Simone Guerrieri

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.

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.

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.

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.

Bi-hemispheric repetitive transcranial magnetic stimulation for upper limb motor recovery in chronic stroke: A feasibility study

With the emerging of a crucial role of non-primary and contralesional motor areas in the recovery of upper extremity (UE) after acute stroke [1,2], the ‘‘bimodal-balance recovery model“ has been proposed [3], with the hypothesis that the contribution of ipsiand contralesional primary and secondary motor areas might vary according to the structural reserve of the ipsilesional corticospinal tract. This model opens to novel non-invasive brain stimulation approaches for improving the effects of neurorehabilitation, targeting bilateral, wide motor cortical regions rather than focusing on the ipsilateral or contralesional M1. We tested safety, feasibility and efficacy of simultaneous high-frequency rTMS of bilateral motor/premotor areas using the H5-coil, associated with unilateral motor training of the paretic UE.

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

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 diseases course.

ID 214 – Optical coherence tomography and multifocal visual evoked potentials usefulness to detect visual pathway abnormalities in clinical practice

Objective Full-field visual evoked potentials (ff-VEP) are fundamental in neurological practice to define the nature of visual disturbances. We explored whether, in case of normal ff-VEP and suspected organic visual pathway involvement, multifocal visual evoked potentials (mf-VEP) and optical coherence tomography (OCT) can be useful in the diagnostic workup. Methods Observational case reports. Results Three patients arrived at our department for visual disturbances. Two had relapsing optic neuritis (ON) and visual acuity (VA) loss, with normal or non-significant ff-VEP outside acute clinical episodes. In both cases OCT showed a retinal nerve fiber layer (RNFL) thickness reduction, allowing visual pathway damage identification. The third, with meningioma involving left optic nerve, complained of blurred vision in the nasal field of the left eye as confirmed by computerized perimetry (CP). While ff-VEP showed normal latency and non-significant amplitude reduction in the left eye, mf-VEP showed important amplitude reduction in the whole lower left eye field. OCT scan confirmed axonal damage showing left RNFL thinning. Conclusions Sometimes ff-VEP fails in identifying abnormalities in patients with processes involving the visual pathway, particularly in cases with axonal or sectoral optic nerve involvement. We suggest the importance of a multimodal evaluation, including OCT and mf-VEP.

13. Optical coherence tomography and multifocal visual evoked potential clinical usefulness in identifying visual pathway involvement

Full-field visual evoked potentials (ff-VEP) are fundamental in neurological practice, for defining the nature of visual disturbances. We explored whether, in case of normal ff-VEP and suspected organic visual pathway involvement, multifocal visual evoked potentials (mf-VEP) and optical coherence tomography (OCT) can be useful in the diagnostic workup. Observational case reports on 3 patients presenting with visual disturbances. Two had relapsing optic neuritis (ON) and visual acuity (VA) loss, with normal or non-significant ff-VEP outside acute clinical episodes. In both cases OCT showed a retinal nerve fiber layer (RNFL) thickness reduction, allowing visual pathway damage identification. The third, with meningioma involving left optic nerve, complained of blurred vision in the nasal field of the left eye as confirmed by computerized perimetry (CP). While ff-VEP showed normal latency and non-significant amplitude reduction in the left eye, mf-VEP showed important amplitude reduction in the lower visual field of the left eye. OCT scan confirmed axonal damage showing left RNFL thinning. Sometimes ff-VEP fails in identifying abnormalities in patients with pathologic processes involving the visual pathway, particularly in cases with axonal or sectorial optic nerve involvement. We suggest the importance of a multimodal evaluation, including OCT and mf-VEP.

P573: Optical coherence tomography and visual evoked potentials in monitoring neural damage in multiple sclerosis

Background: In the assessment of visual pathway involvement in Multiple Sclerosis-MS, optical coherence tomography-OCT is used to measure retinal nerve fiber layer-RNFL thickness as a marker of axonal loss and visual evoked potentials-VEPs as an indicator of demyelination. However, no clear indications are available on their combined use in MS monitoring. We evaluated cross-sectional and longitudinal correlations and sensitivity of OCT and VEPs and their correlates with clinical and magnetic resonance imaging-MRI evidence of disease activity in a real-world clinical setting. Methods: 80 MS patients (13 clinically isolated syndrome-CIS, 55 relapsingremitting-RR, 9 secondary progressive-SP, 3 primary progressive-PP), age 36.7+9.7 years, disease duration 6.0+6.6 years, underwent neurological and neurophysiological evaluation with OCT and VEPs, with routine clinical and MRI monitoring for a mean period of 1 year. Additional OCT-VEPs follow-up was obtained in 50 patients. Results: While VEPs were more sensitive than OCT in eyes with recent (<3 months) optic neuritis-ON at baseline (80.0% Vs 6.7%, p=0.001), the two sensitivities were similar in chronic ON eyes (78.4%). Comparing eyes with and without previous ON, VEP latency and RNFL thickness were respectively significantly higher (131.2 ms Vs 118.8 ms, p=0.008) and lower (78.15 μm Vs 90.00 μm, p<0.001) in the first subgroup. No significant differences were found between the two subgroups when analyzing VEP latency and RNFL thickness evolution during the follow-up period. However, eyes with baseline recent ON had significant reduction in VEP latency (−15.3 ms) and RNFL thickness (−7,7 μm) at follow-up. No significant correlation was found between OCT-VEPs parameters and disease activity. Similar results were found when considering only RR and CIS patients. Conclusions: These results would exclude recommending OCT and VEPs as surrogate biomarkers in MS phase II clinical trials evaluating disease modifying drugs, even when focusing on relapsing form of MS. The main role for OCT and VEPs in short-to-medium term follow-up programs would consist in monitoring neural damage after acute ON. However, these findings cannot exclude the usefulness of these techniques for longer follow-ups and/or large phase III studies.