Efficacy of Plasma Exchange Treatment for Demyelinating Optic Neuritis Associated with Various Serum Antibodies: A Prospective Cohort Study

Demyelinating optic neuritis (ON), which can cause acute or subacute vision loss, occurs worldwide, but incidence varies among races [1]. The discovery of two biomarkers, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies, has allowed recognition of the cause of atypical ON, which is characterized by severe visual loss (worse than 6/60 or 20/200), no recovery within 3 weeks of onset, and progression of visual loss for more than 2 weeks [1]. The AQP4 antibody is pathogenic and highly specific for neuromyelitis optica spectrum disorder (NMOSD) [2], whilst the MOG antibody is a biomarker of MOG antibody-associated disorder (MOG-AD) [3]. AQP4 antibody-positive ON (AQP4-ON), which is dominant in the Asian population, is associated with more severe episodes and poor visual recovery [4]. In contrast, MOG antibody-related ON (MOG-ON) exhibits no distinct ethnic predilection, although associated with recurrent ON [5, 6]. With no biomarker currently recognized, double-antibody-negative ON (D-ON), exhibits a distinct clinical presentation, and idiopathic ON [7, 8] or multiple sclerosis (MS)-related ON [9] without a recognized biomarker may also be included as “D-ON.” Demyelinating ON tends to relapse, leading to cumulative blindness and disability, so timely and effective treatment is essential to save vision. Intravenous high-dose methylprednisolone (IVMP) is the standard first-line treatment for acute ON, while plasma exchange (PE) is performed as a rescue method in patients with ON refractory to IVMP treatment. PE has been reported to be useful in treating steroid-resistant ON [10‐13], severe ON due to NMOSD [14‐16], and recurrent ON at risk for poor recovery [17].

The seventh edition of the clinical treatment guidelines of the American Society for Apheresis (2016) identified PE as the recommended grade IB and class II indications for the treatment of acute NMOSD [18]. Several studies and subsequent meta-analyses have revealed that PE can lower disease activity and improve functional scoring (Expanded Disability Status Scale, EDSS) in NMOSD [15, 19‐28]. However, confounding factors and different disease entities can lead to several contradictions. One concern is whether different antibody subtypes are related to prognosis. While some studies have concluded that a positive AQP4 antibody result is associated with time to complete improvement [29, 30], others have suggested that AQP4-Ab-seronegative patients are associated with a superior response to PE therapy [17, 20]. There is limited evidence about the efficacy of PE for MOG-ON or D-ON patients. Benefit-related factors, including the correlation between the benefit of PE and the timing of PE initiation are also somewhat controversial. Most studies concur that early initiation may increase the benefit to NMOSD patients [17, 20, 21, 25, 29, 30], while some studies reported no strong correlation between the interval from relapse to PE treatment and 3-month functional scoring [14], and another study concluded that the time window from the onset of attack to PE initiation was not significantly associated with treatment outcome in children with acute inflammatory demyelinating central nervous system (CNS) syndromes [24]. Due to the scarcity of plasma resources, determining the optimal timing of treatment is valuable for clinical guidance. Our previous study showed that PE treatment effectively improved the visual outcomes of a small group of patients experiencing their first attack of severe acute isolated ON [28]. Clinically, many ON patients suffer a long disease duration, experiencing episodes of relapse. However, research on the therapeutic effect of PE for these patients is scarce. This study aimed to evaluate the efficacy of PE in improving visual outcomes in ON patients with different serum antibodies after treatment with IVMP and to determine the factors associated with visual improvement.

This paper reports the findings of a relatively large cohort study of PE rescue treatment for ON attacks unresponsive to IVMP, which revealed that PE treatment effectively improved VA in AQP4-ON patients. This study also identified the time window from onset to PE initiation as the key factor for VA prognosis. The concept “Time is Vision” should be emphasized in the treatment of acute ON.

A previous study reported that patients with D-ON often displayed early development of severe visual impairment, with about 75% of patients experiencing very poor outcomes after the first ON attack. Recovery of VA in the D-ON group was as poor as that of the AQP4-ON group [7, 8]. There is currently a paucity of data on D-ON. Mild D-ON patients may have excellent functional central acuity recovery spontaneously or recover after IVMP treatment, rendering PE therapy unnecessary. In this cohort study, 18 of 22 D-ON patients experienced their first attack with a mean PE initiation of 22.78 ± 11.37 days (range 7–49 days). However, VA improvement was limited even after five-cycle PE therapy (Friedman P = 0.659, Fig. 2a), indicating that PE therapy may be of limited benefit for patients with severe D-ON.

As a large proportion of MOG-ON patients achieved relatively better prognosis after IVMP, only a small cohort of MOG-ON patients were recruited in the current study; therefore, only descriptive data could be reported for this condition (Table S2, Fig. 2b). For two patients (patient 2 and patient 4), the treatment was implemented after their first ON attack. Both had bilateral eye involvement and were of similar age (47 years and 54 years), and their VA before PE treatment was NLP. However, patient 4 recovered to 20/25, whilst patient 2 remained NLP. Other than the small age gap, the major difference was the time window from onset to PE initiation (19 and 75 days, respectively). Of the remaining four patients, patient 1 had experienced 12 ON attacks over the past 7 years, and received timely PE treatment within 11 days of onset. The worst VA before treatment was 20/50, after IVMP but before PE was 20/30, after PE was 20/25, and finally achieving 20/20 Snellen VA. For the other three patients who had different ages of PE initiation, experiencing between three and six ON episodes over the past 3–20 years, although PE initiation was relatively timely (within 20 days for patient 3 and patient 5), no obvious VA improvement occurred. Patient 4 improved dramatically from NLP to 20/25 after receiving PE treatment. However, it was still difficult to ensure that the improvement after PE in these patients was due to the additional PE treatment. This issue will need to be addressed in further studies.

In contrast, the mean logMAR VA measurements in the AQP4-ON group improved markedly after five cycles of PE treatment (Friedman P < 0.001, Fig. 2c), and the VA of 95 eyes was steadily maintained, despite a longer disease duration (3.52 ± 4.25 years) and a higher proportion of past ON history (70.8%). The proportions of patients in each visual outcome category shifted significantly toward an improved distribution after PE therapy (adjusted P = 0.001, Fig. 3, Table S3). These results indicate that PE therapy effectively improves visual outcomes in AQP4-ON patients.

It was observed that VA improvement leveled off, showing no difference in VA or proportion of patients in each VA category at four time points after PE treatment. A multivariate analysis was conducted to determine the factors associated with achieving VA score improvement ≥ 2 levels, which produced a combined predictive factor equation: the combined factor (Y) = (−1) × time window from onset to PE treatment (days) − 11.11 × the number of previous ON episodes. The derived ROC curve demonstrated that a combination of the number of previous ON episodes and the time window of PE initiation could more efficiently predict the occurrence of VA score improvement ≥ 2 levels after PE treatment and the cutoff point that optimizes the balance between sensitivity and specificity was −49.78 (sensitivity 80.6% and specificity of 64.6%) (Fig. 4a). This indicates that the time window is 49.8 days for patients with their first attack of ON, 38.6 days for patients with one previous ON episode, 27.5 days for patients with two, 16.5 days for patients with three, and 5.3 days for patients with four. It also reveals a low probability of achieving a score improvement of two or more levels after PE therapy for patients with five or more episodes.

The same analysis showed that the logMAR VA before PE treatment combined with the time window from onset to PE treatment could predict the likelihood of regaining less than 1.0 logMAR vision with the cutoff point −83.42 (87% sensitive and 64.4% specific) (Fig. 4b) and the predictive factor (Y) = (−1) × time window from onset to PE treatment − 22.73 × the logMAR VA before PE treatment. That is, the treatment time window was 22 days for patients with HM VA before PE treatment and 51.6 days for patients with CF VA before PE treatment. The histogram directly demonstrated that patients who received early initiation of PE treatment had a greater opportunity to achieve increased improvement in VA. When the treatment time window exceeded 60 days, there was a low probability of achieving a visual improvement score > 3 (Fig. 5, Table S6).

In summary, the smaller number of attacks, the better VA before treatment, and the shorter treatment time window are indicators of the likely success of the PE therapy. Early diagnosis of ON, together with timely commencement of PE to prevent permanent visual disability should be given higher priority [35]. Our results emphasize that “Time is Tissue,” a core principle in neuroimmunology, and the precept that “Time is Vision” should be considered in either IVMP or PE initiation therapy [36], viewing AQP4-ON as an emergency. Because less serious adverse events occurred in our cohort, we would recommend the treatment approach for demyelinating ON as follows: after patients are diagnosed with demyelinating ON, initiation of IVMP treatment is recommended as soon as possible, followed by oral prednisone. When AQP4-ON can be confirmed and is “unresponsive to initial IVMP therapy,” we recommend escalating to five-cycle PE treatment immediately for AQP4-ON patients. The recommended time window is within 49.8 days for patients with first attack of ON, 38.6 days for patients with one previous ON episode, 27.5 days for patients with two episodes, 16.5 days for patients with three episodes, and 5.3 days for patients with four episodes. The treatment time window for PE should be within 22 days for patients with VA of HM and 51.6 days for VA of CF.

Previous studies have shown that progressive axonal loss may follow acute inflammatory demyelination, and ongoing subclinical inflammation may continue to develop over several years after an attack, as evidenced by a reduction in the pRNFL and decrease in the macular ganglion cell layer and inner plexiform layer (GCIPL) in longitudinal OCT studies [37, 38] and a mean decrease in the optic nerve area over a 1-year follow-up period in serial magnetic resonance imaging (MRI) studies [39, 40]. Further episodes of ON, leading to additional demyelination and failure of remyelination of the initial lesion, may contribute to conduction block, and over time, to secondary axonal degeneration [41]. In addition, the loss of critical macular axons may affect the ability of the visual system to compensate. Therefore, timely control of inflammation and prevention of recurrence are crucial. The rationale behind the improvement of prognosis by PE is as follows: The principle of PE is to separate the patient’s blood into plasma and blood cells via a blood cell separator to remove harmful and pathogenic components in the plasma and replace these with an equal amount of fluid and then transfuse the blood cells and PE fluid back into the patient [42]. PE can improve disease activity by reducing circulating antibodies, abnormal plasma proteins or cytokines, and other pathogenic macromolecules [42]. Early initiation of PE treatment can alleviate complement activation and subsequent inflammatory tissue destruction in AQP4-ON patients by clearance of AQP4-IgG, a critical driver in the evolving NMOSD lesion, which may decrease the synthesis and secretion of complement components, cytokines, and chemokines. Timely removal of complement protein may block the crosstalk between astrocytes and microglia [43, 44], rapidly blocking ganglion cell loss and preserving visual function [45]. In the future, we intend to evaluate the relationship between the pathogenic AQP4 antibody and prognosis, as well as to establish a model of PE efficacy and determine the concentration of the pathogenic AQP4 antibody.

This study does have several limitations. Firstly, only six patients with MOG-ON were included in this study of PE therapy, allowing only a descriptive analysis about the changes in logMAR VA with PE treatment in MOG-ON. The number of patients with D-ON was also relatively small, so a larger study is still needed to support the conclusions of this study for D-ON. Secondly, as this was a one-arm study, the effect of IVMP treatment is difficult to exclude. No statistically significant differences existed in mean logMAR VA before and after IVMP treatment, but a difference existed after IVMP treatment in each VA category. Further research should include equivalent-baseline ON patients who only received treatment for acute IVMP, in order to separate the effect of the IVMP therapy. Thirdly, the AQP4 antibody titer was not quantified longitudinally because of difficulty in conducting follow-ups related to changes in antibody titer changes. Thus, the correlation between therapeutic effect and the change in antibody titer should be investigated to improve the clinical estimation of the value of the therapy. Moreover, because some of the attacks were recurrent, and the patients received the initiation IVMP for their first attack outside the study site, the information on the initiation of IVMP, such as time or dosage, was missing. Furthermore, due to the paucity of plasma resources, not all the patients could receive PE treatment at the expected time after onset. There is currently no evidence-based data about the exact initiation window for PE therapy. These factors lead to inconsistency in the time window for therapeutic PE. However, based on the large time window of PE initiation to onset, which ranged from 9–157 days (some patients’ PE initiation > 60 days), in this observational study, the time window of PE initiation which benefited prognosis could be determined. Lastly, optic disc swelling causes difficulties in assessing the degree of severity. One (0.1%) AQP4-ON patient with optic disc edema was excluded from the analyses. Unfortunately, neither GCIPL nor pRNFL was collected at follow-up in the current study.

The most salient points of this study are the importance of antibody detection and serotyping of acute ON, to guide the use of PE treatment. PE therapy effectively improves visual outcomes for AQP4-ON patients, but provides limited value for D-ON patients. This study has provided a statistically rational treatment time window for AQP4-ON patients dependent on the previous history of their disease. In summary, the earlier the treatment commences, the greater the benefits.