Optic neuritis, characterized by inflammation of the optic nerve, is a common cause of visual loss amongst young patients.1 It can be associated with central nervous system inflammatory demyelinating diseases (CNS IDD), such as multiple sclerosis,2 neuromyelitis optica spectrum disease (NMOSD),3 and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).4
The Optic Neuritis Treatment Trial (ONTT)5 was a landmark trial that randomized patients with isolated acute unilateral optic neuritis into 1 of 3 treatment regimens—intravenous methylpred-nisolone, oral steroids, and placebo. Treatment with intravenous steroids accelerated visual recovery but did not make a significant difference in terms of final visual acuity, contrast sensitivity, or visual field outcomes. The clinical and therapeutic implications of this study have been variably adopted worldwide.6
More recently, the discovery of disease-specific neural antibody testing such as anti–aquaporin-4 (AQP4)7 and anti-MOG antibodies8 has allowed a better understanding of distinct phe-notypes of these different CNSIDD.9 The prevalence of CNSIDD differs between the Asian and White population,10 with local data showing comparatively lower rates of multiple sclerosis and higher rates of NMOSD and MOGAD in the multiethnic Singapore population compared to White.11
However, despite the higher prevalence of NMOSD (3.8/ 100,000) and MOGAD (1.3/100,000) in Singapore,11 little is known regarding how the clinicians manage these patients. In addition, as most previous studies reporting management of optic neuritis were based on surveys of clinicians managing a White population before the era of wide access to testing for NMOSD and MOGAD,12–15 it is not clear as to whether these observations are directly applicable in Asia, in particular, Singapore.
The aim of this study was to evaluate the practice patterns of optic neuritis investigation and management of neuro-ophthal-mologists and neurologists in the era of NMOSD and MOGAD from an Asian perspective and to compare it with current knowledge in the literature.
We created a 21-question online survey regarding the investigation and treatment ofoptic neuritis. Definition ofoptic neuritis was based on the ONTT,5 with a history consistent with acute unilateral optic neuritis in a young patient with visual symptoms lasting 8 days or less, evidence of an impaired afferent pupillary response, and a visual field defect in the affected eye. The survey was formulated based on 4 clinical vignettes, reflecting various clinical situations: (1) optic neuritis associated with mild visual loss, (2) optic neuritis associated with severe visual loss, (3) relapsing optic neuritis in a patient with known NMOSD, and (4) relapsing optic neuritis in a patient with known MOGAD (Supplementary Digital Content, Appendix 1, https://links.lww.com/APJO/A133). Demographic data about the respondents were also collected, including their subspecialty training, seniority, and current place of practice.
This survey was sent to all 17 Singapore Medical Council– registered ophthalmologists who had undergone or are undergoing a neuro-ophthalmology fellowship, and 25 neurologists, who manage optic neuritis on a regular basis (at least 1 case per year), from the major public hospitals in Singapore (National University Hospital, Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital, Ng Teng Fong General Hospital and Singapore National Eye Centre) and private practice. Informed consent was obtained from the respondents in the online survey form and the results were anonymized before data analysis. As this research was an anonymized educational survey with no identifiable subjects, it was determined to be exempt from Institutional Review Board under category 2.
In view of the small sample size of respondents (n = 42), our data were not powered to achieve comparison between the groups. As such, data analysis performed was descriptive.
Of the 42 respondents, 59.5% were neurologists and 40.5% were neuro-ophthalmologists. Amongst the 17 Singapore Medical Council–registered ophthalmologists who had undergone or are undergoing a neuro-ophthalmology fellowship, we obtained a 100% response rate. However, we were unable to calculate the response rate of the neurologists as not all neurologists in Singapore manage optic neuritis routinely. The 25 respondents who were invited to participate in our survey had an affiliation to the local neuroimmunology community and confirmed that they manage at least 1 case of optic neuritis per year. Majority were Consultants (n = 18, 42.9%) and Senior Consultants (n = 17, 40.5%), and the remaining 7 were Associate Consultants (16.6%). A vast majority practiced at a public hospital (88.1%), whereas the rest were in private practice (11.9%).
Clinical Vignette 1 — Optic Neuritis With Mild Visual Loss
Inthe case of unilateral typical optic neuritis with good visual acuity, unsurprisingly, 100% of respondents indicated that they would perform a magnetic resonance imaging (MRI) scan of the brain and anterior visual pathway with gadolinium contrast. Majority also chose to test for anti-AQP4 antibodies (88.1%), anti-MOG antibodies (76.2%), perform a screen for autoimmune diseases (66.7%) and a lumbar puncture (66.7%), in descending frequency. Regarding treatment, 90.5% of the respondents indicated that they would initiate steroids in this situation, and 100% stated intravenous administration of methylprednisolone (IVMP). Majority (84.2%) chose to give this as a once-daily regimen (1 g Q24H), whereas only 15.8% preferred to administer a divided dose (250 mg Q6H). The preferred duration ofIVMP was 3 days in 71.1%, and 5 days in the remaining 28.9%.
Clinical Vignette 2 — Optic Neuritis With Severe Visual Loss
In the case of unilateral optic neuritis with poor visual acuity, the majority of respondents offered an MRI brain (92.9%) in addition to the MRI anterior visual pathway already performed for the patient and would test for anti-AQP4 antibodies (97.6%) and anti-MOG antibodies (88.1%), perform an autoimmune screen (76.2%) and a lumbar puncture (73.8%). Figure 1 compares the respondents’ initial investigations performed in optic neuritis differentiated by severity of visual loss.
In optic neuritis with severe visual loss, 92.9% of respondents chose to administer standard doses of IVMP alone, whereas the remaining 7.1% preferred to administer both IVMP and plasma-pheresis concurrently at onset, even before the return of serologi-cal testing results for anti-AQP4 or anti-MOG antibodies. No respondent expressed the intent to initiate either oral steroids or plasmapheresis alone as initial treatment in this situation.
If the visual recovery was limited (ie, 6/60 after 3 days of 1 g/ d of IVMP), 95.2% of respondents elected to extend the IVMP, whereas 85.7% opted to escalate the treatment to plasmapheresis. Considerations for treatment escalation to plasmapheresis included lack of improvement in visual acuity after IVMP for 3 days (50.0%) and 5 days (40.5%). The remaining 9.5% opted to offer plasmapheresis only after obtaining formal proof that patients were positive for anti-AQP4 antibodies.
Clinical Vignette 3 — Known NMOSD Relapsing Optic Neuritis
In the case of relapsing optic neuritis in a patient with known NMOSD, all respondents opted for starting IVMP treatment and 83.3% opted for plasmapheresis. Minority of respondents would initiate immunosuppressants at the same sitting, and were divided over the choices—oral mycophenolate mofetil (38.1%), intravenous rituximab (28.6%), and oral azathioprine (21.4%). There was a higher percentage of neurologists [9/25, (36.0%)] compared to neuro-ophthalmologists [3/17, (17.6%)] who were keen to start intravenous rituximab. An even smaller minority (11.9%) would consider intravenous immunoglobulins. The respondents were divided equally (50% response each) over the decision to treat a patient with known NMOSD relapsing optic neuritis without first obtaining an MRI scan.
With regards to the timing of starting plasmapheresis, halfof the respondents would initiate it concurrently with intravenous steroids, whereas the other half would only initiate it after the completion of intravenous steroids. With regards to the timing of starting immunosuppression, the majority of the respondents (59.5%) would initiate it after the completion of intravenous steroids, whereas the remainder would initiate it concurrently with steroids. Compared to typical optic neuritis, respondents were more likely to initiate plasmapheresis (95.2%) and all were more likely to initiate immunosuppression in NMOSD relapsing optic neuritis.
Clinical Vignette 4 — Known MOGAD Relapsing Optic Neuritis
In the case of relapsing optic neuritis in a patient with known MOGAD, all respondents opted for IVMP treatment (100%) and 59.5% opted for plasmapheresis. A minority of respondents would initiate immunosuppressants at the same sitting and were again divided over the choices—oral mycophenolate mofetil (21.4%), intravenous rituximab (19.0%), intravenous immunoglobulins (19.0%), and oral azathioprine (16.7%). There was a higher percentage of neurologists [6/25, (24.0%)] compared to neuroophthalmologists [2/17, (11.8%)] who were keen to start intravenous rituximab. Figure 2 compares the respondents’ initial treatments offered in relapsing optic neuritis differentiated by NMOSD and MOGAD. Compared with typical optic neuritis, respondents were less likely to initiate plasmapheresis (52.4%) but were more likely to initiate immunosuppression (71.4%) in MOGAD relapsing optic neuritis.
Comparison of NMOSD and MOGAD Versus Typical Optic Neuritis
The signs indicating a higher suspicion for NMOSD were (from highest to lowest percentage of response)—intractable vomiting and hiccups (97.6%), chiasmal involvement on MRI (85.7%), limb numbness and weakness (83.3%), bilateral involvement (83.3%), recurrent attacks (66.7%), and steroid dependence (59.5%). The signs indicating a higher suspicion of MOGAD were (from highest to lowest percentage of response)—bilateral ophthalmic involvement (85.7%), exquisite steroid responsiveness (81.0%), optic disc swelling (66.7%), perineural enhancement on neuroimaging (66.7%), steroid dependence and recurrent attacks (64.2%).
Comparing total steroid duration in NMOSD relapsing optic neuritis to typical optic neuritis, respondents were more likely to give a longer duration of steroids (81.0%) and taper the steroids more slowly (88.1%). Comparing total steroid duration in MOGAD relapsing optic neuritis to typical optic neuritis, respondents were more likely to give a longer duration of steroids (66.7%) and taper the steroids more slowly (73.8%).
The main findings of this report are that the majority of clinicians managing optic neuritis in Singapore state routine testing for anti-AQP4 antibodies and anti-MOG antibodies in most patients with optic neuritis regardless of severity of the visual loss, and are willing to escalate treatment to plasmapheresis in cases with poor response to IVMP, even before obtaining serological evidence of anti-AQP4 antibodies or anti-MOG antibodies. Compared to typical optic neuritis, clinicians were more likely to initiate plasmapheresis in relapsing NMOSD but not MOGAD, and more likely to initiate immunosuppression in both relapsing NMOSD and MOGAD. Oral mycophenolate mofetil was the immunosuppressant of choice in our local context.
The strength of our study includes a robust response from stakeholders within the neuro-ophthalmic and neurology community in Singapore. We received a 100% response rate from all 17 Singapore Medical Council-registered ophthalmologists, who had undergone or were undergoing a neuro-ophthalmology fellowship, which is much higher than the response rates of 34.5% to 46.0% reported in previous surveys related to optic neuritis.6,12–15 In addition, the majority of respondents (83.4%) were either Consultants or Senior Consultants (senior clinicians in our local context with at least 3 or 7 years of specialist experience, respectively) who are the key decision-makers of investigation and treatment. As such, our survey results are likely to be reflective of the clinical practice locally.
Investigations for Optic Neuritis
Our survey results showed that almost all respondents obtain MRI imaging of the brain and anterior visual pathway with contrast in patients with presenting optic neuritis regardless of mild (100%) or severe (92.9%) visual loss.
Traditionally, ONTT has recommended obtention of brain MRI with contrast in patients with clinical optic neuritis to stratify a patient's risks of subsequently developing multiple sclerosis.5 More recently, it has been suggested that MRI of the anterior visual pathway with contrast in addition to the brain MRI may be useful to rule out alternative diagnoses and to provide radiologic confirmation of intrinsic optic nerve inflammation.16,17 In addition, certain patterns of enhancement may suggest a specific cause of optic neuritis, such as NMOSD with chiasmal involvement18,19 or MOGAD, with perineural and orbital fat enhancement.20
Overall, the practice in Singapore is in line with the ONTT recommendations of obtaining a brain MRI in all patients with optic neuritis to risk-stratify for multiple sclerosis. Also, the majority of responding clinicians also stated to include an MRI of the anterior visual pathway to examine for radiologic features that may suggest either NMOSD or MOGAD and identify or rule out alternative etiologies.
In vignette 1, the respondents were not provided with any information in terms of neuroimaging. In vignette 2, the respondents were provided with information of an MRI anterior visual pathway with contrast showing enhancement of the optic nerve, Due to the nature of the survey, we were unable to determine the rationale behind the 7.1% of respondents who did not offer an MRI brain, however, we hypothesize that they felt that an MRI of the anterior visual pathway was sufficient at that point in time.
There is currently no consensus with regards to systematic testing for autoimmune antibodies in optic neuritis. In Asia, Zhao et al21 showed in a retrospective observational study of 65 Chinese patients with demyelinating optic neuritis, 19 of the 45 (42.2%) patients with NMOSD had positive anti−Sjogren-syndrome-related antigen A (SSA)/Sjogren syndrome−related antigen B (SSB) anti-ANA, Human leukocyte antigen-B27 (HLA-B27) antibodies and thyroid-related autoantibodies. In the same study, none of the patients with MOGAD had similar autoantibodies. The Neuromyelitis Optica Study Group (NEMOS)22 and Liu et al23 also recommended testing for auto-antibodies in patients with suspected NMOSD.
Our survey results showed that the majority of respondents would routinely perform autoimmune testing [anti-nuclear antibody (ANA), anti-double stranded deoxyribonucleic acid (anti-dsDNA), anti-neutrophil cytoplasmic antibody (ANCA), extract-able nuclear antigen (ENA) profile, rheumatoid factor, anti-Ro, and anti-La] in mild cases of visual loss, and were even more likely to do so in severe cases. Although systematic testing for autoimmune antibodies is controversial, we suggest that our local practice reflects the clinician's increased suspicion for NMOSD in patients presenting with optic neuritis and poor vision.
Anti-AQP4 Antibody Testing
Routine systematic testing for anti-AQP4 antibodies is controversial, especially in low NMOSD-prevalent Western populations, because of the risk of false positives and the potential harm from unnecessary immunosuppression.24 The NEMOS has advocated antibody testing only in patients highly suspicious for NMOSD optic neuritis, that is, those with severe, relapsing or bilateral visual loss,22,25,26 and a positive result indicates a poorer visual prognosis.27
Since the discovery of the anti-AQP4 antibody, multiple diagnostic tests such as cell-based assays (CBA), tissue-based indirect immunofluorescence, enzyme-linked immunosorbent assays, fluorescence immunoprecipitation assays, and radio-immunoprecipitation assays have been developed. The CBA is the most specific (99.8%), highly sensitive (76.7%) with a high positive likelihood ratio of 383.5.24 A positive CBA result provides a high degree of confidence in establishing a diagnosis of NMOSD. In fact, the International Panel for NMO Diagnosis recommends testing with CBA (microscopy or flow cytometry-based detection) whenever possible because they optimize auto-antibody detection.28 More recent studies evaluating live CBA in a high-throughput setting demonstrated a specificity of1% and sensitivity of 8%.29 The highly specific CBA has led to proponents arguing for routine testing as the risk of recurrent attacks leading to severe disability is greater than the risk of receiving a false-positive test result.30
Without a clear consensus for systematic anti-AQP4 antibody testing, we might consider testing to be modulated geographically or by the ethnicity of the considered populations. Indeed, the prevalence of NMOSD differs by racial populations—it is 1/1, in White compared to 3.5/1, in the population with Asian ancestry and in East Asians, and 1 /1, in Africans.1,23 In multiethnic Singapore, the prevalence of NMOSD was 3.8/1, or 32.5% of 468 patients with CNS IDD.11 More specifically for optic neuritis, the seroprevalence of NMOSD also differs geographically and might be as high as 27% in Asians, compared to only 4% in non-Asians.31 In Asia, the prevalence of NMO seropositivity in patients with severe optic neuritis is variable, ranging from 39. 5% in Thailand32 to 32.4% in China33 and 20% in India.34
In Singapore, a recently published retrospective review of 106 Singaporean patients with optic neuritis, Siantar et al35 proposed a low threshold for anti-AQP4 antibody testing, especially in high prevalence populations, as the clinical features were nondiscriminatory for NMOSD in the cohort. Laboratory testing of the AQP4 antibody testing at the National Neuroscience Institute Singapore was performed using the Euroimmun CBA that has a reported high specificity of 100% and a sensitivity of 68%.36
The current survey results showed that the majority of respondents systematically screen for anti-AQP4 antibodies in both mild (88.1%) and severe (97.6%) optic neuritis. We suggest that this is due to NMOSD being more prevalent in our ethnically Asian Singaporean population compared to a White population. Our practices were in line with recent papers recommending that all optic neuritis should be tested for anti-AQP4 antibodies, as a positive result has significant implications for subsequent treatment.37,38
Anti-MOG Antibody Testing
Several factors affect the detection of MOG antibody. Firstly, timing of testing is important as antibody titers fluctuate greatly. They are higher during the acute attack in young children than in adolescents or adults.39 Antibody titers may decrease over months from presentation and become negative after the attack.40 Secondly, assay-specific factors such as those that affect conformation of the MOG protein, type of secondary antibodies, and whether the tests are conducted in the research or clinical setting may affect the assay sensitivities and specificities.41
A recent study by Sechi et al42 showed that although the MOG antibody test was highly specific (97.8%), its positive predictive value was titer dependent. The overall positive predictive value was 72%, and at low titers (using a cutoff of 1:20), it was even lower at 51%. As such, using it in low pretest probability situations will increase the proportion of false-positive results.
Given that the MOG antibody assay is less specific compared to the AQP4 antibody assay, some authors have advocated that testing for anti-MOG antibodies be reserved for patients exhibiting high clinical suspicion to reduce the risks of misdiagnosis.38 An international expert panel proposed indications for MOG testing to be based on specific clinical and paraclinical findings (i.e. monophasic or relapsing acute optic neuritis, myelitis or encephalitis with radiological findings compatible with CNS demyelination with either MRI, cerebrospinal fluid results, his-topathology, clinical findings, or treatment response character-istics).43 Similarly, Meltzer et al44 report routine testing for MOGAD only for patients with severe visual loss or bilateral eye involvement, as seropositive patients would benefit from a prolonged steroid course but may potentially be spared the toxicities from immunotherapies.
In a meta-analysis of adults with isolated optic neuritis, the seroprevalence of MOGAD ranged from 8% in non-Asian populations to 20% in Asian populations.31 In Singapore, the reported local prevalence is 1.3/100,000 or 10.9% of 468 patients with CNS IDD.11 Similar findings were reported in Japan45 and China, ranging from 10% to 19.6%, respectively.46
Our survey results showed that the majority of respondents screen for MOG antibodies in both mild (76.2%) and severe cases of (88.1%) optic neuritis. We hypothesize that the reason for increased testing even amongst the cases with mild optic neuritis could be due to the expert recommendations suggesting MOG testing for patients with prominent papilledema, papillitis, or optic disc swelling,43 coinciding with local data that suggest a higher incidence of papillitis within the Singaporean cohort of patients with optic neuritis compared with those in the ONTT (60% vs 35.3%).47 The presence of papillitis was similarly reflected in the case vignettes for both mild and severe optic neuritis as a realistic portrayal of patients our clinicians would encounter in their practice and could have led to more clinicians opting to test for anti-MOG antibodies.
Given that the clinical characteristics for Asian and White patients with optic neuritis differ, more work needs to be done to confirm if the recommendations for anti-MOG antibody testing proposed by the international expert panel43 can be directly applied to our cohort of patients.
Treatment of Mild and Severe Optic Neuritis
Based on the ONTT, the rationale for treatment with intravenous steroids included a hastening of visual recovery and a lower rate of progression to clinically definite multiple sclerosis at 2 years, although there was no eventual difference in visual acuity, contrast sensitivity, or visual field outcomes.5 Interestingly, in a post-hoc investigation, none of the patients included in the initial ONTT tested positive for anti-AQP4 antibodies and only 1.7% (3/ 177) tested positive for anti-MOG antibodies.48
Mild Optic Neuritis
The majority of our respondents (90.5%) would initiate IVMP treatment for patients with mild optic neuritis and good presenting visual acuity. With regards to the preferred dosage regimen for IVMP, some authors49 have reported a simplified regime of 1 g Q24H instead of the 250 mg Q6H regime used in the ONTT. Majority of our respondents preferred the simplified regime for 3 days. More importantly, we suggest that the frequency and duration of IVMP treatment have to be balanced against the risks of treatment, where adverse events could be potentially life-threatening.
Severe Optic Neuritis
In severe optic neuritis, a large majority of the respondents offered intravenous steroids treatment at onset. Subsequently, the majority would also extend treatment from 3 to 5 days if there was minimal improvement in the patient's vision. If there was no further improvement after 5 days of IVMP, the majority would then escalate treatment to plasmapheresis, even before any sero-logical evidence of either NMO or MOG antibodies.
Plasmapheresis can be effective in cases of optic neuritis with nonresponse to intravenous steroids, although this assumption is not based on large randomized clinical trials. Roesner et al50 reported improvement in 70% of 23 patients, with improvement of mean visual acuity of 16% to 45% after plasmapheresis. Deschamps et al51 reported improvement of median visual acuity from 0.1 or less to 0.8 after plasmapheresis in 41 eyes of 34 patients. Tan et al49 reported improvement in mean logMAR visual acuity of 2.61 to 1.66 after plasmapheresis in 37 patients. In all these 3 reports, the patients were escalated to plasmapheresis after showing minimal response to IVMP.
Adjuvant plasmapheresis can be offered before receiving confirmatory anti-AQP4 antibody results.37,44,53–55 The clinician should not delay performing plasmapheresis in patients who have poor response to steroids while awaiting the anti-AQP4 antibody confirmation, as there is no evidence associated with NMO status and plasmapheresis response,56,57 and delay may impact the patient's long-term prognosis.
With regards to the timing of plasmapheresis, 50% and 40.5% of the respondents would offer it if there was no improvement in the patient's visual acuity after 3 or 5 days of treatment with intravenous steroids, respectively. Again, there is no consensus for the timing at which plasmapheresis is performed. The mean duration between onset of symptoms and plasmapheresis reported by Deschamps et al51 was 34.6 days (median 28 days, range 6–92 days) and Tan et al52 was 27.2 ± 12.7 days (range 6–53 days). In addition, Tan et al52 also found that the eyes with good visual outcomes (visual acuity ≥20/40) had a significantly shorter symptom onset to plasmapheresis with a mean time window of 22.4 ± 11.1 days.
As such, we suggest that our local practices are in line with what is known in the literature about escalation of treatment to plasmapheresis in patients with minimal response to steroids.
Treatment of Anti-AQP4 Positive Relapsing Optic Neuritis
In the acute phase, the first-line treatment for relapsing optic neuritis in a patient with known NMOSD typically is IVMP.3 Rapid initiation of this treatment might improve visual out-comes58 and preserve retinal nerve fiber layer thickness.54 This was in line with our practices locally where all respondents considered initial treatment with IVMP. With regards to the dosage regimen, Guo et al59 found no significant difference in the effect of intravenous methylprednisolone treatment at either 500 mg or 1 g per day.
In many cases, plasmapheresis is required if monotherapy with steroids does not provide satisfactory results.60 This can be performed every other day for 5 to 7 cycles61,62 to remove potentially pathogenic antibodies in the circulation. Multiple retrospective studies have shown that plasmapheresis, in addition to treatment with intravenous steroids, may improve outcomes if given early63,64 and is superior to steroids alone.55,64–67 In a meta-analysis, plasmapheresis significantly reduced the mean expanded disability status scale (EDSS) score by 1.04 points [95% confidence interval (CI): −1.44 to −0.64].68
In addition, plasmapheresis can also be initiated as first-line therapy in known NMOSD patients with relapsing optic neuritis, who have previouslyrespondedwell to plasmapheresis.22,69 Inthe clinical vignette describing relapsing optic neuritis in a patient with known NMOSD, majority of our respondents (83.3%) stated performing plasmapheresis as treatment. The decision to use plasmapheresis needs to be balanced by the risks ofcomplications (hypotension, paresthesia, or occasionally anaphylaxis) that may occur in approximately 4% of patients.70
Early initiation of plasmapheresis might be associated with better outcomes, although there are no guidelines as to the exact timing of initiation.57,63 The optimal timing has been reported in a meta-analysis to range from between 8 and 23 days of symptom onset.68
In the Singapore survey, half of the respondents stated initiating plasmapheresis concurrently with IVMP, whilst the other half would initiate plasmapheresis after completion of treatment with IVMP with no improvement in visual acuity. Comparing relapsing optic neuritis in a patient with known NMOSD to that of an idiopathic typical optic neuritis, almost all (97.6%) of our survey respondents would be more likely to initiate plasmapheresis.
Interestingly, 50% of respondents stated that they would initiate this treatment for a patient with relapsing optic neuritis, without ordering additional neuroimaging.
In our survey results, only a minority (11.9%) of respondents would consider this as an acute treatment option for relapsing optic neuritis in a known NMOSD patient.
This is in line with small studies that report the use of intravenous immunoglobulins in the acute phase of relapses, because of a lack of response to steroids with/without plasma-pheresis.71 There have also been case series and case reports that describe patients with NMOSD whose clinical condition stabilized after initiation ofmonthly intravenous immunoglobulins.72–74 This suggests that intravenous immunoglobulins may be an alternative treatment option for patients with contraindications to first-line IVMP, plasmapheresis, or in children.
Long-term immunosuppression is recommended for all patients with NMOSD, including those who only have a single attack or those with negative anti-AQP4 antibodies with a severe relapse and incomplete remission,22 with the aim to prevent relapses and neurological disability.
Rituximab. Rituximab is a monoclonal antibody that targets the CD20 expressed on the surface of B cells, leading to its depletion, and is commonly used as an agent for immunosuppression in patients with NMOSD.
Tahara et al75 reported in a multicenter, randomized, double-blind, placebo-controlled clinical trial at 8 hospitals in Japan the efficacy of rituximab in preventing relapse of NMOSD. Nineteen patients were allocated to placebo and 19 were allocated to rituximab. Seven (37%) relapses occurred in the placebo group and none in the rituximab group (group difference 36.8%, 95% CI: 12.3–65.5; log-rank P
= 0.0058), and hence concluded that rituximab prevented relapses in patients with NMOSD for 72 weeks.
In an earlier randomized controlled trial by Collongues et al76 in 2015, they found that of the 21 relapsing NMOSD patients who received rituximab, 11 patients (52.3%) were relapse-free over a mean follow-up period of 31 months, with a mean annualized relapse rate (ARR) reduction from 1.3 to 0.4 (P < 0.001).
In the most recent meta-analysis by Wang et al,77 which evaluated 732 patients with NMOSD in 29 studies, it was reported that rituximab treatment reduced ARR by a mean of − 1.57 (95% CI: −1.78 to −1.35) and EDSS score by a mean of −0.57 (95% CI: −0.69 to −0.44). Comparing White to Africans and Asians, they found that the ARR of White before rituximab treatment was higher. However, there were no significant differences in ARR ratios among these 3 races after rituximab treatment.
Side effects of treatment include possible infusion reaction, opportunistic infections, and delayed leukopenia. Alternatives include low dose rituximab, which is also efficient and well-tolerated in the treatment of NMOSD, with significant decrease in anti-AQP4 antibody concentration after induction treatment and a relapse-free rate of 92.3% in 43 patients followed-up over 12 months.78 In addition, it is more convenient with a less frequent dosing compared to oral immunosuppressants that need to be taken daily.
Mycophenolate Mofetil. Mycophenolate mofetil is an inhibitor of guanine synthesis, preventing T- and B-cell proliferation. In a recent meta-analysis of 14 studies with 930 patients by Wang et al,79 it was shown that mycophenolate mofetil reduced the ARR by a mean of −1.17 (95% CI: −1.28 to −1.07) and was effective as a maintenance therapy for patients with NMOSD.
Azathioprine. Azathioprine is a purine analog and impairs DNA synthesis, preventing lymphocyte proliferation. In a meta-analysis of 21 studies with 1016 patients by Luo et al,80 it was shown that azathioprine reduced the ARR by a mean of −1.164 (95% CI: −1.396 to −0.932) and EDSS score by a mean of −1.117 (95% CI: − 1.668 to − 0.566), and was also effective as a maintenance therapy for patients with NMOSD.
Comparison of Immunosuppressants
A systematic review showed that rituximab was superior to the other treatments in terms of EDSS outcomes, annual relapse rate, time to first relapse, and relapses during treatment.81 In addition, they recommended that azathioprine and mycophenolate mofetil were effective, but had a worse risk-benefit ratio, hence were useful alternatives in places that do not have monoclonal antibodies. Another meta-analysis done also concurred that ritux-imab was hierarchically superior, and mycophenolate mofetil was ranked the most tolerable therapy.82 Comparing azathioprine and mycophenolate mofetil, both were effective in treating patients with NMOSD, with similar relapse-free periods in both, but fewer and milder adverse events due to mycophenolate mofetil.83 Tugizova et al8 reported rituximab as first-line treatment for NMOSD and transitioned those who relapse on rituximab to either azathioprine or mycophenolate mofetil.
Our survey respondents would be more likely to initiate immunosuppression in a patient with known NMOSD with relapsing optic neuritis, compared to a patient with typical optic neuritis. Our respondents indicated the following agents for chronic immunosuppressive treatment after a relapse: (1) oral mycophenolate mofetil, (2) intravenous rituximab, (3) oral aza-thioprine, and (4) intravenous immunoglobulins.
Surprisingly, in the current study, more respondents were keen to start oral mycophenolate mofetil than rituximab, despite the reported superiority in treatment efficacy. We suggest this may be due to our practice patterns in Singapore, where neurologists but not neuro-ophthalmologists, routinely initiate systemic treatment with rituximab. Due to the high proportion of neuro-ophthalmologists in our survey, the respondents might be more comfortable with the use of oral immunosuppressants such as mycophenolate mofetil and azathioprine, which can be initiated as outpatient treatment.
Treatment of MOG Antibody Positive Relapsing Optic Neuritis
There are currently no evidence-based guidelines with regards to treatment of MOGAD optic neuritis. As it is a relatively newly established entity, the natural history of the disease remains unknown. In the acute phase, treatment of MOGAD optic neuritis remains similar, with the use of IVMP 1 g/d for 3 to 5 days. Patients also tend to be highly steroid responsive.38 In the clinical vignette describing relapsing optic neuritis in a patient with known MOGAD, all our respondents would also start high dose intravenous methylprednisolone acutely.
Although the severity of MOG-related optic neuritis resembles NMOSD, many authors21,38,44 have reported a possibly more favorable long-term clinical outcome, with Jairus et al85 reporting 41.5% reaching almost full recovery.
In MOGAD patients with severe visual loss who remain unresponsive to treatment with intravenous steroids, plasmaphe-resis has been used as a second-line treatment.85,86 Jairus et al85 reported around 40% of attacks achieved complete or almost complete recovery after plasmapheresis, either as a stand-alone treatment or in combination with intravenous high-dose steroids. The same study also suggested that the variable response to plasmapheresis might be linked to differences in timing, MOG antibody titers, extension, intensity and sites of inflammation, and the number of cycles applied.
There is debate, however, with regards to the timing of plasmapheresis.87 Chen et al38 proposed the use of plasmapheresis only if the patient does not show demonstrable improvement within 1 to 2 weeks, but do not advocate for early plasmapheresis before treatment with intravenous high dose steroids. Marignier et al88 on the other hand suggested that similar to NMOSD, time to initiation of acute treatment and escalation may be a predictor of long-term outcome.
In the clinical vignette describing relapsing optic neuritis in a patient with known MOGAD with poor visual acuity, majority of the respondents (59.5%) considered plasmapheresis, which is unsurprisingly less than in a situation of known NMOSD (97.6%). Comparing relapsing optic neuritis in a patient with known MOGAD to that of an idiopathic typical optic neuritis, only 47.6% of our survey respondents would be more likely to initiate plasmapheresis.
We suggest that the reason for this difference may be as follows. In the clinical vignette, the poor visual acuity described would have prompted the clinician to consider escalation of therapy with plasmapheresis, hence most respondents would consider it as a treatment option. However, comparing MOGAD relapsing optic neuritis and typical optic neuritis, considering that 81.0% felt that MOGAD was exquisitely steroid-responsive, without visual acuity as a benchmark for severity, the majority of respondents may feel that initial treatment with steroids would be effective, and patients would be less likely to benefit from plasmapheresis.
In MOGAD optic neuritis, there is sparse literature with regards to the use of intravenous immunoglobulins in the treatment of acute relapse for adults. However, Hacohen et al89,90 reported that in the acute setting of pediatric MOGAD optic neuritis, intravenous immunoglobulins seem to be an effective therapy.
In our survey results, only a minority of respondents would consider this as a treatment option for a patient with MOGAD relapsing optic neuritis. More data are required to determine the efficacy ofintravenous immunoglobulins as a possible alternative treatment in adults.
In patients with MOGAD, there is a risk of recurrence in about 50% of patients and relapses can be reduced with the use of immunosuppressants.38 It is an important consideration for patients who have persistent seropositivity despite initial treatment and have more than 1 relapse.91
Like in NMOSD, immunosuppressants used include ritux-imab, azathioprine, mycophenolate mofetil, and intravenous immunoglobulins. A recent meta-analysis of 33 studies with 712 patients, showed that these agents are effective, and reduced the ARR before and after treatment, although the exact values were not reported.92 On the other hand, disease-modifying agents used for multiple sclerosis were found to be ineffective for MOGAD treatment.
However, there is still a risk of relapse despite being on immunosuppressant treatments. A study by Chen et al93 found (ranked from highest to lowest percentage relapse risk): myco-phenolate mofetil 74% (14 of 19; ARR 0.67), rituximab 61% (22 of 36; ARR 0.59), azathioprine 59% (13 of 22; ARR 0.2), and intravenous immunoglobulins 20% (2 of 10; ARR 0). All the 9 patients treated with disease-modifying agents for multiple sclerosis had a breakthrough relapse on treatment (ARR 1.5). Although rituximab reduces relapse rates in MOGAD, it is not as effective as with NMOSD.94
Comparing relapsing optic neuritis in a patient with known MOGAD to that of an idiopathic typical optic neuritis, majority of our survey respondents (71.4%) would be more likely to initiate immunosuppression. Our respondents were inclined to start immunosuppressants for a patient with known MOGAD and relapsing optic neuritis in the following order (highest to lowest percentage): oral mycophenolate mofetil, intravenous rituximab, and immunoglobulins equally, then oral azathioprine.
More work needs to be done to determine if Chen et al's93 results related to MOGAD can be extrapolated to our population in Singapore.
Comparison of NMOSD and MOGAD
Clinical and Imaging Characteristics
Differences in clinical characteristics of typical optic neuritis, NMOSD, and MOGAD have been described in the litera-ture.38,61,62
Both NMOSD and MOGAD are more likely to have bilateral, severe, recurrent visual loss compared to typical optic neuritis. NMOSD is more likely to occur in females, is associated with autoimmune conditions and incomplete recovery. MOGAD does not have a predilection for either gender, is not associated with autoimmune conditions but is associated with optic disc edema, steroid dependence, and more favorable visual recovery.
In addition, their neuroimaging characteristics also slightly differ. Compared to typical optic neuritis, NMOSD tends to affect the anterior visual pathway with extensive longitudinal enhancement of the optic nerve, and more of the posterior segments (intracranial rather than intraorbital region, therefore, less disc edema), hence a higher likelihood for optic chiasmal involvement and bilateral disease.18,19 Brainstem involvement can also cause intractable hiccups or vomiting, symptomatic narcolepsy, and neuroendocrine dysfunctions.95,96
In MOGAD, the disease tends to affect the more anterior segments of the optic nerve, hence optic disc swelling is more common, in addition to perineural enhancement of the optic nerve sheath and peribulbar structures.20,85 Although the optic chiasm can be involved—reported by Zhao et al21 to be 15% in the Chinese cohort of 20 patients, it is less commonly encountered compared to NMOSD.97 In the brain, there can be poorly demarcated “fluffy” deep white matter, juxtacortical, brainstem or cerebellar peduncle lesions.38,61,62
A recent study by Tajfirouz et al98 comparing 74 NMOSD and 80 MOGAD patients reported chiasmal involvement in 20% and 16% respectively (P
= 0.66). Chiasmal involvement in MOGAD was also more likely to be part of a longitudinally extensive optic nerve lesion.
However, not all patients with NMOSD and MOGAD will have the “classic” characteristics and clinically it may still be difficult to distinguish between the 2 conditions given the overlapping similarities in presentation, despite a marked difference in their underlying pathophysiology.99
We put forth questions regarding differences between typical optic neuritis and either NMOSD or MOGAD and found that our respondents were able to discriminate relatively well, in line with evidence from literature.
Signs associated with NMOSD, which had a majority of the responses saying “yes” to, were as follows (highest to lowest percentage): intractable vomiting and hiccups, chiasmal involvement on MRI, limb numbness and weakness, bilateral involvement, recurrent attacks, and steroid dependence. Signs associated with MOGAD, which had a majority of the responses saying “yes” to, were as follows (highest to lowest percentage): bilateral involvement, exquisite steroid responsiveness, optic disc swelling, peri-neural enhancement, steroid dependence, and recurrent attacks.
Steroid Duration and Taper
In the acute phase, treatment of typical optic neuritis with intravenous steroids as per the ONTT is for 3 days, with subsequent use of oral steroids for 11 days with a quick taper.
In NMOSD, recommended treatment by the NEMOS is with intravenous steroids for 5 days for an acute attack.22 In older studies, a second course of steroids has been offered to patients, for example, those with contraindications to plasmaphere-sis.100,101 For prevention of further relapse and a rebound worsening after completion of intravenous steroid treatment, these patients are given a course of tapering oral steroids for 2 to 6 months, to control the inflammation before the immunosup-pressants achieve a therapeutic effect.38,61,62
In MOGAD, there are no consensus guidelines in the literature, butChenetal38 suggest a similar treatment regime of intravenous methylprednisolone is given for 3 to 5 days, depending on response. Subsequently, patients are given a course of oral steroids with a slow taper over 3 to 6 months.102 Various regimens have been suggested including the use of 1 mg/kg per day for 3 months with a progressive tapering over the next 3 months103 as most of the recurrence episodes occurred toward the end of the taper or shortly after prednisolone cessation, whereas others have suggested an even longer taper of oral steroids of up to 12months.84 Chenetal38 suggested that if the patient cannot be tapered to a prednisolone dose of 10 mg or less, a chronic immunosuppressive agent is required.
In our survey response for NMOSD optic neuritis, 81.0% of respondents would give a longer duration of total steroid treatment and 88.1% would taper it gradually over a longer period. In our survey response for MOGAD optic neuritis, 66.7% of respondents would give a longer duration of total steroid treatment and 73.8% would taper it gradually over a longer period. These responses are in line with what is currently known about NMOSD and MOGAD treatments with steroids.
Limitations of Our Study
The clinical vignettes used in our study were created based on “classical” characteristics of each condition and may not represent the entire spectrum of disease a clinician may face in actual clinical practice. However, we have attempted to design the scenarios with minimal ambiguity, aiming to identify typical treatment and practice patterns of the neuro-ophthalmology and neurology community in Singapore.
Another limitation of our study was the forced-choice nature of the survey, which may not reflect the full extent of clinical presentations of patients and treatment options in a “real-world” scenario. Although this may limit the generalizability of our results, majority of the options provided were those that were available to clinicians practicing in our local context.
Various treatment options were theoretically considered before the designing of the study, including mega-dose oral prednisolone and monoclonal antibodies (eculizumab, inebilizu-mab, and satralizumab). However, for practical reasons, these options were not included in the questionnaire as they are not available in Singapore and therefore not discussed in our paper.
The decision to exclude other conditions that may also present with optic neuritis, such as multiple sclerosis and chronic relapsing inflammatory optic neuropathy, was deliberate and made by the coauthors of this paper because we wanted to focus on NMOSD and MOGAD optic neuritis.
Total sample size of our respondents (n = 42) was relatively small, and we were unable to perform statistical analysis to determine if there were significant differences between the groups. As such, most of our results were descriptive.
The purpose of our survey was to understand the practice patterns of physicians who were effectively evaluating and treating patients with optic neuritis in Singapore. Due to the sub-specialized nature of our health care system, not all general ophthalmologists and neurologists in Singapore directly deal with these patients. Hence we only included those who are regularly and actively involved with the management of optic neuritis patients in Singapore, with the inclusion criteria being those who manage at least 1 case of optic neuritis per year, on average.
Practice patterns toward optic neuritis management within the neuro-ophthalmology and neurology community in Singapore are in line with available evidence in the literature. Majority routinely test for anti-AQP4 and anti-MOG antibodies in every presenting optic neuritis case. In severe optic neuritis, clinicians tend to rapidly escalate treatment to plasmapheresis after the use of IVMP, even before obtaining serological evidence of either anti-AQP4 or anti-MOG antibodies. In relapsing optic neuritis associated with known NMOSD or MOGAD, clinicians offer IVMP and plasmapheresis acutely. In both NMOSD and MOGAD, oral mycophenolate mofetil is the preferred agent for chronic immunosuppression; steroids are given for a longer duration and tapered more gradually.
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