Full-field Visual Evoked Potentials Research Articles

Bexarotene leads to durable improvements in visual evoked potential latency: A follow-up study of the Cambridge Centre for Myelin Repair One trial

The Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that 6 months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing-remitting multiple sclerosis (MS). In a single-centre follow-up study of these participants, we re-examined full-field VEP and clinical assessments. Twenty participants (12 bexarotene and 8 placebo) were seen on average 27 months after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo), the adjusted bexarotene-placebo treatment difference in P100 latency was −7.79 (95% confidence interval (CI) = −14.76, −0.82) ms, p = 0.044. We conclude that there were durable improvements in VEP latency, suggesting long-term benefits from exposure to a remyelinating drug.

Teriflunomide treatment is associated with optic nerve recovery in early multiple sclerosis.

Background and aims:Various attempts have been made to support recovery following optic neuritis (ON), but the respective trials have mostly been negative. The aim of this study was to determine whether disease-modifying treatment (DMT) following ON as first manifestation of relapsing-remitting multiple sclerosis influences long-term outcomes.Methods:A total of 79 patients with ON were identified and evaluated at relapse, DMT induction, and 12 months following treatment induction with either glatiramer acetate (GLAT), interferon-beta (IFN), or teriflunomide (TRF). Low-contrast letter acuity (LCLA) and full-field visual-evoked potentials (FF-VEP) were compared between treatment groups using multivariable regression models. The impact of TRF treatment induction compared with IFN or GLAT following relapses outside the optic nerves was evaluated in an independent cohort of 122 patients. Magnetic resonance imaging (MRI) outcomes and rates of confirmed improvement of relapse-related disability were evaluated.Results:TRF-treated patients exhibited higher LCLA and lower relative P100 latencies normalized to the fellow-eye. Findings were significant following covariate-adjustment by multivariable analyses. Cranial MRI lesion load as well as disability progression rates were not significantly different between groups. The cohort of patients following relapses other than ON showed no differences in confirmed improvement of disability.Conclusion:TRF treatment is associated with favorable outcomes regarding functional optic nerve recovery following ON in early multiple sclerosis.

Editors' note: Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders

In the article “Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders,” Drs. Ringelstein et al. observed progressive delays in visual evoked potential (VEP) latency, occurring independently of acute optic neuritis, in 167 patients with neuromyelitis optica spectrum disorders (NMOSD) using 548 longitudinally assessed full-field VEP studies over the course of ≥3 months. In response, Dr. Chen seeks clarification about the authors' finding of a reduction in VEP amplitude with ≥3 months of follow-up but not among those with ≥12 months of follow-up. Dr. Chen wonders whether there may be similar correlations between VEP amplitude and disease activity as seen with optical coherence tomography (OCT) measurements of the peripapillary retinal nerve fiber layer thickness—which seem to decrease in NMOSD patients with non-ocular relapses vs those with stable disease—and calls for prospective longitudinal studies with VEP, OCT, and MRI to further explore this topic. Responding to these comments, the authors note that whereas their more restricted analysis of patients with ≥12 months of follow-up was intended to address the potential amplification of measurement variability that may have occurred with their interpolation of shorter-interval data—i.e., for patients with <12 months follow-up—their sample size may have been insufficient to achieve significance for analyses of amplitude changes. Nonetheless, they note that latency findings showed consistent and reliable increases in both the main and sub-analyses. This exchange highlights the ongoing evolution of our understanding about progressive tissue damage in NMOSD, previously thought to occur only in the context of relapses. We agree with Dr. Chen that longitudinal correlation of visual tests of structure, physiology, and function will be necessary to understand how frequently subclinical progressive disease might occur in NMOSD. In the article “Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders,” Drs. Ringelstein et al. observed progressive delays in visual evoked potential (VEP) latency, occurring independently of acute optic neuritis, in 167 patients with neuromyelitis optica spectrum disorders (NMOSD) using 548 longitudinally assessed full-field VEP studies over the course of ≥3 months. In response, Dr. Chen seeks clarification about the authors' finding of a reduction in VEP amplitude with ≥3 months of follow-up but not among those with ≥12 months of follow-up. Dr. Chen wonders whether there may be similar correlations between VEP amplitude and disease activity as seen with optical coherence tomography (OCT) measurements of the peripapillary retinal nerve fiber layer thickness—which seem to decrease in NMOSD patients with non-ocular relapses vs those with stable disease—and calls for prospective longitudinal studies with VEP, OCT, and MRI to further explore this topic. Responding to these comments, the authors note that whereas their more restricted analysis of patients with ≥12 months of follow-up was intended to address the potential amplification of measurement variability that may have occurred with their interpolation of shorter-interval data—i.e., for patients with <12 months follow-up—their sample size may have been insufficient to achieve significance for analyses of amplitude changes. Nonetheless, they note that latency findings showed consistent and reliable increases in both the main and sub-analyses. This exchange highlights the ongoing evolution of our understanding about progressive tissue damage in NMOSD, previously thought to occur only in the context of relapses. We agree with Dr. Chen that longitudinal correlation of visual tests of structure, physiology, and function will be necessary to understand how frequently subclinical progressive disease might occur in NMOSD.

O9 Early macular atrophy at optical coherence tomography is predicted by visual evoked potentials and precedes peripapillary neurodegeneration after acute optic neuritis

Background Demyelination and axonal loss following acute optic neuritis (AON) can be respectively measured as delayed visual evoked potentials (VEPs) and as reduced thickness of retinal nerve fiber (RNFL) and ganglion cell-inner plexiform layer (GCL-IPL) at optical coherence tomography (OCT). Traditionally, atrophy of GCL and IPL, which contains cell bodies and dendrites of the ganglion cells, is measured at the macula, but can be also measured with faster peripapillary scans at the optic nerve head. We explored if, in addition to the GCL measured at the macula, GCL-IPL atrophy could be detected with peripapillary scans and its association with VEPs evolution after AON. Methods Twenty subjects with unilateral AON underwent OCT and full-field VEP at baseline in the acute phase (8 ± 6 days after onset) and after 1 month (33 ± 5 days) and 4 months (128 ± 11 days). RNFL and GCIPL were segmented from peripapillary scans, GCL from macular scans. We explored the time evolution of RNFL, GCIPL, and GCL thickness over time and their correlation with VEP latency. Results Macular GCL was significantly reduced at 1 month (34.49 ± 4.42 μ m) compared to baseline (36.31 ± 3.67 μ m; p = 0.008). Peripapillary RNFL and GCIPL reduction was instead significant only at 4 months (RNFL: 97.32 ± 16.07 μ m at baseline and 96.65 ± 16.73 μ m at 1 month vs 92.11 ± 16.98 μ m at 4 month, p = 0.023; GCIPL: 47.94 ± 3.22 μ m at baseline and 46.61 ± 4.63 μ m at 1 month vs 43.96 ± 6.65 μ m at 4 month, p = 0.005). Baseline VEP latency correlated with OCT measures both at 1 month (RNFL: r = −0.648, p = 0.001; GCIPL: r = −0.495, p = 0.019; GCL: r = −0.742, p r = −0.616, p = 0.004; GCIPL: r = −0.564, p = 0.010; GCL: r = −0.748, p Discussion After AON, macular changes seem to precede detectable atrophy at peripapillary level, even within ganglion cell layers, suggesting this region as the most suitable to track early neurodegeneration. Demyelination in the acute phase, as measured by early VEPs, is associated with subsequent neuroretinal neurodegeneration and suggests the usefulness of VEPs as early predictor of ON outcome for individualized treatment and for patients’ selection for clinical trials assessing remyelination and neuroprotective strategies.

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. Biogen.

Optic neuritis as a phase 2 paradigm for neuroprotection therapies of multiple sclerosis: update on current trials and perspectives.

In multiple sclerosis as the most common inflammatory demyelinating disease in Western countries, major therapeutic success has been achieved with regard to strategies targeting immunological master switches. These approaches effectively reduce inflammatory disease activity but fail to address ongoing neurodegeneration or disturbed regeneration. However, intense research efforts investigating molecular mechanisms of disease have identified 'druggable' targets for prevention of inflammatory neurodegeneration and disturbed regeneration. This review covers recent developments in clinical trials using optic neuritis as a model for screening such neuroprotective and neuroregenerative therapeutic approaches. Optic neuritis has been used in a series of recent pilot studies investigating the effects of erythropoietin, simvastatin, autologous mesenchymal stem cells, phenytoin, as well as blockade of LINGO-1 (opicinumab). Of note, these studies applied novel outcome measures related to function and structure of the visual pathway, including optical coherence tomography, full-field visual-evoked potentials, multifocal visual-evoked potential, high as well as low-contrast visual acuity. Comparison of these different approaches reveals novel insights into short-term evolution of neurobiological effects during optic neuritis and the window of opportunity for therapeutic interventions. Translation of neuroprotective and neuroregenerative approaches to clinical reality represents a huge challenge. Optic neuritis as a prototypic autoimmune demyelinating disease offers an option for testing new therapies targeting key deleterious processes in multiple sclerosis.

Acute optic neuritis: a clinical paradigm for evaluation of neuroprotective and restorative strategies?

What makes the acute optic neuritis model unique in an era of trials for neuroprotective and myelin repair agents? Acute optic neuritis (AON) is a common, and often the earliest manifestation of central nervous system (CNS) inflammatory demyelinating disorders like multiple sclerosis (MS) and neuromyelitis optica (NMO). It affects at least half the patients with MS and is the presenting feature in 15–20% of patients. Vision loss in AON secondary to NMO tends to be more severe with less potential for recovery and greater axonal degeneration, as measured by optical coherence tomography (OCT) (Bennett et al., 2014). Several unique features of the afferent visual pathway (AVP) make the AON model an ideal system to study disease pathogenesis and evaluate potential neuroprotective and myelin repair strategies.

Effect of binasal occlusion (BNO) on the visual-evoked potential (VEP) in mild traumatic brain injury (mTBI)

Primary objective: The purpose of the experiment was to assess the effect of binasal occlusion (BNO) on the visually-evoked potential (VEP) in visually-normal (VN) individuals and in those with mild traumatic brain injury (mTBI) for whom BNO frequently reduces their primary symptoms related to abnormally-increased visual motion sensitivity (VMS).Design and methods: Subjects were comprised of asymptomatic VN adults (n = 10) and individuals with mTBI (n = 10) having the symptom of VMS. Conventional full-field VEP testing was employed under two conditions: without BNO and with opaque BNO which blocked regions on either side of the VEP test stimulus. Subjective impressions were also assessed.Results: In VN, the mean VEP amplitude decreased significantly with BNO in all subjects. In contrast, in mTBI, the mean VEP amplitude increased significantly with BNO in all subjects. Latency was normal and unaffected in all cases. Repeat VEP testing in three subjects from each group revealed similar test–re-test findings. Visuomotor activities improved, with reduced symptoms, with BNO in the mTBI group.Conclusions: It is speculated that individuals with mTBI habitually attempt to suppress visual information in the near retinal periphery to reduce their abnormal VMS, with addition of the BNO negating the suppressive influence and thus producing a widespread disinhibition effect and resultant increase in VEP amplitude.

Innovative evaluation of visual field defects in epileptic patients after standard anterior temporal lobectomy, using partial field visual evoked potentials

The purpose of this paper is to obtain an electrophysiological evaluation of visual field defects consecutive to the direct lesion of optic radiations in drug-resistant epileptic patients after a standard electrocorticographically adjusted lobectomy, and to correlate it with conventional perimetric results, and with the volume of resected tissue during surgical treatment. Twenty-four patients with temporal lobe epilepsy defined through long term EEG-video, ictal and interictal SPECT, as well as Magnetic Resonance Imaging were studied. Visual evoked potentials (VEPs) with partial and total visual field stimulation were carried out before and after 6, 12 and 24 months surgical treatment. A control group was also studied. No differences between patients and control subjects were observed during the evaluation of the full-field VEPs. However, there were statistical differences between groups in the half-field VEP recordings and in the VEP recordings of contralateral to resected side superior quadrant (CSQ) before lobectomy and 6 months later (Mann-Whitney's U-test, p<0.05). Significant associations were found between VEP abnormalities and perimetric results in CSQ. A close relationship between perimetry, VEPs and volume of the resected tissue in hippocampus, parahippocampus, medial and lower temporal giri was also found. Visual field defects consecutive to standard temporal lobe resection in epileptic patients could be objectively evaluated by partial stimulation VEPs corresponding to the size of resected tissue.

Correlation between full-field and multifocal VEPs in optic neuritis

To compare performance of multi-focal and full-field Visual Evoked Potentials (VEP) in patients with optic neuritis (ON). 26 patients with unilateral ON were enrolled. Multi-focal VEP (MF VEP) was recorded using AccuMaptrade mark system. Four bipolar channels were analysed. Full-field VEP (FF VEP) was performed according to ISCEV standard using ESPION with frontal-occipital electrode placement. Pattern-reversal protocol was implemented with check size of 60' and field of view of 30 degrees . For both tests amplitude and latency of affected eye were statistically different from non-affected eye. The asymmetry of amplitude and latency between two eyes was also very similar for both tests. Averaged Relative Asymmetry Coefficient of amplitude (RAC) for the FF VEP was 0.10 +/- 0.15 and for the MF VEP was 0.12 +/- 0.12 (P = 0.21, paired t-test). Averaged latency difference between affected and non-affected eyes was 13.0 +/- 12 ms for FF and 14.1 +/- 11.1 ms for MF VEPs (P = 0.14, paired t-test). Coefficient of correlation (r) of p100 component of the FF VEP and averaged MF VEP was 0.60 (P < 0.0001) for amplitude and 0.79 (P < 0.0001) for latency. Correlation improved when amplitude and latency asymmetry between two eyes was analysed (r = 0.81 and r = 0.92 respectively). Overall 73% of affected eyes were identified as abnormal by amplitude and/or latency of the FF VEP and 89% was considered abnormal when MF VEP was used. Analysis of individual cases revealed superior performance of MF VEP in detecting small or peripheral defects.

The multifocal visual evoked potential.

With the multifocal technique, visual evoked potentials (VEPs) can be recorded simultaneously from many regions of the visual field. For the multifocal VEP (mfVEP), the patient views a display that typically contains 60 sectors, each with a checkerboard pattern. The display covers about the same retinal area as the 24-2 Humphrey visual field (HVF). However, due to the scaling of the sectors of the mfVEP display, the fields are sampled differently by the mfVEP and HVF. To assess local defects in the visual field, the mfVEP responses must be compared with normal controls. These comparisons require relatively sophisticated analyses and software. Whereas the mfVEP can be recorded relatively easily with the same equipment used to record multifocal electroretinograms (mfERGs), the software needed to perform the analysis is not yet widely available. The mfVEP is valuable for ruling out non-organic visual loss, diagnosing and following patients with optic neuritis/multiple sclerosis, evaluating patients with unreliable or questionable HVFs, and following disease progression. When combined with the mfERG, diseases of the outer retina (before the retinal ganglion cells) can be distinguished from diseases of the ganglion cells and/or optic nerve. The difficulties encountered in recording and analyzing mfVEP responses are greater than those involved in full-field VEP testing. Thus, in its current form, the mfVEP is best recorded and interpreted by ophthalmologists and electrophysiologists experienced with the technique. However, this technique is developing rapidly; advances in commercial hardware and software are expected in the near future.

Effects of attention on pattern-reversal visual evoked potentials: foveal field stimulation versus peripheral field stimulation.

The effects of foveal field attention on pattern reversal visual evoked potential (VEP) were investigated in thirteen normal subjects. Conventional monocular VEP was recorded during the three conditions of control, foveal concentration and reaction time task. Three patterns of checker-board, which were full field (radius, 0-9 degrees), peripheral field (2.5-9 degrees) and foveal field (0-2.5 degrees), were presented for the stimulation in each condition. The P100 and N145 amplitude of the peripheral field VEP were significantly smaller during the concentration and the reaction time task conditions that that in the control session, while the foveal field VEP amplitudes were enhanced in the concentration and reaction time tasks conditions. The full field VEP amplitudes were not significantly changed by the conditions. We concluded that the act of concentration to the foveal field or the task requiring attention to the foveal field, enhanced the VEP response to foveal field stimulation and suppressed the VEP to the peripheral field. A gating effect in area V1 was speculated, although extra-striate cortex might contribute.

Visual evoked potential abnormalities in compressive chiasmal lesions: the relevance of central visual field defects

In healthy subjects, the pattern visual evoked potential (VEP) arises predominantly from the stimulation of the central 5 degrees of the visual field. This central-field paradigm is well confirmed in VEP studies of retrochiasmal lesions, but it appears to be more ambiguous in patients with compressive lesions of the chiasm. To further clarify how central and peripheral visual field defects affect VEP, we compared the Goldmann perimetric charts with the frequency and type of VEP abnormalities in 25 patients in whom a compressive chiasmal lesion had been confirmed by CT. Perimetric findings were compared with the full-field and half-field VEP records with regard to the presence or absence of defects within the 0-5 degrees of the visual field. Full-field VEP abnormalities were present in all eyes with absolute, in 81% of the eyes with relative central visual field defects, and in 59% of the eyes with no impairment of the central visual field. Half-field VEP abnormalities were found in all half-fields with absolute, in 89% of half-fields with relative central visual field defect, and in 77% of half-fields that manifested visual field defects without macular involvement. We also found abnormalities in 36% of half-field VEP recordings, obtained by stimulation of apparently normal visual half-fields. The analysis of the types of VEP abnormalities showed that Pi00 amplitude attenuation typically reflected the central field defect, while Pi00 asymmetry, Pi00 prolongation, and Pi35 appearance could be detected in both the presence or absence of the central field impairment. Our results confirm that central visual field defects are associated with VEP abnormalities. However, the high proportion of VEP abnormalities in eyes with field defects not affecting the central 5 degrees, and the VEP half-field abnormalities even in an absence of visual field defect indicate that compressive chiasmal lesions may be reflected in abnormal VEP well before the appearance of central-field defects in the Goldmann perimetric tests.

Mapped distribution of pattern reversal VEPs to central field and lateral half-field stimuli of different spatial frequencies

Visual evoked potentials (VEPs) to pattern reversal vertical bar stimuli of 3 different sizes (1, 2, 4 c/deg) were recorded from 19 scalp derivations in 50 controls. The stimuli were presented on a full-field (FF) screen of 24° visual angle, and on left and right half-fields (HF) of 12° radius. In 15 controls partial HF stimuli were presented on the central 3 and 6° and as hemiannular stimuli of 12° with occlusion of the central 3 and 6°. An antero-posterior polarity reversal of the N1-P1-N2 sequence was observed for FF VEPs. A tangential polarity reversal was observed for HF VEPs. Also with central or hemiannular stimuli polarity reversals of all VEP components were observed within the scalp. Variants of VEP distribution, absence of prominence of some of the ipsi- or contralateral VEP components were observed in 8–40% of controls. The FF and HF VEP distribution, and the variant VEP asymmetries were partly dependent on the pattern spatial frequency.