Multiple Sclerosis-associated Optic Neuritis Research Articles

Factors That Influence Clinician Prescribing of Corticosteroids for Acute Idiopathic and Multiple Sclerosis-Associated Optic Neuritis: A Qualitative Study.

Treatment with corticosteroids is common for patients with idiopathic and multiple sclerosis-associated optic neuritis (I/MS-ON). Yet, the Optic Neuritis Treatment Trial and meta-analyses confirm that few patients benefit and that visual benefit is of questionable clinical significance, short-lived, and comes with potential harms. The purpose of this study was to uncover the breadth of factors that underlie clinicians' treatment decisions and determine how these factors may influence corticosteroid use for I/MS-ON. We performed semistructured, one-on-one, qualitative interviews with neurologists, neuro-ophthalmologists, and emergency department clinicians at 15 academic and private practices across the United States. The interview guide used the Theoretical Domain Framework and a vignette to explore numerous factors that might influence decision making for definite I/MS-ON. We analyzed transcripts using inductive thematic analysis to generate themes. A total of 22 clinicians were interviewed before thematic saturation was reached: 8 neuro-ophthalmologists, 8 neurologists, and 6 emergency medicine (EM) clinicians (2 physician assistants, 4 physicians). All neuro-ophthalmologists and nearly all neurologists (7 of 8) were aware of risks/benefits of corticosteroid treatment for I/MS-ON. However, neuro-ophthalmologists varied in their corticosteroid treatment recommendation (n = 3 recommended treatment, n = 2 recommended observation, n = 3 recommended shared decision making), whereas all neurologists recommended corticosteroids, indicating that knowledge of corticosteroid risk/benefit alone does not drive decision making. EM clinicians were not aware of risk/benefits of corticosteroid treatment for I/MS-ON and relied on the treatment recommendations of neurologists. Clinicians recommending corticosteroids held personal beliefs that corticosteroids benefit those with worse vision loss, relieve pain, allow earlier return to work, or have easily mitigated side effects. They also perceived that prescribing steroid was the principal method of "doing something," which fit a key provider role. Clinicians who did not recommend corticosteroids or were neutral perceived the risks as nontrivial, considered discussing treatment trade-offs as "doing something" and incorporated patient preferences. Knowledge of risk/benefits of corticosteroids are necessary but not sufficient for evidence-based I/MS-ON practice. Variation in how clinicians treat patients with acute I/MS-ON is influenced largely by psychosocial factors, such as beliefs about corticosteroid risk/benefit trade-offs and the role of the clinician to provide treatment. Interventions to support evidence-based decision making for I/MS-ON treatment will need to provide risk/benefit information to support clinicians with varying levels of expertise, incorporate patient preference, and normalize the option to observe.

Features and associations of optic neuritis in the Middle East: A cross-sectional study

BackgroundDifferences exist in the clinical profile of optic neuritis (ON) among various populations. The present study outlines the features of optic neuritis and its associations in Middle Eastern population. MethodsIn a single tertiary care neuro-ophthalmology clinic, we reviewed charts between 2016 and 2021, to identify patients with optic neuritis. Patients with at least one single episode of ON, and a follow up for at least 6 months were only included. Patients from countries outside the Middle East were not eligible. We performed a sub-analysis using data from the clinic, laboratory, and radiological findings to classify patients with optic neuritis into 4 groups: idiopathic ON, multiple sclerosis associated optic neuritis (MS-ON), neuromyelitis optica spectrum disorder associated optic neuritis (NMOSD-ON), and myelin oligodendrocyte glycoprotein associated disease optic neuritis (MOGAD-ON). Results77 patients met the criteria for inclusion in the study. Approximately, two thirds of the patients (64%, 95% CI [0.52–0.74]) had MS-ON, 17 patients had idiopathic ON (22.6%, 95% CI [0.13–0.33]), 6 patients were diagnosed with NMOSD-ON (8%, 95% CI [0.02–0.16]), and 4 patients had MOG-ON (5.3%, 95% CI [0.01–0.13]). More than half of patients with idiopathic ON were found to have clinically isolated syndrome (CIS) and thus to be at high risk of developing MS. Among all patients enrolled in the study, the mean age was 29.8 ± 9.53 years. Patients with MS-ON and MOG-ON were relatively younger compared to patients from other groups (P = 0.0005). There was a female preponderance among all groups except MOG-ON, where 80% were males (P = 0.11). The pre- and post-treatment logMAR visual acuity (VA) tended to be worse in NMOSD-ON than other categories (P = 0.062). Optic disc swelling was more common among patients with MOGAD-ON, and least common in patients with NMOSD (100% vs 0%, P = 0.001). 5 patients presented with simultaneous bilateral involvement, and all but one had NMOSD-ON. 29% of patients had recurrence during the time of the study with significant difference in prevalence across groups. There was no difference in the involvement of the chiasm, or the retro-chiasmal pathways across groups. ConclusionsOur study demonstrates that multiple sclerosis (MS) is the predominant CNS demyelinating disease associated with optic neuritis (ON) in the Middle Eastern population, mirroring trends observed in Western populations. The clinical and radiological features of each subtype showed no significant divergence compared to findings from studies conducted in other regions globally. These insights contribute to a deeper understanding of ON's clinical spectrum and aid in refining diagnostic and management strategies in the Middle Eastern population.

Trends in Plasma Exchange Use in Optic Neuritis Hospitalizations in the United States

To report use trends of plasma exchange (PLEX) as well as sociodemographic and medical comorbidities associated with PLEX in the United States. Retrospective cross-sectional study. Adult patients (≥ 18 years) admitted for inpatient hospitalization with a primary diagnosis of optic neuritis (ON). Data from the National Inpatient Sample database was compiled to assess PLEX use rates between 2000 and 2020. The cohorts of patients receiving PLEX versus not receiving PLEX were analyzed between quarter 4 of 2015 through 2020 (International Classification of Diseases, Tenth Revision [ICD-10], only) for patient sociodemographic variables, medical diagnoses, insurance types, hospital characteristics, cause of disease, time to therapy, length of stay (LOS), and total charges incurred. Incidence of ON, incidence of PLEX, demographics, diagnoses associated with PLEX therapy, total charges, and LOS. From 2000 through 2020, 11 209 patients hospitalized with a primary diagnosis of ON were identified, with a significant majority managed at urban teaching hospitals. Use of PLEX increased steadily over 2 decades from 0.63% to 5.46%. Use was greatest in the western United States and least in the eastern United States. In the subset of ICD-10 cases, 3215 patients were identified. The median time to therapy of PLEX was 1 day after admission, and PLEX use was highest in patients with neuromyelitis optica spectrum disorder (NMOSD) (21.21%) and lowest in multiple sclerosis-associated ON (3.80%). Use of PLEX was associated with significantly longer LOS and higher total charges incurred. Medical comorbidities associated with PLEX included adverse reaction to glucocorticoids (adjusted odds ratio [aOR], 31.50), hemiplegia (aOR, 28.48), neuralgia (aOR, 4.81), optic atrophy (aOR, 3.74), paralytic strabismus (aOR, 2.36), and psoriasis (aOR, 1.76). Over the last 2 decades in the United States, PLEX therapy for ON has increased, with the highest use in the western United States and for patients with the diagnosis NMOSD ON. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Differences in morphology and visual function of myelin oligodendrocyte glycoprotein antibody and multiple sclerosis associated optic neuritis

BackgroundMyelin oligodendrocyte glycoprotein immunoglobulin G associated optic neuritis (MOG-ON) is a recently described entity. Recent studies have shown that MOG-ON has a more severe clinical presentation than classic optic neuritis (ON).ObjectiveThis study aimed to define morphological characteristics of MOG-ON, correlate these with clinical characteristics and compare them with multiple sclerosis associated ON (MS-ON) and healthy controls (CTRL).MethodsIn a retrospective study, we included MOG-ON and MS-ON patients seen between 2011 and 2018 at the University Hospital Bern. Data from clinical examination, perimetry, and optical coherence tomography (OCT) were analyzed.ResultsA total of 66 eyes of 43 patients were included; 22 MS-ON and 33 CTRL eyes were sex- and age-matched to 11 MOG-ON eyes. We found significantly worse visual acuity at nadir, but better recovery and thinner global peripapillary retinal nerve fiber layer thickness in MOG-ON patients compared to MS-ON patients. Both groups exhibited irregular thinning of the macular ganglion cell layer. Furthermore, the visual acuity and visual field parameters correlated to retinal layer thickness only in MOG-ON eyes.ConclusionIn comparison to MS-ON, MOG-ON is associated with more prominent acute vision loss and more pronounced global thinning of the pRNFL. Both entities result in similar final visual acuity and atrophy of the macular ganglion cell layer.

Influence of retinal NMDA receptor activity during autoimmune optic neuritis.

Autoimmune optic neuritis (AON), a model of multiple sclerosis-associated optic neuritis, is accompanied by degeneration of retinal ganglion cells (RGCs) and optic nerve demyelination and axonal loss. In order to investigate the role of N-methyl-d-aspartate (NMDA) receptors in mediating RGC degeneration, upstream changes in the optic nerve actin cytoskeleton and associated deterioration in visual function, we induced AON in Brown Norway rats by immunization with myelin oligodendrocyte glycoprotein. Subsequently, visual acuity was assessed by recording visual evoked potentials and electroretinograms prior to extraction of optic nerves for western blot analysis and retinas for quantification of RGCs. As previously reported, in Brown Norway rats RGC degeneration is observed prior to onset of immune cell infiltration and demyelination of the optic nerves. However, within the optic nerve, destabilization of the actin cytoskeleton could be seen as indicated by an increase in the globular to filamentous actin ratio. Interestingly, these changes could be mimicked by intravitreal injection of glutamate, and similarly blocked by application of the NMDA receptor blocker MK-801, leading us to propose that prior to optic nerve lesion formation, NMDA receptor activation within the retina leads to retinal calcium accumulation, actin destabilization within the optic nerve as well as a deterioration of visual acuity during AON.

Aquaporin-4 IgG seropositivity is associated with worse visual outcomes after optic neuritis than MOG-IgG seropositivity and multiple sclerosis, independent of macular ganglion cell layer thinning

Background: Comparative studies of characteristics of optic neuritis (ON) associated with myelin oligodendrocyte glycoprotein-IgG (MOG-ON) and aquaporin-4-IgG (AQP4-ON) seropositivity are limited. Objective: To compare visual and optical coherence tomography (OCT) measures following AQP4-ON, MOG-ON, and multiple sclerosis associated ON (MS-ON). Methods: In this cross-sectional study, 48 AQP4-ON, 16 MOG-ON, 40 MS-ON, and 31 healthy control participants underwent monocular letter-acuity assessment and spectral-domain OCT. Eyes with a history of ON >3 months prior to evaluation were analyzed. Results: AQP4-ON eyes exhibited worse high-contrast letter acuity (HCLA) compared to MOG-ON (−22.3 ± 3.9 letters; p < 0.001) and MS-ON eyes (−21.7 ± 4.0 letters; p < 0.001). Macular ganglion cell + inner plexiform layer (GCIPL) thickness was lower, as compared to MS-ON, in AQP4-ON (−9.1 ± 2.0 µm; p < 0.001) and MOG-ON (−7.6 ± 2.2 µm; p = 0.001) eyes. Lower GCIPL thickness was associated with worse HCLA in AQP4-ON (−16.5 ± 1.5 letters per 10 µm decrease; p < 0.001) and MS-ON eyes (−8.5 ± 2.3 letters per 10 µm decrease; p < 0.001), but not in MOG-ON eyes (−5.2 ± 3.8 letters per 10 µm decrease; p = 0.17), and these relationships differed between the AQP4-ON and other ON groups (p < 0.01 for interaction). Conclusion: AQP4-IgG seropositivity is associated with worse visual outcomes after ON compared with MOG-ON and MS-ON, even with similar severity of macular GCIPL thinning.

Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.

Optic neuritis may be monophasic or occur as part of a relapsing demyelinating syndrome (RDS), such as multiple sclerosis, aquaporin-4 antibody (AQP4-Ab) neuromyelitis optical spectrum disorder (NMOSD), or myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease. The aims of this study were to test whether clinical, electrophysiological, and microstructural parameters differ in multiple-sclerosis-associated optic neuritis (MS-ON) and antibody-associated optic neuritis (Ab-ON); to identify the clinical and paraclinical characteristics of children suffering worse long-term visual outcome of RDS-optic neuritis; and to explore the relationship between RNFL thickness and clinical parameters in RDS-optic neuritis. Forty-two children with optic neuritis were retrospectively studied: 22 with multiple sclerosis (MS-ON) and 20 with antibody-associated demyelination (Ab-ON: MOG-Ab=16 and AQP4-Ab=4). Clinical and paraclinical features were analysed. Complete recovery of visual acuity was reported in 25 out of 42 children; eight out of 38 (21%) suffered moderate or severe visual impairment (logarithm of the minimum angle of resolution [logMAR]>0.5) in their worse eye, including four out of 38 who were blind (logMAR>1.3) in their worse eye (two with multiple sclerosis, two with AQP4-Ab NMOSD). None of the children with MOG-Ab were blind. Recurrence of optic neuritis was more common in the Ab-ON group than the MS-ON group (15 out of 20 vs seven out of 22, p=0.007). Retinal nerve fibre layer (RNFL) thickness at baseline inversely correlated with visual acuity at final follow-up (r=-0.41, p=0.008). There was no significant relationship between the number of episodes of optic neuritis and mean RNFL (r=-0.08, p=0.628), nor any significant relationship between the number of episodes of optic neuritis and visual impairment (r=0.03, p=0.794). In children with RDS, long-term visual impairment inversely correlated with RNFL thickness, but not with the number of relapses of optic neuritis. Optical coherence tomography may have a role in assessing children with optic neuritis to monitor disease activity and inform treatment decisions. Long-term visual impairment is reported in 40% of children with a relapsing demyelinating syndrome following optic neuritis. Relapse of optic neuritis, occurring more frequently in the non-multiple-sclerosis group. Retinal nerve fibre layer thinning is associated with worse visual outcome. Optical coherence tomography can be used alongside clinical parameters as an objective measure of neuroretinal loss.

Diagnostic accuracy of optical coherence tomography inter-eye percentage difference for optic neuritis in multiple sclerosis.

Multiple sclerosis-associated optic neuritis (MSON) causes atrophy of the inner retinal layers, which can be quantified by optical coherence tomography. It has been suggested that the inter-eye percentage difference (IEPD) of atrophy may be of diagnostic value in MSON. This was a prospective, cross-sectional study in patients with multiple sclerosis and healthy controls (HCs). Spectral-domain optical coherence tomography of both eyes was performed, followed by automated retinal layer segmentation of the peri-papillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (mGCIPL). Receiver operator characteristics curves were plotted and the area under the curve was calculated for group comparisons of the IEPD of the pRNFL and mGCIPL. There were 39 patients with bilateral MSON, 62 patients with unilateral MSON, 106 patients without MSON and 63 HCs. Diagnostic accuracy (area under the curve) of the IEPD was 0.73-0.86 for the pRNFL and 0.75-0.94 for the mGCIPL. The diagnostic sensitivity of the mGCIPL IEPD was 70% with a specificity of 97% for distinguishing unilateral MSON from HCs. For the comparison of bilateral MSON with HCs, sensitivity was 86% with a specificity of 97%. The IEPD of the pRNFL, and more particularly the IEPD of the mGCIPL, is a useful diagnostic measure for MSON. The IEPD is a dimensionless unit and may therefore contribute to overcome device and proprietary segmentation algorithm limitations.

Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis

Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20·10 μm, 95% CI -22·76 to -17·44; p<0·0001) and in MSNON eyes (-7·41 μm, -8·98 to -5·83; p<0·0001). The macula showed RNFL thinning of -6·18 μm (-8·07 to -4·28; p<0·0001) in MSON eyes and -2·15 μm (-3·15 to -1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16·42 μm (-19·23 to -13·60; p<0·0001) for MSON eyes and -6·31 μm (-7·75 to -4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01). The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. None.

Cognitive impairment in patients with multiple sclerosis is associated with atrophy of the inner retinal layers

Background: Inner retinal layer (IRL) atrophy is a potential biomarker for neurodegeneration in multiple sclerosis (MS). Objective: To investigate the relationship between cognitive impairment and IRL atrophy in MS. Methods: Cross-sectional study design, including 217 patients and 59 healthy controls. Subjects were investigated clinically, underwent retinal optical coherence tomography (OCT) and comprehensive cognitive assessments. The association between these modalities was evaluated by regression analyses. Results: Of the patients, 44.2% were cognitively impaired. In the absence of multiple sclerosis–associated optic neuritis (MSON), cognitively impaired patients had a significantly lower mean peripapillary retinal nerve fiber layer (pRNFL, Δ: 8.13 µm, p < 0.001) and mean macular ganglion cell–inner plexiform layer (mGCIPL, Δ: 11.50 µm, p < 0.001) thickness compared to cognitively preserved patients. There was a significant association between the presence of cognitive impairment and pRNFL (odds ratio (OR): 1.11, 95% confidence interval (CI): 1.04–1.18, p = 0.001) and mGCIPL (OR = 1.11, 95% CI = 1.05–1.18, p < 0.001) atrophy. This association was masked by the severe IRL atrophy seen following MSON. Conclusion: The strong relationship between cognitive impairment across multiple cognitive domains and atrophy of the pRNFL and mGCIPL in patients who never suffered from MSON suggests that OCT is useful in assessing central nervous system neurodegeneration in MS.

Should plasma exchange be offered to patients with multiple sclerosis-associated optic neuritis?

Should plasma exchange be offered to patients with multiple sclerosis-associated optic neuritis?

Optic neuritis in an ethnically diverse population: Higher risk of atypical cases in patients of African or African-Caribbean heritage

Purpose To investigate the presence of an ethnicity bias within patients presenting with optic neuritis in London. Design Observational cross-sectional study. Methods The ethnicity profile of all patients attending a neuro-ophthalmology clinic in central London with acute optic neuritis over a 16 month period ( n = 86) was studied. A comparison was made with the ethnicity profile of the population of London as well as patients with Multiple Sclerosis-associated optic neuritis ( n = 41), Neuromyelitis Optica spectrum disorder-associated optic neuritis ( n = 27) and patients with an atypical corticosteroid-dependent optic neuropathy (21). Results The ethnicity profile of the patient cohort presenting to our clinic with acute optic neuritis over a 16 month period closely matched the ethnicity profile of London ( P = 0.08). Within this cohort, patients of African or African-Caribbean heritage were found to be more likely to manifest either a pattern or aetiology of optic neuritis requiring immunosuppressive treatment in comparison with patients of a white Caucasian background (relative risk 3.47; 95% CI = 1.092 to 11.007). There was a disproportionately high representation of patients from an African or African-Caribbean background within the Neuromyelitis Optica spectrum-related optic neuritis diagnostic group ( P < 0.00). Conclusions Patients with acute isolated optic neuritis from African or African Caribbean backgrounds are over 3 times more likely than patients of white Caucasian backgrounds to have an ‘atypical’ pattern of optic neuritis where corticosteroid therapy may be required. Our results suggest that a patient's ethnic background is an important factor to be taken into consideration when deciding on the diagnosis and management of acute isolated optic neuritis.

Neuromyelitis Optica Antibodies in Patients With Severe Optic Neuritis in China

Severe visual loss is seen in both multiple sclerosis-associated optic neuritis (ON) and neuromyelitis optica (NMO)-associated ON. NMO (aquaporin 4) antibodies have been reported to have diagnostic and prognostic value for visual and neurological outcomes of recurrent ON. We performed this study to investigate the frequency of NMO antibodies and its prognostic value for visual and neurological outcomes in Chinese patients with severe ON. Single-center prospective cohort study. Detection of NMO antibodies was by indirect immunofluorescence method using human aquaporin 4-transfected cells. Severe ON was defined as visual acuity of 20/200 or worse in at least 1 eye at the nadir of the patients' course. Clinical features at baseline, visual outcome, and sequential neurological events were compared between seropositive and seronegative groups. NMO antibodies were detected in 11 of 34 patients (32.4%) with severe ON. Five seropositive patients with recurrent ON had significantly higher titers (range: 1:512 to 1:65,536; median: 1:512) than those of 6 seropositive patients with only 1 episode (range: 1:16 to 1:512; median: 1:32) (P=0.021). Female to male ratio (10:1) and antinuclear autoantibody positivity in seropositive patients (3 of 9, 33.3%) were statistically higher than those of the seronegative group (12:11; 0 of 19; P=0.026). The seropositive patients had significantly poorer visual outcomes than seronegative patients (P=0.025). During the averaged 32-month follow-up, 2 of 11 seropositive patients (18.2%) developed clinically incomplete transverse myelitis, while no similar symptoms were reported in the seronegative group. NMO antibody positivity is relatively high in Chinese patients with severe ON and suggests a poorer visual outcome, probably higher risk of developing spinal cord lesions and a closer association with systemic autoimmune disorders.

Early Relapse in Multiple Sclerosis-Associated Optic Neuritis Following the Use of Interferon b-1a in Chinese Patients

The incidence of multiple sclerosis (MS) is relatively rare in Chinese. The beneficial effect of interferon beta-1a in modifying the disease course of MS has been rarely analyzed in Chinese patients. The aim of this study was to investigate the clinical response to interferon beta1-a in Chinese patients with MS-associated optic neuritis (ON). A retrospective case control study was conducted in 20 MS patients with optic nerve involvement. The interferon (IF) group comprised ten patients receiving interferon beta-1a. The noninterferon (NIF) group comprised another ten MS patients with optic nerve involvement who did not receive interferon treatment. The clinical characteristics, laboratory data, management, and disease course were retrospectively analyzed. The main outcomes of the study were the annualized relapse rate (ARR) for MS, and final visual outcome data. The ARR did not differ between the pretreatment period and the posttreatment period within the IF group. There was also no significant decrease of ARR in the IF group when compared with the NIF group. However, we observed an early recurrence of ON in 50% of the IF cases following the use of interferon beta-1a. The final visual outcome did not differ between the IF group and the NIF group. The use of interferon beta-1a should be carefully monitored because early relapse of ON may complicate the treatment course in this patient group.