Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. METHODS: Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. RESULTS: A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. CONCLUSIONS: Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

Subclinical anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes.

Optical coherence tomography (OCT) is gaining increasing relevance in the assessment of patients with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS. The present study aims at exploring the usefulness of OCT as a marker of inflammation and disease burden in the earliest phases of the disease. Thus, a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder; among those 32 patients had another previous misdiagnosed episode. For the present study, patients also received a visual pathway assessment (OCT, visual evoked potentials, visual acuity), measurement of CSF inflammatory markers (17 cytokines-chemokines, extracellular vesicles of myeloid origin), and dosage of plasma neurofilaments. Subclinical optic nerve involvement is frequently found in clinically isolated syndromes by visual evoked potentials (19.2%). OCT reveals ganglion cell layer asymmetries in 6.8% of patients; retinal fibre layer asymmetries, despite being more frequent (17.8%), display poor specificity. The presence of subclinical involvement is associated with a greater disease burden. Second, ganglion cell layer thinning reflects the severity of disease involvement even beyond the anterior optic pathway. In fact, the ganglion cell layer in eyes without evidence of subclinical optic involvement is correlated with Expanded Disability Status Scale, low contrast visual acuity, disease duration, brain lesion load, presence of gadolinium enhancing lesions, abnormalities along motor and somatosensory evoked potentials, and frequency of CSF-specific oligoclonal bands. Third, the inner nuclear layer thickens in a post-acute (1.1-3.7 months) phase after a relapse, and this phenomenon is counteracted by steroid treatment. Likewise, a longitudinal analysis on 65 patients shows that this swelling is transient and returns to normal values after 1 year follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study are strictly associated with one another, but none of them are associated with the inner nuclear layer. Our findings challenge the current hypothesis that the inner nuclear layer is an acute phase marker of inflammatory activity. The present study suggests that instrumental evidence of subclinical optic nerve involvement is associated with a greater disease burden in clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.

Beyond Neuropsychiatric Manifestations of Systemic Lupus Erythematosus: Focus on Post-traumatic Stress Disorder and Alexithymia.

PURPOSE OF REVIEW: To deepen the comprehension of the role of specific psychological conditions in the pathogenesis and in the treatment of systemic lupus erythematosus (SLE). Specifically, the present comprehensive review aims at examining the association between SLE, alexithymia (AT)-a personality construct referring to the inability to identify, describe, and express sensations, emotions, and physical state-and post-traumatic stress disorder (PTSD), to infer potential biological relationships between these psychopathological issues and disease course, and to draw up a research agenda on gray areas of these topics. RECENT FINDINGS: Whereas several studies document the presence of neuropsychiatric symptoms in patients with SLE, psychological distress, alexithymia, and post-traumatic manifestations are usually neglected by healthcare professionals and poorly investigated in research contexts. However, the interplay of these aspects, which affect physiologic stress coping mechanisms, potentially plays an important role in SLE pathogenesis. In particular, research documents that cytokine repertoire pattern alteration and hypothalamic-pituitary-adrenal axis impairment leading to inflammation and pain represent the main links between emotional health and immunity. AT and PTSD seem to be common in patients with SLE and account for multiple aspects of SLE-related morbidity. Furthermore, abnormal processing of stressful stimuli as hallmarks of PTSD and AT might promote neuroendocrine dysfunction and dysregulated immunity, thus contributing to the pathogenesis of SLE. A comprehensive, multidisciplinary clinical approach, based on a cooperation between immunologists, rheumatologists, neurologists, and mental health professionals, is crucial to promote patients' global health.

Subclinical neurodegeneration in multiple sclerosis and neuromyelitis optica spectrum disorder revealed by optical coherence tomography.

BACKGROUND: Neuroretinal atrophy is associated with whole-brain atrophy and disease activity in multiple sclerosis (MS). Recent findings support that subclinical visual pathway involvement might also occur in neuromyelitis optica spectrum disorders (NMOSDs). OBJECTIVE: The objective of this study is to assess retinal thinning in MS and NMOSD and its association with disease activity. METHODS: In total, 27 NMOSD and 54 propensity-score-matched MS patients underwent optical coherence tomography, visual acuity, and visual-evoked potentials at 2.4 years apart, in addition to routine clinical and magnetic resonance imaging (MRI) assessment. We excluded eyes with acute optic neuritis. RESULTS: In NMOSD, we detected peripapillary retinal nerve fiber layer (pRNFL) thinning in patients with disease activity during follow-up (-0.494 µm/year), but not in stable patients (-0.012 µm/year). Macular ganglion cell-inner plexiform layer (GCIPL) thinning occurred instead in all patients (-0.279 µm/year). Relapsing-remitting multiple sclerosis (RRMS) meeting NEDA-3 criteria had no pRNFL or GCIPL thinning during follow-up. Active-disease RRMS and progressive MS, both active and stable, displayed pRNFL (-0.724, -0.586, -0.556 µm/year, respectively) and GCIPL loss. CONCLUSION: In MS, neuroretinal atrophy was associated with disease activity but occurred in progressive MS even when achieving NEDA-3 criteria. In NMOSD, pRNFL thinning was associated with non-ocular relapses due to a spreading of inflammatory activity. GCIPL thinning was found in all patients, supporting a primary retinal pathology targeting AQP4-rich structures.

Assessing the role of innovative therapeutic paradigm on multiple sclerosis treatment response.

OBJECTIVE: Within the last decade, many changes have been made to the management of patients with multiple sclerosis (MS). The aim of our study was to investigate the global impact of all these changes on the disease's course. MATERIALS AND METHODS: This single-centre study was carried out on patients with multiple sclerosis (pwMS) who started treatment with first-line disease-modifying therapies. We have compared three large cohorts of patients with MS diagnosis, for three consecutive periods within July 2001, August 2001-December 2005, and January 2006-September 2011. RESULTS: A total of 1068 relapsing-remitting pwMS cases were included. Patients in the last cohort began treatment earlier (P < 0.0001), started more frequent treatment with high-dose interferon beta or glatiramer acetate (P < 0.0001), and had experienced a more frequent treatment escalation strategy (P = 0.004) than patients in other cohorts. The multivariate analysis adjusted for baseline characteristics showed that pwMS of the last cohort had a high probability of showing no evidence of disease activity (NEDA3) at 4 years (OR 3.22, 95% CIs 1.89-5.47; P < 0.0001). These results were confirmed in a propensity score analysis. CONCLUSIONS: Our study showed an improvement over the last 15 years in the treatment response; this observation can be associated to a paradigm shift in MS treatment strategies.

Visual Evoked Potentials as a Biomarker in Multiple Sclerosis and Associated Optic Neuritis.

: ABSTRACT:: Multiple sclerosis (MS) is an inflammatory, degenerative disease of the central nervous system (CNS) characterized by progressive neurological decline over time. The need for better "biomarkers" to more precisely capture and track the effects of demyelination, remyelination, and associated neuroaxonal injury is a well-recognized challenge in the field of MS. To this end, visual evoked potentials (VEPs) have a role in assessing the extent of demyelination along the optic nerve, as a functionally eloquent CNS region. Moreover, VEPs testing can be used to predict the extent of recovery after optic neuritis (ON) and capture disabling effects of clinical and subclinical demyelination events in the afferent visual pathway. In this review, the evolving role of VEPs in the diagnosis of patients with ON and MS and the utility of VEPs testing in determining therapeutic benefits of emerging MS treatments is discussed.

Resting-state fMRI functional connectivity: a new perspective to evaluate pain modulation in migraine?

Resting-state (RS) functional magnetic resonance imaging (fMRI) is a relatively novel tool which explores connectivity between functionally linked, but anatomically separated, brain regions. The use of this technique has allowed the identification, at rest, of the main brain functional networks without requiring subjects to perform specific active tasks. Methodologically, several approaches can be applied for the analysis of RS fMRI, including seed-based, independent component analysis-based and/or cluster-based methods. The most consistently described RS network is the so-called "default mode network". Using RS fMRI, several studies have identified functional connectivity abnormalities in migraine patients, mainly located at the level of the pain-processing network. RS functional connectivity is generally increased in pain-processing network, whereas is decreased in pain modulatory circuits. Significant abnormalities of RS functional connectivity occur also in affective networks, the default mode network and the executive control network. These results provide a strong characterization of migraine as a brain dysfunction affecting intrinsic connectivity of brain networks, possibly reflecting the impact of long lasting pain on brain function.

Optical coherence tomography and visual evoked potentials: which is more sensitive in multiple sclerosis?

OBJECTIVE: To assess the sensitivity of optic coherence tomography (OCT) and visual evoked potentials (VEPs) to visual pathway abnormalities in multiple sclerosis (MS). METHODS: A total of 40 MS subjects, 28 with optic neuritis (ON) at least 3 months before (bilateral in 5), underwent assessment of visual acuity, Expanded Disability Status Scale (EDSS), OCT and VEPs, the latter quantified with a 0-4 conventional score. RESULTS: OCT and VEPs were abnormal in 36% and 56% respectively in all eyes (p=0.11), 68% and 86% in eyes with previous ON (p=0.12), and in 19% versus 40% in eyes without ON history (p=0.007). Combining VEP and OCT increased sensitivity to 89% in ON and 44% in non-ON eyes. Considering all eyes, global retinal nerve fibre layer (RNFL) thickness and VEP score were significantly correlated between them (ρ=-0.63, p<0.001) and with EDSS (RNFL: ρ=0.40, p<0.001; VEP score: ρ=0.47, p<0.001). Disease duration correlated with VEP score (ρ=0.25, p=0.025) and RNFL thickness (ρ=-0.71, p<0.001). CONCLUSIONS: In eyes without ON, VEPs were more frequently abnormal than OCT, while the two techniques showed similar sensitivity in eyes previously affected by ON. The correlation of VEPs and OCT measures with disability prompts further exploration of the two techniques as potential markers of disease burden.

Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis.

Neurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry-optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry-optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry-optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.

Fast but not furious: Rapid ocrelizumab infusion as a strategy to optimize multiple sclerosis patients' management.

OBJECTIVES: Multiple sclerosis clinicians are continuously challenged to be innovative in delivering therapies and there is ongoing pressure to maximize day-hospital vacancies. We describe our single-center experience with ocrelizumab (OCR) rapid infusion (OCR-RI) in patients with MS (pwMS). METHODS: For pwMS with prior exposure to OCR standard infusion (OCR-SI) for at least one year/two cycles, infusion time was reduced from 3.5 to 2.0 h. A comparative analysis between OCR-RI vs OCR-SI patients was conducted. RESULTS: 283 (76.7%) out of 369 OCR-treated pwMS performed OCR-RI; 86 subjects did not start OCR-RI due to infusion-related reactions (IRR) occurring with OCR-SI (n = 13) or OCR-treatment duration shorter than one year (n = 73). Disease duration was longer in OCR-RI (p < 0.001). Median numbers of overall-OCR and OCR-RI cycles were 7 (IQR = 5-8) and 4 (IQR = 2-5) (p < 0.001). Overall, 38 (10.3%) IRR were reported, 25 (8.8%) in OCR-RI and 13 (15.1%) in OCR-SI group. IRR frequency did not differ between the two groups (p = 0.106). IRR included throat irritation, rash, hypotension, fever and gastrointestinal symptoms. IRR severity was mild (81.6%) or moderate (18.4%), all resolved and did not differ in distribution between the two groups. When IRR occurred, infusions were temporarily stopped, hydration and/or symptomatic medications were given and infusions were subsequently resumed at standard velocity. OCR-RI was not a risk factor for IRR (OR 0.55, 95% CI: 0.27-1.13, p = 0.096). CONCLUSIONS: In our cohort, IRR frequency, severity and management were comparable to literature. No severe IRR were observed. RI protocols represent a strategy to optimize patients' management in the clinic.

Intensive Neurorehabilitation and Gait Improvement in Progressive Multiple Sclerosis: Clinical, Kinematic and Electromyographic Analysis.

BACKGROUND: Gait deficit is a hallmark of multiple sclerosis and the walking capacity can be improved with neurorehabilitation. Technological advances in biomechanics offer opportunities to assess the effects of rehabilitation objectively. OBJECTIVE: Combining wireless surface electromyography and wearable inertial sensors to assess and monitor the gait pattern before and after an intensive multidisciplinary neurorehabilitation program (44 h/4weeks) to evaluate rehabilitation efficiency. METHODS: Forty people with progressive multiple sclerosis were enrolled. Wireless wearable devices were used to evaluate the gait. Instrumental gait analysis, clinical assessment, and patient report outcome measures were acquired before and after the neurorehabilitation. Spatiotemporal gait parameters, the co-activation index of lower limb muscles, and clinical assessments were compared pre- and post-treatment. RESULTS: Significant improvements after intensive neurorehabilitation were found in most of the clinical assessments, cadence, and velocity of the instrumental gait analysis, paralleled by amelioration of thigh co-activation on the less-affected side. Subjects with better balance performance and higher independence at baseline benefit more from the neurorehabilitation course. CONCLUSIONS: Significant improvements in gait performance were found in our cohort after an intensive neurorehabilitation course, for both quantitative and qualitative measures. Integrating kinematic and muscle activity measurements offers opportunities to objectively evaluate and interpret treatment effects.

Optical Coherence Tomography and Visual Evoked Potentials as Prognostic and Monitoring Tools in Progressive Multiple Sclerosis.

Understanding the mechanisms underlying progression and developing new treatments for progressive multiple sclerosis (PMS) are among the major challenges in the field of central nervous system (CNS) demyelinating diseases. Over the last 10 years, also because of some technological advances, the visual pathways have emerged as a useful platform to study the processes of demyelination/remyelination and their relationship with axonal degeneration/protection. The wider availability and technological advances in optical coherence tomography (OCT) have allowed to add information on structural neuroretinal changes, in addition to functional information provided by visual evoked potentials (VEPs). The present review will address the role of the visual pathway as a platform to assess functional and structural damage in MS, focusing in particular on the role of VEPs and OCT, alone or in combination, in the prognosis and monitoring of PMS.

In vivo structural and functional assessment of optic nerve damage in neuromyelitis optica spectrum disorders and multiple sclerosis.

Early detection of neuromyelitis optica spectrum disorders (NMOSD), especially after optic neuritis, a presenting manifestation commonly observed also in multiple sclerosis (MS), is crucial for timely treatment and prognosis. Integrated visual pathway assessment with optical coherence tomography (OCT) and visual evoked potentials (VEP) may help in this task, showing in vivo different pathophysiological backgrounds. We evaluated combined VEP and OCT in a cross-sectional, single-centre study assessing 50 consecutive NMOSD patients, 57 MS patients and 52 healthy controls. After optic neuritis, VEP were more frequently absent in NMOSD compared to MS; most NMOSD eyes with recordable VEP showed prolonged latency, but extreme latency delays were less common than in MS. OCT showed predominantly axonal involvement in NMOSD, with 88% eyes (95% CI: 69-97%) displaying retinal nerve fibre layer thickness <60 µm even after first optic neuritis episode. Accuracy of OCT was further enhanced by combination with VEP into a new Z-score derived OCT-VEP index, measuring prevalence of axonal damage or demyelination. Our results suggest that integrated optic nerve assessment may elucidate differences in optic neuritis pathophysiology; conduction slowing with relatively preserved nerve fibre layer suggests MS, while severe neuroaxonal loss after optic neuritis, often hindering VEP response, characterizes NMOSD.

Concurrence of NMOSD and ALS in a patient with hexanucleotide repeat expansions of C9orf72.

We describe a patient, previously known for NMOSD, who presented a rapidly progressive worsening of muscle strength, respiratory, and bulbar functions. ALS associated with cognitive impairment was diagnosed, while genetic analysis revealed a hexanucleotide repeat expansion in the C9orf72 gene. To the best of our knowledge, this is the first reported C9orf72-ALS patient with concurrent NMOSD. In consideration of the low prevalence of these two diseases, a by-chance co-occurrence is unlikely. Although the discovery of a disease-specific serum AQP4-IgG antibody has led to a broadening of the NMOSD, a progressive neurological deterioration, as shown by our patient, should be considered as a "red flag", leading to alternative diagnostic hypotheses. Our report supports the hypothesis that in C9orf72-ALS neuroinflammation may contribute to disease penetrance or to determine an aggressive clinical phenotype. Further investigations are needed in order to establish possible shared neuroinflammatory patterns between ALS, NMOSD, and other neuroinflammatory disorders.

No evidence of disease activity is associated with reduced rate of axonal retinal atrophy in MS.

OBJECTIVE: To explore, in a longitudinal study, the usefulness of optical coherence tomography (OCT) in monitoring people with multiple sclerosis (MS) by testing the association between retinal nerve fiber layer (RNFL) thinning and clinical and brain MRI criteria of no evidence of disease activity (NEDA). METHODS: OCT, visual evoked potentials (VEPs), and disability, using the Expanded Disability Status Scale (EDSS), were tested at baseline and after 2 years in 72 patients, 63 with routine yearly brain MRI. RESULTS: Longitudinal mean binocular RNFL thinning, in absence of optic neuritis during follow-up, was correlated with EDSS worsening, also controlling for baseline EDSS, RNFL, disease duration, and MS subtype (Spearman ρ -0.462, p < 0.001; partial correlation coefficient -0.437, p < 0.001). At follow-up, patients classified as NEDA (20; 31.7%) had RNFL loss of -0.93 µm ± 1.35 SD, while patients with active disease had -2.83 µm ± 2 SD thinning (t test; p < 0.001). At logistic regression, mean RNFL reduction correctly classified 76.2% of patients as NEDA at 2 years (R2 0.355; p = 0.003). A cutoff of -1.25 µm RNFL loss classified NEDA status with specificity 81.4% and sensitivity 80% (receiver operating characteristic curve: area under the curve 0.8; p < 0.001). No significant longitudinal correlations were found between changes in RNFL and in VEP latencies or scores. CONCLUSIONS: NEDA is associated with a relatively preserved RNFL over 2 years. A greater neuroretinal loss was detected even in patients with clinical evidence of disease activity independently from changes in brain MRI lesions, prompting further validation of OCT as an additional tool in MS monitoring.

Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study.

BACKGROUND: Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. METHODS: In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. FINDINGS: 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 µm or less than or equal to 88 µm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume. INTERPRETATION: Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. FUNDING: Instituto de Salud Carlos III.