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Sensitivity of visual evoked potentials and spectral domain optical coherence tomography in early relapsing remitting multiple sclerosis
Multiple Sclerosis and Related Disorders, Volume 12, February 2017, Pages 15-19
Visual evoked potentials and spectral-domain optical coherence tomography are common ancillary studies that assess the visual pathways from a functional and structural aspect, respectively.
To compare prevalence of abnormalities of Visual evoked potentials (VEP) and spectral-domain optical coherence tomography (SDOCT) in patients with relapsing remitting multiple sclerosis (RRMS).
A cross-sectional study of 100 eyes with disease duration of less than 5 years since the diagnosis. Correlation between retinal nerve fiber layer and ganglion-cell/inner plexiform layer with pattern-reversal visual evoked potentials amplitude and latency and contrast sensitivity was performed.
The prevalence of abnormalities in pattern-reversal visual VEP was 56% while that of SOCT was 48% in all eyes. There was significant negative correlations between the average RNFL (r=−0.34, p=0.001) and GCIPL (r=−0.39, p<0.001) with VEP latency. In eyes with prior optic neuritis, a significant negative correlation was seen between average RNFL (r=−0.33, p=0.037) and GCIPL (r=−0.40, p=0.010) with VEP latency.
We have found higher prevalence of VEP abnormalities than SCOCT in early relapsing-remitting multiple sclerosis. This suggests that VEP has a higher sensitivity for detecting lesions of the visual pathway in patients with early RRMS.
- We have compared Spectral Domain Optical Coherence Tomography to Visual-evoked potentials in early relapsing remitting multiple sclerosis (less than 5 years since diagnosis).
- Visual Evoked Potentials showed higher prevalence of abnormalities compared to Spectral Domain Optical Coherence Tomography.
- There was significant negative correlation between the latency of Visual Evoked Potentials and retinal nerve fiber layer thickness and the ganglion cell/inner plexiform layer.
- Visual Evoked Potentials may be more sensitive in detecting occult visual pathway lesions in early relapsing remitting multiple sclerosis.
Keywords: Optical coherence tomography, Retinal nerve fiber layer, Ganglion cell/inner plexiform layer, Multiple sclerosis, Axonal loss, Visual evoked potentials.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system characterized by relapses in its early course and subsequent progression over time. The visual pathways are commonly involved in MS as an initial manifestation in the form of optic neuritis, or during the course of the disease (Optic Neuritis Study Group, 2008). Visual pathways lesions can be detected by delayed visual-evoked potentials (VEP) latencies and axonal loss using optical coherence tomography (OCT) even in patients with no clinical visual manifestations (Naismith et al., 2009; Klistorner et al., 2013; Alshowaeir et al., 2014; Sriram et al., 2014). Therefore, detecting sub-clinical lesions of the visual pathway has become a diagnostically significant aspect in the assessment of newly diagnosed MS cases (Galetta and Balcer, 2013). VEP assesses visual pathway functional integrity from the retina to the occipital cortex by measuring the latencies, amplitudes and symmetry of cortical responses to standardized visual stimuli. OCT, given its high spatial resolution however, is useful in assessing structural changes in the retinal layers arising from axonal loss and neurodegeneration (Kolappan et al., 2009). Few studies have compared the prevalence of abnormalities of VEP compared to OCT in MS patients with and without history of optic neuritis (Naismith et al, 2009, Klistorner et al, 2013, Di Maggio et al, 2014, and Chilinska et al, 2015). Some of these studies were done using time-domain OCT, which has a lower spatial resolution than the current spectral-domain OCT (SDOCT). Segmentation algorithms in SDOCT measure individual retinal layers including the ganglion-cell/inner plexiform layer (GCIPL), which can serve as an additional structural index for correlation with functional tests such as VEP and contrast sensitivity.
This is a cross-sectional study conducted at the MS clinic in Dasman Institute. Subjects who were at least 18 year old with RRMS according to the revised 2010 McDonald diagnostic criteria, had a disease duration of less than 5 years since the since the diagnosis, and expanded disability status scale (EDSS) scores ≤3.5 were included (Polman et al., 2011). Patients with progressive MS (primary or secondary), disease duration of more than 5 years, other demyelinating disorders (neuromyelitis optica or acute disseminated encephalomyelitis), high refractive error (±6 diopters) or who had optic neuritis onset within the 6 months of assessment, were excluded. All patients had neuro-ophthalmologic assessment and were tested using Pelli-Rosbon contrast sensitivity charts at one meter (Metropia Ltd. Cambridge, UK) and were given a logarithmic score. Patients` demographics (age, gender), clinical characteristics (age at disease onset, disease duration, presentation at onset, baseline EDSS score) were obtained from their medical records. We have performed both VEP and SDOCT on our study subjects within 6-month period of each other. The objective of this study was to compare the prevalence of abnormalities in VEP compared to SDOCT in early RRMS patients with and without optic neuritis. Furthermore, the correlations between VEP p-100 latency and amplitude with peri-papillary retinal nerve fiber layer (RNFL), ganglion-cell/inner plexiform layer (GCIPL), and Pelli-Robson contrast sensitivity logarithmic score were assessed. This study was approved by the ethical committee of Dasman Institute and all patients provided written informed consents.
Data of SDOCT results (average and all quadrants RNFL thickness, ganglion cell/inner plexiform layer thickness) were obtained using SDOCT (Cirrhus HDOCT 5000; Carl Zeiss Meditec). The SDOCT scan was performed by an experienced operator and only measurements of good quality and adequate signal strength were included.
OCT was considered abnormal if at least one quadrant of the RNFL and/or the average ganglion cell/inner plexiform layer thickness were 2 standard deviations lower than the built-in normal values of the, p<0.05, in either eye of a single patient.
Pattern-reversal VEP was recorded by the same qualified neurophysiology technician on a 4-channel EP machine (Natus Keypoint TM). We followed the standard techniques according to the Guideline of American Clinical Neurophysiology Society (American Clinical Neurophysiology Society, 2006). The P100 latency and the highest peak to peak amplitude in the N75-P100-N145 complex were measured by placing the cursors manually. On the Fz-mastoid channel, the N100 frontal potential was identified and used to identify possible sources of abnormality in the shape of the VEP. The patients were seated 1 m in front of the stimulator in a dark quiet environment. Subjects with refractory anomalies used their appropriate corrective lenses during the recording. They were instructed to focus attentively their vision on the marker in the center of the stimulating screen and to be as relaxed and calm as possible during the study. Evoked responses were recorded from Oz, O1 and O2 electrode sites with the reference over the Fz; and from Fz referred to one of the mastoids (all positions designated according to the International 10–20 system), at impedance below 5 kOhm, filter bandwidth 1–100 Hz, sensitivity 5 microV division and epoch of 300 ms. Pattern-reversal stimuli were delivered by an oscilloscope screen, that represented 12° visual angle in the patients visual fields. White and black checkerboard stimuli with a size of 32′ visual angle and reversal frequency of 3 Hz were delivered. At least 200 traces were recorded by monocular stimulation and averaged from each eye. The P100 latency and the highest peak to peak amplitude in the N75-P100-N145 complex were measured by placing the cursors manually. On the Fz-mastoid channel, the N100 frontal potential was identified and used to identify possible sources of abnormality in the shape of the VEP.
VEP was considered abnormal if any of the following criteria was fulfilled; (1) Absolutely prolonged latency in one or both eyes (P100 more than 108 ms in females and more than 110 ms in males). (2) Side-to-side difference of P-100 latency of more than 7 ms, (3) Absolute decrease of VEP amplitude, (4) Side-to-side amplitude ratio of more than 2:1. Our control values for detecting abnormality are based on our laboratory normal values for adults, derived from a study of 110 healthy controls (age 18–55 years, median 32 years, 64 male) and represent the 97.5th percentile of the obtained data for each parameter.
2.2.1. Statistical analysis
All statistical analyses were performed using JMP® (SAS Institute Inc., Cary, NC). Pearson correlation analyses were performed to calculate the correlations of the VEP p-100 latency and amplitude with RNFL and GCIPL thickness. Spearman rho correlation analysis was used to calculate the correlations of the Pelli Robson contrast sensitivity scores with VEP p-100 latency and amplitude, RNFL and GCIPL thickness. One way analysis of variance (AVOVA) was used to compare the RNFL and GCIPL thickness between normal and delayed VEP p-100 latency status. Results were described as mean±standard deviation. A p-value <0.05 was considered statistically significant.
3.1. Prevalence VEP and OCT abnormalities
Our study comprised 50 subjects (100 eyes) and their baseline demographic data are summarized in Table 1. The prevalence of VEP abnormalities was 56% while with OCT was 48% in all eyes. In patients with abnormal OCT, RNFL abnormalities were seen in 48% while GCIPL abnormalities were seen in 40% of patients. In patient with history of optic neuritis, prevalence of VEP abnormalities was 80% while in OCT it was 70% (RNFL was abnormal in 70% and GCIPL abnormal in 60%), while in patients with no prior history of optic neuritis, VEP abnormalities were seen in 40% and OCT abnormalities was seen in 33.3% of patients. (RNFL was abnormal in 30% and GCIPL was abnormal 26.%).
Baseline Demographic data for study subjects.
|Total Subjects (Number of Eyes)||50 (100)|
|Age in years Mean±SD (Min-Max)||31.1±7.16 (19–52)|
|Sex (Number of Subjects)||Males (19), Females (31)|
|History of Optic Neuritis (%)||20 (40%)|
|Disease Duration Since Diagnosis in years Mean±SD (Min-Max)||3.94±1.02 (1–5)|
|EDSS Mean±SD (Min-Max)||1.23±0.68 (0–3.5)|
EDSS: Expanded disability status scale; SD: Standard deviation.
3.2.1. Spectral domain OCT correlates with VEP latency but not amplitude
When all eyes (N=100) were analyzed, we have found significant negative correlations between OCT and VEP P-100 latency in the average RNFL (r=−0.34, p=0.001), superior quadrant RNFL (−0.25, p=0.011), inferior quadrant RNFL (r =−0.30, p=0.003), temporal quadrant RNFL (r=−0.39, p<0.001), and GCIPL (r=−0.39, p<0.001). When only eyes with prior history of optic neuritis were analyzed, there was a significant negative correlation between the OCT and VEP latency in average RNFL (r=−0.33, p=0.037), temporal quadrant RNFL (r=−0.42, p=0.007), inferior quadrant RNFL (r=−0.41, p=0.010), GCIPL (r=−0.40, p=0.010). Finally, in eyes with no prior history of optic neuritis, we found significant negative correlation between OCT and VEP latency in only the temporal quadrant RNFL (r=−0.28, p=0.028). We could not find a significant correlation between the VEP amplitude and any of the RNFL or GCIPL in our subjects. A summary of the all correlations is outlined in Table 2.
Correlation between Average RNFL, Temporal RNFL quadrant, and GCIPL with VEP P-100 Latency and Pelli-Robson contrast sensitivity.
|VEP P-100 Latency a||Contrast Sensitivity b|
|All Eye (N=100)|
|Average RNFL||r=−0.34, p=0.001||ρ=0.28, p=0.006|
|Temporal RNFL||r=−0.39, p<0.001||ρ=0.20, p=0.049|
|Superior RNFL||r=−0.25, p=0.011||ρ=0.26, p=0.010|
|Nasal RNFL||r=−0.19, p=0.062||NS|
|Inferior RNFL||r=−0.30, p=0.003||ρ=0.25, p=0.014|
|ON Eyes (N=40)|
|Average RNFL||r=−0.33, p=0.037||ρ=0.39, p=0.012|
|Temporal RNFL||r=−0.42, p=0.007||ρ=0.29, p=0.073|
|Nasal RNFL||NS||ρ=0.37, p=0.020|
|Inferior RNFL||r=−0.41, p=0.009||ρ=0.45, p=0.004|
|GCIPL||r=−0.40, p=0.010||ρ=0.38, p=0.017|
|Non-ON Eyes (N=60)|
|Average RNFLT||r=−0.25, p=0.058||NS|
|Temporal RNFL||r=−0.28, p=0.028||NS|
|Superior RNFL||NS||ρ=0.29, p=0.035|
a Pearson correlation.
b Spearman ρ correlation.
ON=optic neuritis, RNFL=retinal nerve fiber layer, GCIPL=ganglion cell/inner plexiform layer, NS=not statistically significant.
In the Spearman ρ correlation analysis of contrast sensitivity Spearman ρ correlation, eye with missing Pelli-Robson contrast sensitivity score (N=6) were excluded from the analysis.
3.2.2. Patients with delayed VEP have thinner RNFL and GCIPL
When patients were divided into two groups based on whether the VEP latency was normal or delayed, patients with delayed latency had statistically significant lower average RNFL (75.8±12.9 vs 89.2±12.6 µm) (ANOVA p<0.001), lower temporal quadrant RNFL, (48.2±10.0 vs 58.1±13.4 µm) ( ANOVA p=0.003) and lower GCIPL (69.1±10.6 vs 78.1±1.5 µm) (ANOVA p=0.001), compared to patients with normal VEP latency (Fig. 1). There was no significant correlation between the VEP amplitude with neither RNFL nor GCIPL in all eyes or eyes with or without history of optic neuritis.
Box plot shows patients with delayed VEP latency had significantly (A) lower Average RNFL (75.8±12.9 vs 89.2±12.6 µm; p<0.001), (B) lower temporal quadrant RNFL (48.2±10.0 vs 58.1±13.4 µm; p=0.003) and (C) lower GCIPL (69.1±10.6 vs 78.1±10.0 µm; p=0.001), than patients with normal VEP latency.
3.2.3. OCT correlates with contrast sensitivity while VEP did not
When considering all eyes, SDOCT correlated with contrast Pelli-Robson contrast sensitivity logarithmic score in the average RNFL (Spearman ρ=0.28, p=0.006), superior RNFL (ρ=0.26, p=0.010), temporal RNFL (ρ=0.20, P=0.049), inferior RNFL, (ρ=0.25, p=0.014), and GCIPL (ρ=0.26, p=0.011). In eyes with no prior history of optic neuritis, there was significant correlation between contrast sensitivity and the superior quadrant RNFL (ρ=0.29, p=0.035) only. In eyes with prior history of optic neuritis, the average RNFL (ρ=0.39, p=0.012), nasal (ρ=0.37, p=0.020), inferior quadrant RNFL (ρ=0.45, p=0.004) and GCIPL (ρ=0.38, p=0.017) showed significant correlation with contrast sensitivity (Table 2). There was no significant correlation between the VEP amplitude or latency with contrast sensitivity neither in eyes with nor eyes without prior history of optic neuritis.
In our study, there was higher prevalence of VEP abnormalities (56%) compared with SDCCT (48%) in patients with early RRMS, irrespective of prior history of optic neuritis. The prevalence of abnormalities is higher in patients with prior history of optic neuritis (80%) compared to patients with no prior optic neuritis (70%). Other studies using multifocal VEP (mfVEP) found it was more sensitive (56%) than SDOCT (36%) in detecting visual pathway lesions in eyes with no prior history of optic neuritis with higher sensitivity in patients with prior optic neuritis (86%) compared to OCT (68%) (Di Maggio et al., 2014; Laron et al., 2010). Studies on non-involved eyes in patients with early MS and/or clinically isolated syndrome of optic neuritis also found greater sensitivity of mfVEP in detecting abnormalities (latency and amplitude) than time-domain OCT (Klistorner et al., 2008).
In this study, we have used the more widely available conventional VEP, which measures the cortical stimulation of the central 30 degrees of the visual field. Multi-focal VEP (mfVEP) offers advantage of measuring response in a particular site of the visual field and this can be correlated with the corresponding retinotopic site, but it is a more technically-demanding and time-consuming test and is probably less widely-available (Kolappan et al., 2009). It is not clear whether mfVEP is more sensitive than standard VEP, but a study did find it slightly more sensitive and specific in patients with optic neuritis (Grover et al., 2008). Since the diagnostic value of ancillary tests such as VEP and OCT is most useful in the early stages of MS, we have limited our study subjects to patients with relatively early relapsing-remitting MS (<5 years since the diagnosis) and mild neurologic disability (EDSS ≤3.5). The diagnostic utility of ancillary tests such as VEP and SDOCT becomes less significant with longer duration and more clinically evident course. Similar studies which compared the sensitivity of the two tests included patients with wider range of disability, and longer disease duration, which can lead to the bias of over-detection of visual pathway involvement in patients who already have established disease (Di Maggio et al., 2014). It seems that VEP is more dependent on lesion load and widespread involvement the posterior visual pathway and is thus more sensitive in detecting sub-clinical lesions in early MS, while OCT is more useful in detecting more discrete localized lesions of the optic nerve and anterior visual pathway. Moreover, the ability of OCT to detect abnormalities also depends on the development of trans-synaptic degeneration resulting from posterior visual pathway lesions (Gabilondo et al., 2014).
We have found significant inverse correlation in all eyes between SDOCT in both average RNFL, and GCIPL with VEP P-100 latency. (Table 2) The temporal RNFL quadrant showed the strongest correlation with VEP latency both in eyes with prior optic neuritis (r=−0.42, p=0.007) and without prior optic neuritis (r=−0.28, p=0.028). The GCIPL correlated with VEP latency only in.
eyes with prior optic neuritis (r=−0.40, p=0.010). This correlation was supported by further analysis in which patients with delayed VEP latency had significantly lower average RNFL and GCIPL than patients with normal latency (Fig. 1). Our results suggest that the temporal quadrant RNFL may be a better structural index for correlation with posterior visual pathway lesions and no prior optic neuritis. Other studies similarly have found significant inverse correlation between temporal RNFL quadrant and GCIPL with VEP latency in MS eyes with no optic neuritis, while we only found significant correlation between GCIPL and VEP latency in eyes with prior optic neuritis (Klistorner et al., 2013; Sriram et al., 2014). This discrepancy of findings may be attributed to the differences in inclusion criteria in subjects across studies such as disease duration and disability scale. Spectral domain OCT offers new algorithms which allow segmentation of retinal layers, although with most algorithms cannot separate the ganglion cell layer from the inner plexiform owing to similar reflectivity and they are measured as one layer known as the ganglion cell/inner plexiform layer (GCIPL). The correlation between temporal RNFL, which contains the maculo-papular bundle, and VEP latency is most likely attributed to the magnification of the macular VEP at the level of the occipital cortex. Similarly, the higher density of the retinal ganglion cells the macula can probably explain the correlation between VEP latency and GCIPL. The GCIPL may offer advantages over the RNFL as a structural surrogate for correlation with VEP since it is less amenable to axonal swelling the in the early and recovery stages optic neuritis (Kupersmith et al., 2015). Finally, GCIPL can be a more direct index to assess trans-synaptic neuronal loss from sub-clinical posterior visual pathway lesions, rather than the indirect axonal loss in RNFL from ganglion cell degeneration (Meier et al., 2015). We could not find a significant correlation between the VEP amplitude and OCT in our subjects. The VEP amplitude is largely dependent on axonal integrity and although a significant proportion of our subjects had prior optic neuritis (40%), most of them had early MS and mild neurologic disability and thus were not expected to have significant axonal loss (Toledo et al., 2008).
Our study has several limitations including the relatively small sample size, and referral bias to a tertiary care center. Moreover, information about prior attack of optic neuritis was obtained retrospectively or by direct questioning and frequently the exact side of involvement could not be ascertained. Finally, we did not include a control group of normal subjects for OCT as we have relied on the built-in normative database. For VEP we have relied on normative data form previous unreported normal subject series from our neurophysiology laboratory.
In summary, we have found that higher prevalence of VEP abnormalities than SDOCT in patient with early relapsing-remitting MS. This suggests that VEP is more sensitive at detecting occult lesion of the visual pathway than SDOCT in RRMS. There is good correlation between structure SDOCT, especially temporal quadrant RNFL, with function (VEP, contrast sensitivity) regardless of prior onset of optic neuritis. The role of OCT and VEP will remain complementary as VEP may be more useful to detecting early demyelinating lesions, whereas SDOCT is more useful in monitoring axonal loss and neurodegeneration. Longitudinal studies are needed to correlate SDOCT, with possibly special attention to the ganglion cell layer (GCIPL), with VEP to explore the causal relationship between occult visual pathway lesions and retinal neuronal loss in MS.
The authors have no conflict of interest to disclose.
We would like to acknowledge D. Sriraman, MBA for his help in the statistical analysis of the data.
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a Opthalmology Clinic, Dasman Institute, Dasman, Kuwait
b Al-Bahar Ophthalmology Center, Ibn Sina Hospital, Kuwait
c Department of Neurology, Ibn Sina Hospital, Kuwait
d Department of Neurology and Psychiatry, Minia University, Egypt
e Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait
f Division of Neurology, Amiri Hospital, Sharq, Kuwait
⁎ Correspondence to: FRCSC, P.O Box 1180, Dasman 15462, Kuwait.
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