ABSTRACT
Optic neuritis can be an early sign of demyelinating diseases like multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). We investigated the presence or absence of head and spinal cord lesions on magnetic resonance imaging (MRI) and assessed whether cerebrospinal fluid (CSF) tests are useful in detecting demyelinating disease in patients with first diagnosed optic neuritis. We conducted a retrospective study of 111 patients (47 idiopathic, 19 NMOSD, 16 MOGAD, 16 MS, 6 optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS (ON+)), and 7 chronic relapsing inflammatory optic neuropathy) diagnosed with optic neuritis without cerebral or spinal symptoms. Patients underwent evaluations including orbital, head, and spine MRI, along with CSF analysis. Among the 111 patients, 20 (35.1%: 4 NMOSD, 4 MOGAD, 7 MS, and 6 ON+) exhibited intracerebral or spinal cord lesions. Twelve patients showed findings on both orbital and head MRI, while six had no orbital MRI findings except for optic neuritis but exhibited lesions on head MRI. Five patients had spinal lesions without intracerebral lesions. CSF analysis revealed positive oligoclonal bands and elevated myelin basic protein levels indicate the high likelihood with systemic inflammatory demyelinating diseases. Even in the absence of concomitant encephalitis or myelitis symptoms or a history of these conditions, MRI images of patients with optic neuritis sometimes reveal lesions in the brain or spinal cord. CSF abnormalities were indicative of systemic demyelinating disease presence, extending beyond MS to NMOSD and MOGAD.
KEYWORDS: Optic neuritis, MRI, cerebrospinal fluid test, demyelinating diseases
Introduction
Optic neuritis primarily manifests as idiopathic optic neuritis,1 a condition typically associated with a favourable prognosis, as evidenced by 92% of patients achieving visual recovery.2 However, optic neuritis can also present as an initial symptom of the central nervous system inflammatory demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). In individuals affected by these diseases, recurrence is anticipated, and in severe cases, visual impairment may occur, alongside motor disturbances, and bladder or bowel dysfunction, substantially diminishing the overall quality of life (QOL).
Significant advancements have been made in recent years in the treatment of these neuroimmune disorders. For instance, in the case of MS, numerous disease-modifying therapies (DMTs) are available, allowing many patients to lead normal daily lives.3 Formerly considered refractory optic neuritis, NMOSD now offers treatment options beyond intravenous methylprednisolone pulse (IVMP) therapy, including apheresis4 and intravenous immunoglobulin (IVIg) therapy5 during the acute phase. Moreover, immunosuppressants and emerging molecular-targeted drugs have shown promise in reducing recurrence rates during the post-acute phase.6,7 MOGAD, a recently identified clinical entity, typically responds well to IVMP with a favourable visual prognosis. However, it is susceptible to epilepsy due to cortical encephalitis, which significantly impacts QOL.8
Prompt identification of the underlying inflammatory demyelinating disease upon initial optic neuritis diagnosis is crucial for administering appropriate management after acute-phase therapy, ultimately preserving patient QOL. In our institution, in collaboration with the division of Neurology, optic neuritis patients undergoing IVMP, receive comprehensive evaluations including orbital magnetic resonance imaging (MRI), head MRI, spine MRI, and cerebrospinal fluid (CSF) testing to expedite the detection of concurrent cerebral and spinal cord lesions and uncover any underlying neuroimmune diseases.
While previous studies have explored classifying MS/NMOSD/MOGAD based on optic nerve MRI lesion patterns in optic neuritis patients,9–11 only one study, conducted two decades ago, focused on brain and spinal cord lesions in optic neuritis patients, predating the recognition of pathologies such as NMOSD and MOGAD.12 Regarding cerebrospinal fluid (CSF) testing, Olesen et al. reported that it can help differentiate between MS and idiopathic disease in patients with optic neuritis,13 but its efficacy in distinguishing NMOSD and MOGAD in optic neuritis patients remains unclear.
Therefore, we investigated the presence of concurrent lesions in the intracerebral and spinal cord regions in newly diagnosed optic neuritis patients, along with abnormalities in CSF tests. This study aims to demonstrate the extent to which these additional approaches were useful for the early detection of systemic neuroimmune diseases.
Methods
We conducted a retrospective review of patients diagnosed with optic neuritis for the first time at our hospital since 2010, who have been followed up for more than one year. The diagnosis of optic neuritis was established based on the presence of hyperintensities in the optic nerve parenchyma accompanied by contrast enhancement on orbital MRI in patients experiencing acute visual impairment. Additionally, one patient with a history of asthma, who could not undergo contrast-enhanced MRI, was included due to high signal intensity in the optic nerve parenchyma observed on short tau inversion recovery (STIR) imaging. Patients were excluded if they met any of the following criteria: 1. Past history of optic neuritis, encephalitis, or myelitis; 2. Obvious neuroimmune disease presenting with cerebral and spinal symptoms at the onset of optic neuritis; 3. Perineuritis with only contrast effect around the optic nerve without involvement of the optic nerve parenchyma; 4. Secondary optic neuropathy due to anterior ischemic optic neuropathy,14 infection,15 or hypertrophic pachymeningitis.
Optic neuritis management at our hospital adheres to the algorithm depicted in Figure 1. Patients with a visual acuity of approximately 20/40 or better and an expected spontaneous recovery, as reported in the Optic Neuritis Treatment Trial (ONTT) study, are observed without treatment and are not hospitalized.2 Hospitalized patients with optic neuritis undergo neurological examination and CSF testing by a neurologist. Subsequently, one to three courses of IVMP are administered based on the patient’s clinical improvement, with additional head and spine MRI scans performed during hospitalization if available. The decision to perform contrast imaging is made based on the IVMP administration schedule. In other words, when MRI is performed during the IVMP period, a contrast MRI is performed, and when it is performed during the IVMP withdrawal period, a simple plain imaging is performed. Aquaporin 4 (AQP4) antibody testing via the Enzyme-linked immunosorbent assay (ELISA) method and MOG antibody testing via the Cell Based Assay (CBA) method aid in determining the underlying NMOSD and MOGAD. Based on these test results, we classified patients with optic neuritis as idiopathic or associated with NMOSD, MOGAD, MS, optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS (ON+), acute disseminated encephalomyelitis (ADEM), and other relapsing optic neuritis. In cases where IVMP is insufficiently effective, apheresis was considered,4 although IVIg therapy,5 covered by Japanese national health insurance, is now preferred. Patients are discharged and transitioned to long-term relapse prevention management.
Figure 1.
Our algorithm for optic neuritis.
NMOSD: Neuro Myelitis Optica spectrum disorder, MOGAD: Myelin Oligodendrocyte Glycoprotein Andibody-Associated Disease, MS: Multiple Sclerosis, ON+: optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS.
Commercially, the CBA method for measuring AQP4 antibodies is unavailable in Japan. However, during a nationwide optic neuritis survey,1 we conducted AQP4 antibody testing using both ELISA and CBA methods. After this nationwide survey, we sometimes measure AQP4 antibodies using the CBA method in some cases in which the presence of NMOSD was suspected due to poor response to IVMP. Patients positive for anti-AQP4 antibodies were diagnosed with NMOSD, while those positive for MOG antibodies were diagnosed with MOGAD. Patients negative for these antibodies, with dissemination in time and dissemination in space, were classified as MS, and those with intracerebral lesions but without definitive MS identification due to lack of dissemination in time were classified as ON+. ADEM patients were excluded in this study due to concurrent cerebral symptoms. Other relapsing was defined as cases negative for both AQP4 and MOG antibodies, with no brain lesions suggestive of MS, yet experiencing optic neuritis recurrence during follow-up.
Data collected included: age at optic neuritis onset, sex, affected eye (left, right, or bilateral), serum AQP4 antibody results (ELISA and CBA), serum MOG antibody results (CBA), follow-up duration at our hospital, monophasic lesion status, presence of cerebral or spinal lesions on orbital/head/spine MRI, and presence of oligoclonal bands, increased myelin basic protein, or IgG index elevation in CSF. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Kobe University (No. B240011).
Results
Table 1 presents patient information for all 111 individuals, classified by coexisting demyelinating diseases. Among them, 47 had idiopathic optic neuritis, 19 had NMOSD, 16 had MOGAD, 16 had MS, 6 had ON+, and 7 had other relapsing. One female NMOSD patient tested positive for anti-MOG antibodies, albeit with a low titer, raising suspicions of a false positive. This case exhibited a poor response to IVMP and was categorized as NMOSD due to the presence of longitudinal myelitis presence. Additionally, despite multiple negative tests for AQP4 antibodies, including the CBA method, one patient with optic neuritis, brain lesions, and long myelitis involving three vertebral bodies was classified as NMOSD. No NMOSD patients tested negative by ELISA but positive by CBA for AQP4 antibodies. Furthermore, five optic neuritis cases initially diagnosed as ON+ demonstrated new intracerebral lesions on follow-up MRI, leading to classification as MS due to multiple occurrences.
Table 1.
Status of optic neuritis patients divided by coexisting demyelinating diseases.
| Idiopathic | NMOSD | MOGAD | MS | Other relapsing | ON+ | All | |
|---|---|---|---|---|---|---|---|
| Number | 47 | 19 | 16 | 16 | 7 | 6 | 111 |
| Age: y.o. Mean (IQR) | 37 (30, 56) | 47 (41, 61) | 38 (15, 58) | 35 (26, 39) | 55 (37.5, 57) | 27.5 (21.8, 51.3) | 40 (28, 57) |
| Sex: male, female (male ratio) | 18, 29 (38) | 2, 17 (11) | 6, 10 (38) | 9, 7 (56) | 4, 3 (57) | 2, 4 (33) | 41, 70 (37) |
| Right, Left, Both (each ratio) | 14, 24, 9 (30, 51, 19) |
7, 9, 3 (37, 47, 16) |
3, 6, 7 (19, 38, 44) |
9, 5, 2 (56, 31, 13) |
2, 5, 0 (29, 71, 0) |
4, 2, 0 (67, 33, 0) |
39, 51, 21 (35, 46, 19) |
| AQP4 (ELISA): negative, positive, (positive rate) | 46, 0 (0) | 1, 18 (95) | 16, 0 (0) | 14, 0 (0) | 7, 0 (0) | 6, 0 (0) | 90, 18 (17) |
| AQP4 (CBA): negative, positive (positive rate) | 13, 0 (0) | 1, 6 (86) | 6, 0 (0) | 4, 0 (0) | 3, 0 (0) | 0, 0 (0) | 27, 6 (18) |
| MOG (CBA): negative, positive, (positive rate) | 28, 0 (0) | 8, 1 (11) | 0, 16 (100) | 9, 0 (0) | 7, 0 (0) | 3, 0 (0) | 55, 17 (24) |
| Duration of follow-up: Year. Mean (IQR) | 1 .5(1, 1.5) | 7 (4.8, 10) | 5 (2.3, 5.8) | 6.3 (4.3, 10) | 5 (3, 7.3) | 3.3 (1.3, 6.4) | 2 (1.5, 6) |
| Hospitalisation (implementation ratio) | 39 (83) | 19 (100) | 16 (100) | 16 (100) | 7 (100) | 6 (100) | 103 (93) |
| Monophasic (positive ratio) | 47 (100) | 9 (47) | 9 (56) | 6 (38) | 0 (0) | 6 (100) | 77 (69) |
NMOSD: neuromyelitis optica spectrum disorders, MOGAD: myelin oligodendrocyte glycoprotein antibody-associated diseases, MS: multiple sclerosis, ON+: optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS, IQR: interquartile range, AQP4: aquaporin 4, MOG: myelin oligodendrocyte glycoprotein, ELISA: enzyme-linked immunosorbent assay, CBA: cell based assay.
Table 2 outlines the presence or absence of intracerebral or spinal cord lesions on orbital/head/spine MRI and abnormalities in CSF among patient groups. Although CSF tests were attempted in hospitalized cases, patient refusal or discontinuation of test drug production, such as myelin basic protein, may limit test parameters. Lesions challenging to differentiate between intracerebral demyelination and chronic ischemic changes are categorized as ‘difficult’. Abnormalities in cerebral and spinal cord lesions and CSF tests were prevalent in MS/ON-DIS patients, with some abnormalities also observed in NMOSD and MOGAD cases. Idiopathic or other relapsing patients exhibited no MRI abnormalities, although some idiopathic cases showed oligoclonal bands and elevated myelin basic protein levels.
Table 2.
MRI and Cerebrospinal fluid test findings divided by coexisting demyelinating diseases.
| Idiopathic | NMOSD | MOGAD | MS | Other relapsing | ON+ | All | |
|---|---|---|---|---|---|---|---|
| Number | 47 | 19 | 16 | 16 | 7 | 6 | 111 |
| Findings in Orbital MRI, negative, positive (positive rate) | 0, 47 (0) | 2, 17 (11) | 3, 13 (19) | 4, 12 (25) | 0, 7 (0) | 3, 3 (50) | 12, 99 (11) |
| Findings in Head MRI, negative, positive, difficult (positive rate) | 20, 0, 1 (0) | 9, 3, 1 (23) | 9, 3, 2 (21) | 5, 6, 0 (64) | 5, 0, 0 (0) | 0, 6, 0 (100) | 48, 18, 4 (26) |
| Findings in Spinal Cord MRI, negative, positive, (positive rate) | 14, 0 (0) | 9, 2 (18) | 10, 1 (9) | 7, 1 (14) | 4, 0 (0) | 4, 1 (20) | 48, 5 (9) |
| Cerebrospinal Fluid Test | 27 (57) | 15 (79) | 16 (100) | 13 (81) | 7 (100) | 6 (100) | 84 (76) |
| Oligoclonal Bands, negative, positive (positive rate) | 25, 1 (4) | 10, 4 (29) | 16, 0 (0) | 8, 5 (38) | 7, 0 (0) | 2, 4 (67) | 68, 14 (17) |
| Myelin Basic Protein. negative, positive (positive rate) | 17, 5 (23) | 9, 7 (44) | 6, 8 (57) | 7, 8 (53) | 5, 0 (0) | 2, 3 (60) | 46, 31 (40) |
| IgG Index, negative, positive (positive rate) | 23, 0 (0) | 9, 3 (25) | 13, 1 (7) | 10, 3 (23) | 7, 0 (0) | 5, 1 (17) | 67, 8 (11) |
NMOSD: neuromyelitis optica spectrum disorders, MOGAD: myelin oligodendrocyte glycoprotein antibody-associated diseases, MS: multiple sclerosis, ON+: optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS, MRI: magnetic resonance imaging.
Table 3 compares abnormality presence between groups, exploring factors suggesting co-occurrence of demyelinating diseases like NMOSD/MOGAD/MS/ON+ rather than idiopathic optic neuritis. Serum antibody positivity and intracerebral lesions on MRI were significant factors, whereas no significant difference was observed in spinal cord lesions. Positive oligoclonal bands and elevated myelin basic protein levels in CSF suggested the presence of inflammatory demyelinating disease presence, though no significant difference was found in the elevated IgG index. Among 57 inflammatory demyelinating disease cases, 30 were monophasic with no recurrence of optic neuritis, encephalitis, or myelitis.
Table 3.
Comparison of parameters divided into idiopathic and systemic demyelinating diseases.
| Idiopathic | NMOSD/MOGAD/MS/ON+ | p value | |
|---|---|---|---|
| Number | 47 | 57 | |
| Age: y.o. Mean (IQR) | 37 (30, 56) | 41 (26, 56) | .84 |
| Sex: male, female (male ratio) | 18, 29 (38) | 19, 38 (33) | .68 |
| Right, Left, Both (each ratio) | 14, 24, 9 (30, 51, 19) | 23, 22, 12 (40, 39, 21) | .43 |
| AQP4(ELISA): negative, positive, (positive rate) | 46, 0 (0) | 37, 18 (33) | <.00001 |
| AQP4(CBA): negative, positive (positive rate) | 13, 0(0) | 11, 6 (35) | .02 |
| MOG(CBA): negative, positive, (positive rate) | 28, 0 (0) | 20, 17 (46) | <.00001 |
| Findings in Orbital MRI (positive rate) | 0 (0) | 12 (18) | .0001 |
| Findings in Head MRI: negative, positive, difficult (positive rate) | 20, 0, 1 (0) | 23, 18, 3 (41) | .0004 |
| Findings in Spine Cord MRI: negative, positive, (positive rate) | 15, 0 (0) | 29, 5 (15) | .31 |
| Oligoclonal Bands: negative, positive, (positive rate) | 25, 1 (4) | 36, 13 (27) | .03 |
| Myelin Basic Protein (negative, positive) | 17, 5 (23) | 24, 26 (41) | .03 |
| IgG Index, negative, positive (positive rate) | 23, 0 (0) | 37, 8 (17) | .09 |
| Hospitalisation (implementation ratio) | 39 (83) | 57 (100) | .001 |
| Monophasic (positive ratio) | 47 (100) | 30 (53) | <.00001 |
NMOSD: neuromyelitis optica spectrum disorders, MOGAD: myelin oligodendrocyte glycoprotein antibody-associated diseases, MS: multiple sclerosis, ON+: optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS, IQR: interquartile range, AQP4: aquaporin 4, MOG: myelin oligodendrocyte glycoprotein, ELISA: enzyme-linked immunosorbent assay, CBA: cell based assay, MRI: magnetic resonance imaging. Bold font indicates statistical significance (p< .05).
Table 4 illustrates overlapped results of orbital MRI and head or spine MRI. Six cases showed no cerebral lesions except for the optic nerve on orbital MRI but exhibited intracerebral lesions on head MRI besides the optic nerve. Conversely, spine MRI revealed no cases with lesions observed in both the orbital and spine MRI, but identified five cases with lesions in spine MRI but not lesions in brains in addition to optic neuritis. In this study, three patients were found to have new lesions on both spinal cord and head MRI, bringing the total to eight patients (7.2%) with new lesions identified on additional spinal cord or head MRI.
Table 4.
Head or spine MRI findings compared to orbital MRI.
| Head MRI |
||||
|---|---|---|---|---|
| positive | negative | |||
| Orbital MRI | positive | 12 | 0 | 12 |
| negative | 6 | 48 | 54 | |
| 18 | 48 | 66 | ||
| Spine MRI |
||||
| |
|
positive |
negative |
|
| Orbital MRI | positive | 0 | 6 | 6 |
| negative | 5 | 42 | 47 | |
| 5 | 48 | 53 | ||
MRI: magnetic resonance imaging.
Discussion
In our study of 111 patients with initial optic neuritis lacking cerebral or spinal symptoms, 20 patients exhibited lesions in the cerebrum or spinal cord. Among these, 4 had NMOSD, 4 had MOGAD, 7 had MS, and 5 had ON-DIS. Remarkably, 20 (35.1%) of the 57 cases, after excluding idiopathic or other relapsing cases, displayed cerebral and spinal cord lesions without apparent symptoms. This highlights the importance for ophthalmologists to be vigilant regarding the presence or absence of intracranial and spinal cord lesions.
Of these cases, 12 showed findings on both orbital and head MRI, while six presented no findings on orbital MRI without optic neuritis but displayed abnormalities on head MRI. Orbital MRI predominantly captures approximately 5–10 cm of the orbital region, whereas head MRI offers a broader imaging scope, including the parietal lobe. The significance of head MRI lies in its utility for early detection of cerebral lesions. However, considering the limitations of head MRI resolution in diagnosing optic neuritis, as the slice width approximates 2–2.5 mm while the intraorbital optic nerve diameter spans approximately 1.5–4 mm, it may not suffice.16 In addition, one of these six patients exhibited asymptomatic pyramidal signs during a neurologist examination, demonstrating the additional value of neurological assessments in uncovering underlying inflammatory demyelinating lesions. Conversely, five patients displayed lesions on spine MRI but not on orbital MRI without optic neuritis. Among these, two had NMOSD, one had MOGAD, and one each had MS/ON+.
In our dataset of 111 patients, a total of 8 individuals (7.2%) showed intracerebral or spinal cord lesions suggestive of systemic inflammatory demyelinating disease upon supplementary head or spine MRI. Particularly in MS cases lacking specific antibodies, MRI serves as a valuable tool for detecting lesions beyond the optic nerve. At our institution, patients with intracerebral lesions, lacking dissemination in time, are initially managed as ON+ and undergo MRI follow-ups every six months to a year.17 Intriguingly, five of these patients subsequently exhibited new asymptomatic lesions, leading to MS diagnosis and initiation of disease-modifying therapy to prevent further attacks.
Few studies have focused on intracerebral or spinal cord lesions in optic neuritis patients. In a 2003 British study, 81 (70%) of 117 optic neuritis patients displayed brain lesions, while 31 (27%) exhibited spinal cord lesions.13 Although our data significantly deviates from these percentages, it is likely due to the advancement of management after IVMP such as DMTs, rather than racial disparities.
Moreover, our study highlights oligoclonal bands and elevated myelin basic protein levels in CSF as indicators of systemic demyelinating disease presence. CSF findings are crucial in uncovering underlying diseases associated with optic neuritis. While previous reports linked CSF abnormalities to MS,14 our study suggests their relevance extends to NMOSD or MOGAD as well.18,19 Though not covered in our study, CSF also plays a vital role in excluding diseases like infiltrative optic neuropathy and infections.14
It is essential to note that our data may not directly reflect the proportion of intracerebral lesions in optic neuritis patients. As a neuro-ophthalmology consultation center, our hospital attracts many NMOSD and MOGAD patients needing specialized management to prevent relapse, skewing our data from past nationwide surveys of Japan.1 However, with the increasing prevalence of antibody measurements like AQP4 and MOG, research focusing on cerebral or spinal MRI abnormalities in newly diagnosed optic neuritis patients becomes imperative, underscoring the value of our findings. Another limitation of this study is that not all parameters were measured in every patient. Consequently, we have provided the actual counts of positive and negative findings to inform readers about the testing implementation rate. To truly assess the significance of these additional examinations, a prospective study testing all parameters in every case will be essential.
In conclusion, neuro-ophthalmology consultation centers frequently encounter patients with optic neuritis coexisting with NMOSD/MOGAD/MS/ON+, where brain findings are detectable using orbital contrast-enhanced MRI. It is crucial not to overlook these findings. Nonetheless, supplementary head MRI or spinal MRI uncovers additional brain or spinal lesions in 7.2% of patients. Particularly in MS cases lacking specific serum antibodies, it is essential to diagnose accurately, leveraging cerebrospinal fluid tests indicating characteristic brain lesions and demyelination.
Acknowledgments
This study will be presented at the 62th Annual Meeting of The Japanese Neuro-Ophthalmology Society held in Kanazawa, Japan.
Funding Statement
The author(s) reported there is no funding associated with the work featured in this article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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