nerve damage that may occur in NMOSD ON compared with MOGAD.[30]

At 6-months of follow-up, fundus changes (atrophy), OCT changes (thinning of RNFL), and macular changes (thinning of GCL) were observed in all the groups of ON, but vision improved in all, except NMOSD. Hence, these parameters are inconclusive of visual outcome in demyelinating disorders.

Examining OCT changes after bouts of ON in both MS and NMOSD patients by Shen et al.[31] discovered a larger loss in the ganglion cell layers in NMOSSD than MS. In MS, the macula’s morphologic and functional loss seems to be more uniformly distributed, but in NMOSD, it seems to be more restricted to the foveal and parafoveal region.[32,33]

These findings emphasize the need for early intervention and management strategies aimed at preserving the thickness of these specific quadrants to improve long-term visual outcomes in NMOSD. The finding of quadrantal thinning, particularly affecting the arcuate fibers in NMOSD, raises the possibility that vascular compromise playing a role in the pathogenesis of tissue damage in this condition. The presence of retinal vascular alterations observed in vivo and the identification of vascular fibrosis and hyalinization in pathological studies of NMOSD lesions support this hypothesis. Further research is needed to elucidate the precise mechanisms by which vascular compromise contributes to the tissue injury observed in NMOSD.

EDSS score at 6 months of follow-up suggested a higher proportion of NMOSD having less functional independence as compared with MOGAD and MS, possibly due to greater disease affection, relapses, and LETM. Relapse occurred more in ON+ group (53.33%) in comparison to ON- group (18.75%), which was statistically significant P value (0.031). The median number of relapses in the ON+ group was 1, (range 1-8) with a significant P value (0.016). Our study showed MOGAD had monophasic disease with lesser relapses similar to study by Kitley J et al.[34] A higher recurrence rate (80%) was seen in NMOSD, similar to Ying Zhao et al.[14] In recent studies, ON has been an important predictor of relapse in IDD.[35,36]

We applied baseline characteristics to assess the visual outcome in various subgroup a and found that on univariate analysis, age of onset delay in diagnosis leading to delay in initial treatment, NMOSD, LEON involvement and chiasmal lesions were associated with poor outcome and on further multivariate analysis NMOSD subgroup and LEON were associated with statistically significant poor visual outcome. According to study by Hansapinyo et al.,[37] NMOSD and initial BCVA <6/60 were independently associated with poor visual outcome in ON. In another study by Kemchoknatee et al.,[38] NMOSD (strongest predictor) and delay in initiating methyl prednisolone >7 days were significantly associated with poor visual outcome in ON. In a study targeted at optic nerve length for visual outcome done by Denis et al.,[39] they observed that greater extent of optic nerve lesion was strongly associated with chronic visual outcome in ON due to retinal neuro-axonal loss, retinal remodeling and chronic visual impairment.

NMOSD is recognized as an autoimmune disorder of astrocyte with secondary demyelination characterized by astrocyte necrosis and dystrophic astrocytic profiles. AQP4 is highly expressed in the retina (astrocytes and Müller glial cells); hence, AQP4-IgG may directly cause retinal injury. In studies of NMOSD, foveal thinning and abnormal morphology have been observed in AQP4-IgG seropositive NMOSD even without a history of clinical ON, suggesting a subclinical ON.[40] The deletion of AQP4 is shown to render Müller cells from the capability of coping with osmotic stress and induce an inflammatory retinal response. These observations suggest that the poor visual prognosis of NMOSD may be mediated by alterations in the homeostatic dynamics of astrocyte and Müller cell. Further understanding the underlying mechanisms of retinal injury in AQP4-IgG–associated disease is crucial for developing effective treatment strategies and improving patient outcomes.

Conclusion

This study highlights the importance of ophthalmic evaluation in primary IDD.[41] The visual outcome is significantly poor in NMOSD as compared with CIS, MOGAD, and MS. Despite a similar severity of GCIPL and RNFL thinning in NMOSD-ON and MOGAD-ON, NMOSD was associated with poor visual outcome. The strength of this study is the extensive baseline work-up, including OCT-GCIPL and complete follow-up at 6 months, with limitation of a relatively smaller sample size.

Ethical clearance

Ethical clearance obtained from Institutional Ethical Committee.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.