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Multifocal VEP assessment of optic neuritis evolution
Clinical Neurophysiology 126 (2015) 1617–1623
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Multifocal VEP assessment of optic neuritis evolution Daniah Alshowaeir a,b,⇑,1, Con Yannikas c,d, Raymond Garrick e, Anneke Van Der Walt f, Stuart L. Graham g, Clare Fraser a, Alexander Klistorner a,h a
Department of Ophthalmology, University of Sydney, Sydney, Australia Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia c Concord Hospital, Sydney, Australia d Department of Neurology, Royal North Shore Hospital, Sydney, Australia e Department of Neurology, St Vincent Hospital, Sydney, Australia f Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia g Department of Ophthalmology, Macquarie University, Sydney, Australia h Australian School of Advanced Medicine, Macquarie University, Sydney, Australia b
a r t i c l e
i n f o
Article history: Accepted 11 November 2014 Available online 20 November 2014 Keywords: Optic neuritis Multiple sclerosis mfVEP Demyelination Axonal loss
h i g h l i g h t s Recovery of amplitude and shortening of latency was fastest within the first 3 months. Multi-focal visual evoked potentials amplitude is an early predictor of post-optic neuritis axonal loss. The apparent more severe involvement of optic neuritis eyes in multiple sclerosis subgroup may be
due to subclinical inflammation along the visual pathway.
a b s t r a c t Objective: To evaluate multifocal visual evoked potentials (mfVEP) changes in optic neuritis (ON) and fellow eyes during first year after the attack. Methods: Eighty-seven patients and twenty-five controls were examined. Patients were classified as multiple sclerosis (MS) group, high risk (HR) or low risk (LR) groups for conversion to MS. mfVEP recordings and retinal nerve fiber layer (RNFL) thickness were analyzed. Results: Recovery of amplitude and shortening of latency was fastest within the first 3 months. The largest amplitude reduction and longest latency delay of the ON eye were recorded in the MS group. This was accompanied by deterioration of both parameters in fellow eyes (p < 0.03). mfVEP remained stable in fellow eyes of the LR group. Inter-eye asymmetry showed similar amount of amplitude reduction and latency delay in all three groups. RNFL thickness strongly correlated with mfVEP amplitude as early as 3 months after ON (R2 = 0.6, p = 0.001). Conclusion: mfVEP amplitude is an early predictor of post-ON axonal loss. The apparent more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. Significance: Severity of amplitude reduction and latency delay after episode of ON is not MS-related. Retro-chiasmal demyelination is a possible factor contributing to amplitude and latency differences between MS and non-MS patients. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Optic neuritis (ON) is a common form of inflammatory demyelination in the central nervous system. ON is often associated with ⇑ Corresponding author at: Save Sight Institute, Sydney Eye Hospital, 8 Macquarie Street, Sydney, NSW 2000, Australia. E-mail address: [email protected] (D. Alshowaeir). 1 Address: P.O. Box 4337, Sydney, NSW 2001, Australia.
multiple sclerosis (MS) and is the presenting symptom in approximately 20% of MS patients (Sorensen et al., 1999). However, in a significant proportion of patients ON remains a single demyelinating episode of unknown, probably viral, etiology, so called Clinically Isolated Syndrome (CIS). In contrast with most demyelinating brain lesions, the effect of the disease on the optic nerve is clinically apparent and quantifiable by objective means. Visual Evoked Potentials (VEP) was developed as an objective means of functional assessment of
http://dx.doi.org/10.1016/j.clinph.2014.11.010 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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the integrity of the visual pathway in ON (Halliday et al., 1972). However, the full-field VEP is limited by the fact that it provides a summed response of all neuronal elements stimulated and is greatly dominated by the macular region due to its cortical overrepresentation. Being the vector sum of numerous differently oriented dipoles, the waveform of the full-field VEP is prone to unpredictable change depending on the part of the nerve/visual field affected. This can lead to detection of apparent rather than real latency delay and waveform distortion (Klistorner et al., 2008). The multifocal VEP is a topographic recording of optic nerve function with measurement of amplitude and latency from locally derived VEP responses. This technique minimize limitations of full-field recording by providing simultaneous, but independent stimulation of a plurality of visual field locations, which reduces waveform’s cancelation and macular over-representation (Klistorner et al., 1998). The current study provides a comprehensive mfVEP evaluation of the evolution of optic neuritis during the first 12 months after the attack using mfVEP. The pattern of amplitude and latency change of ON eyes, fellow eyes and conversion to MS were examined. We also investigated any association between mfVEP parameters and the long-term axonal loss. The study represents an extension of previous work (Fraser et al., 2006a,b) examining larger sample size and assessing changes in the fellow eye to provide a better understanding of mfVEP changes and the time frame of their occurrence. 2. Methodology 2.1. Subjects Ninety-eight subjects were recruited with clinically diagnosed typical acute unilateral ON. No participants had a history of previous demyelinating events. Exclusion criteria were an atypical presentation, involvement of the other eye or other ophthalmic conditions that could affect either the mfVEP or ocular coherence tomography (OCT) measurements. Patients had a brain and spine magnetic resonance imaging (MRI) within 2 weeks of the ON attack and at least one follow up MRI within next 12 months. Diagnosis of clinically definite multiple sclerosis (CDMS) was made by a neurology consultant based on revised McDonald Criteria for multiple sclerosis (Polman et al., 2005). mfVEP recordings were performed at 1, 3, 6 and 12 months from the onset of ON. OCT was performed at 12 months. Twenty-five aged and gender matched healthy subjects were recruited as controls. Approval was obtained from the Human Research Ethics Committee of the University of Sydney (protocol No. 745). Informed consent was obtained from all participants. 2.2. Methods 2.2.1. mfVEP recording and analysis Multifocal VEP testing was performed using Accumap (ObjectiVision Pty. Ltd., Sydney, Australia), described elsewhere (Klistorner et al., 2009). In order to accurately follow the evolution of the latency after the ON attack, only eyes that had at least 75% of traces with sufficient amplitude at 1 month were included. To determine sufficient amplitude, software automatically calculate signal to noise ratio (SNR) at each segment of the stimulated visual field. The signal was considered non-recordable in segments where amplitude of the response was less than 1.96 times of the noise level (determined as Standard Deviation of the trace within the interval 400–1000 ms) (Klistorner et al., 2010).
Mean values of both amplitude and latency were calculated by averaging the amplitude and latency of the individual sectors (Fig. 1). 2.3. OCT recording and analysis OCT was performed using Stratus OCT-3 scanner (Stratus; Carl Zeiss Meditec, Inc., Dublin, CA, USA). The fast retinal nerve fibre layer (RNFL) protocol was used. The mean total RNFL thickness was assessed. Latency Z-scores were calculated for each patient using following formula:
ðPatient’s latency mean normal latencyÞ=Normal latency standard deviation A Z-score greater than 1.96 was classified as latency delay. 2.4. Asymmetry analysis Inter-eye asymmetry of both amplitude and latency of the mfVEP and inter-eye asymmetry of RNFL thickness has been calculated and analyzed. The inter-eye asymmetry was calculated as a difference between fellow and ON eyes and was expressed in volts, milliseconds and micrometers for mfVEP amplitude, latency and RNFL thickness respectively. Inter-eye asymmetry has been used extensively in studies of both mfVEP and RNFL thickness and has proved to be more sensitive in detection of abnormality as well as revealing relationships between various measures compared to absolute values (Hood et al., 2000b; Trip et al., 2005, 2006; Klistorner et al., 2010). 2.5. Statistical analysis Statistical analysis was performed using SPSS 21.0 software. To evaluate the pattern of amplitude and latency change over time, we tested the trend of change with mixed model repeated measure analysis using the visits as a continuous variable. One-way ANOVA was used to assess difference between groups. p-Value of 60.05 was considered statistically significant. 3. Results 3.1. Demographic and clinical characteristics of participants Ninety-eight acute ON patients were recruited. Subsequently, 11 ON patients were excluded from analysis (9 due to recurrent ON, 1 due to noisy traces and 1 due to presence of a maculopathy). At presentation, 27/87 patients without other demyelinating MRI lesions were classified as low risk (LR) for developing MS. 60/ 87 patients had brain and/or spinal cord demyelinating lesions on MRI, but did not meet the criteria for a diagnosis of CDMS. This group was considered high-risk group (HR) for MS (Beck et al., 2003). During regular clinical follow up after the attack (range 1–4 years), 38 patients converted to CDMS with 36/60 (60%) from HR group and 2/27 (7%) from LR group. Demographic and clinical characteristics of the study participants are summarized in Table 1. There was no significant difference between groups with respect to age (p = 0.6, one-way ANOVA). 3.2. Amplitude of mfVEP in ON eyes 3.2.1. Entire study cohort As expected there was a significant reduction of amplitude at 1 month in ON eyes compared to fellow eyes and controls (1.2E07 ± 4.3E08, 1.9E07 ± 4E08, 2.4E07 ± 3.6E08 V for
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Fig. 1. mfVEP of a patient with left eye optic neuritis showing localized amplitude reduction centrally with latency delay at more peripheral locations.
Table 1 Demographic and clinical characteristics of the study participants.
Number of subjects Mean age Male:female ratio
Controls
Patients converted to MS
Patients remained at HR
Patients remained at LR
25 35.9 ± 11.2 6:19
38 34.4 ± 10.5 9:29
24 33.9 ± 8.3 6:18
25 36.5 ± 11.3 9:16
Abbreviations: MS, multiple sclerosis; HR, high risk; LR, low risk.
ON, fellow eyes, and controls respectively, one-way ANOVA p < 0.0001, post hoc Tukey test p < 0.0001). During the study period, amplitude recovered significantly (p < 0.01, mixed model repeated measure analysis). The largest amplitude improvement was seen within the first 3 months (Fig. 2a). Although amplitude continued to improve slowly after 3 months, the change was not significant (p = 0.47, mixed model analysis repeated measure analysis). At the 12-month time-point, the final amplitude remained significantly reduced compared to both normal controls and fellow eyes (p < 0.0001, one-way ANOVA, post hoc Tukey test p < 0.0001).
3.2.2. Group analysis Separate analysis of LR, HR and MS patients revealed similar trend for all three groups with a significant difference between the ON eye versus fellow eyes and controls (Table 2 and Fig. 2a). Mean amplitude of MS group was less than the HR and LR groups throughout the study period, but this difference did not reach statistical significance at any time point. The largest improvement in amplitude in all 3 groups was seen within the first 3 months (p = 0.03, 0.05, 0.02 for MS, HR, and LR respectively) with modest, but not significant improvement
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Fig. 2. (a) Amplitude changes during the study period in the ON eyes in patients’ groups. (b) Latency recovery during study period in ON eyes. Bars show standard error of the mean ( – entire study cohort, triangles – LR, squares – HR, and diamonds – MS group).
Table 2 Statistical difference of amplitude of the optic neuritis eyes compared to fellow eyes and normal controls at 1 and 12 months. (One-way ANOVA, post hoc Tukey test.)
Table 3 Z-scoresa of latency for ON eyes and fellow eyes according to their subgroups. Subgroup
Affected eye
MS HR LR
At 1st month
At 12th month
Fellow eye
Controls
Fellow eye
Controls
p < 0.001 p < 0.001 p < 0.001
p < 0.001 p < 0.001 p < 0.001
p < 0.001 p = 0.007 p = 0.008
p < 0.001 p < 0.001 p < 0.001
MS HR LR Total
Abbreviations: MS, multiple sclerosis; HR, high risk; LR, low risk. a
afterward (p = 0.5, 0.3, 0.6 mixed model repeated measure analysis for MS, HR, and LR respectively). 3.3. Latency of mfVEP in ON eyes 3.3.1. Entire study cohort Fifty-seven eyes (MS-24, HR-18, LR-15) had at least 75% of traces with sufficient amplitude at 1 month and were suitable for analysis. ON eyes had a substantial mfVEP latency delay at 1 month when compared to controls and fellow eyes (p < 0.0001, one-way ANOVA, post hoc Turkey test p < 0.0001). A significant trend of latency recovery was observed during the study period (p < 0.001 mixed model repeated measure analysis) (Fig. 2b). Average rate of latency recovery was 1.33 ms/month between 1 and 3 months, which declined between 3 and 6 months to 0.76 ms/month and slowed to 0.33 ms/month between 6 and 12 months. There was still a significant residual latency delay at 12 months in comparison to controls and fellow eyes (157.9 ± 8.3, 145.6 ± 6.7, 141 ± 5.1 ms for ON, fellow eyes and controls respectively, p < 0.0001 one way-ANOVA-post hoc test). 3.3.2. Group analysis Affected eyes in all groups showed significant latency delay in comparison to controls and fellow eyes throughout the study period p 6 0.003. All three groups follow similar trend of latency recovery (p < 0.001 mixed model repeated measure analysis for each group) (Fig. 2b). The LR group had less latency delay throughout the study period. There was a significant difference in latency delay between LR group and MS and HR groups at 3 months (p = 0.01, one-way ANOVA, Tukey post hoc analysis p = 0.01 for MS and p = 0.05 for HR respectively) and 6 months (p = 0.01 one-way ANOVA, Tukey post hoc analysis p = 0.01 for MS and p = 0.05 for HR respectively) and the tendency for statistical significance at 12 months (p = 0.057, one-way ANOVA).
ON eye
Fellow eye
Z-score P 2 at 1 month
Z-score > 2 at 12 months
Z-score > 2 at 12 months
21/24 (88%) 17/18 (94%) 9/15 (62%) 47/57 (82%)
17/24 (71%) 13/18 (72%) 5/15 (36%) 35/57 (61%)
9/24 (38%) 4/18 (22%) 0/15 (0%) 13/57 (23%)
Z-score less than 1.96 classified as normal latency.
Analysis of the latency Z-scores also revealed that a smaller proportion of LR group ON eyes were abnormal as compared to MS and HR groups (Table 3). 3.4. Retinal nerve fiber thickness analysis At 12 months, RNFL thickness of the entire cohort was significantly reduced in ON eyes in comparison to fellow eyes (84 ± 16 vs. 103 ± 11 lm p = 0.0001). This reduction was similar between the three studied groups (p = 0.46, one-way ANOVA). To assess predictive power of mfVEP amplitude on long-term axonal loss, the inter-eye asymmetry of mfVEP amplitude at every time point was compared with the final inter-eye asymmetry of the RNFL thickness. A high degree of correlation between mfVEP amplitude and RNFL thickness was seen as early as 3 months after the attack, and this marginally increased with time. Separate analysis for each group was also performed. A similar trend was observed for all groups. The correlation by 3 months was already strong and moderately improved with time (Table 4). 3.5. Amplitude of mfVEP in fellow eyes 3.5.1. Entire study cohort The fellow eyes demonstrated lower amplitude in comparison to controls (p < 0001, one-way ANOVA) at all time points. There was no significant change of the amplitude throughout the study period (p = 0.5, mixed model repeated measure analysis). 3.5.2. Group analysis The amplitude in the fellow eye was significantly lower in all three groups, however the LR group demonstrated less amplitude reduction compared to HR and MS groups (p < 0.01 for all). Amplitude of the fellow eye in the LR group remained stable during the follow-up period, while progressive amplitude reduction in the fellow eye was seen in the MS group with difference
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R2 of inter-eye asymmetry of amplitude over time vs. 12 month inter-eye asymmetry of RNFL thickness. 1 month
Total MS HR LR
0.28 0.27 0.29 0.29
3 months p < 0.001 p = 0.0008 p = 0.006 p = 0.005
0.59 0.63 0.59 0.49
6 months p < 0.001 p < 0.001 p < 0.001 p < 0.001
0.61 0.6 0.71 0.65
12 months p < 0.001 p < 0.001 p < 0.001 p < 0.001
0.71 0.73 0.75 0.68
p < 0.001 p < 0.001 p < 0.001 p < 0.001
Fig. 3. (a) Amplitude changes during study period in fellow eyes. (b) Latency changes during study period in fellow eyes. Bars show standard error of the mean ( – entire study cohort, triangles – LR group, squares – HR, and diamonds – MS).
Fig. 4. (a) Amplitude inter-eye asymmetry changes during study period. (b) Latency delay inter-eye asymmetry during study period in patients groups. Bars show standard error of the mean (MS group are shown in diamond, HR in square, and LR group in triangle).
between MS and LR groups reaching significance at 6 months (p = 0.01, one-way ANOVA, post hoc p = 0.02) and at 12 months (p = 0.02, one-way ANOVA, post hoc p = 0.03) (Fig. 3a). 3.6. Latency of mfVEP in fellow eyes 3.6.1. Entire study cohort Latency of the fellow eye was not significantly delayed at the first visit in comparison to the controls (p = 0.17). However, a slow, but consistent increase in latency was seen during the study period. By 3 months the latency delay reached significance (p = 0.03), and this continued to increase during subsequent visits (p = 0.02, and 0.018 in the 6 and 12 month visits Fig. 3b). 3.6.2. Group analysis There was no significant difference between the latency of each individual group and normal controls at 1 month (p = 0.2, one-way ANOVA). By 3 months, however, the MS group displayed significant latency delay compared to controls (p = 0.024, one-way ANOVA, p = 0.023 Tukey post hoc). This trend continued at 6 and 12 months
(p = 0.018, one-way ANOVA, p = 0.013 Tukey post hoc and 0.01 one-way ANOVA, p = 0.01 Tukey post hoc respectively) (Fig. 3b). While latency delay of the fellow eye in HR group increased over time, it was not statistically significant. The latency of the LR group remained stable. Z-score analysis of the fellow eyes revealed abnormal latency in more than third of patients who converted to MS, but none of patients from LR group (Table 3). 3.6.3. Asymmetry analysis Inter-eye asymmetry analysis of the amplitude demonstrated no difference between groups at any time point (ANOVA p = 0.6, 0.3, 0.3, 0.4 for 1, 3, 6 and 12 months respectively) (Fig. 4a), suggesting that the difference in amplitude between the groups is likely due to retro-chiasmal damage. In addition, all three groups demonstrated very similar latency recovery trend (Fig. 4b). There was less latency asymmetry in LR group compared to MS and HR groups, which, however, did not reach statistical significance at any time points (p = 0.2. 0.07, 0.18, 0.29 for 1, 3, 6, and 12 month respectively, one way-ANOVA) (Fig. 4b).
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4. Discussion This report provides prospectively acquired, longitudinal mfVEP data over 12 months of patients presenting with ON as clinically isolated syndrome. The study demonstrated that both amplitude and latency of the mfVEP are grossly abnormal at the early stage of ON. While amplitude of the mfVEP improves considerably during the first year after acute ON, the majority of the recovery occurred within the first 3 months. These results are similar to those reported for full-field VEPs (Jones and Brusa, 2003). This pattern of amplitude recovery is also in line with visual acuity, which demonstrates rapid improvement of vision within early post-acute period (Hickman et al., 2004; Hood et al., 2000a). Similar to amplitude, the speed of latency recovery was fastest during the first 3 months. It is believed that latency shortening after ON is mostly due to the process of remyelination. Remyelination occurs most efficiently during the early post-acute stage, where cells engaging in the formation of new myelin sheaths are frequently observed (Prineas et al., 1993). The environment for successful remyelination may be severely altered afterward (Coles et al., 2006). Thus, the significant latency recovery during the first few months after the attack supports the concept of ‘window of opportunity’ as being fundamentally important for the success of remyelination (Blakemore et al., 2002; Coles et al., 2006). Spontaneous remyelination, which is an early and frequent phenomenon in MS, is often incomplete (Patrikios et al., 2006; Prineas et al., 1993). Our results confirm this, as we showed significant residual latency delay even 12 months after acute ON. This chronically persisting latency delay has been demonstrated in multiple studies and remains the major hallmark of previous ON (Weinstock-Guttman et al., 2003). In this study, patients were divided into those who converted to CDMS and those who remained at high risk or low risk of conversion to the disease. Overall, the group analysis demonstrated smaller amplitude and longer latency in ON eyes of MS patients compared to LR patients. However, the progressive deterioration of both amplitude and latency in the fellow eyes of MS group, and to a lesser extent HR group suggests that the apparent more severe involvement of ON eyes in those subgroups is due to superimposed burden of subclinical inflammatory demyelinating activity along the posterior visual pathway. Hence, the severe involvement of ON of MS group is indirectly a reflection of lesion load and disease burden at presentation and not related to the difference in remyelination pattern between MS and LR groups. The latency of the fellow eye in LR group did not differ from the latency of normal controls and was stable throughout the study period. However, there was a clearly visible trend of latency increase in the fellow eye of MS group. The difference between MS and controls reached statistical significance by 3 months and continued to increase thereafter. Latency of the fellow eye in HR group also demonstrated tendency to increase, although not to the same extent as patients in the MS group. Delayed latency in fellow eyes of ON patients has been suggested as a part of central adaptive mechanism at the cortical level to compensate for delayed cortical visual input from ON eyes (Raz et al., 2013). The fact that fellow eyes of LR subgroup in this study did not show significant latency delay argues against this suggestion. Since both ON and fellow eyes appear to be involved, it is reasonable to assume that this pathological process is occurring in a post-chiasmal location. Optic tract (OT) and optic radiation (OR) are two potential sites of such retro-chiasmal lesions. Lesions of the optic tract, however, are rare in MS (Plant et al., 1992; Rosenblatt et al., 1987). Furthermore, it is unlikely for the acute inflammation of the OT to be missed clinically due to its small
diameter and supposedly preferential damage of small central fibers (Evangelou et al., 2001), which would result in an acute binocular visual deficit. On the other hand, OR lesions, are very common in MS (Hornabrook et al., 1992) and are often clinically silent. This apparent clinical ‘invisibility’ is due to a wide spread of OR fibers, and non-preferential distribution of the lesions, which cause rather small and more peripherally located visual field defects, easily missed by patients. However, since mfVEP covers a significant part of the visual field (48°), demyelinating lesions of the OR are likely to cause amplitude reduction and latency delay for both ON and fellow eyes. Consistent with this, we have recently reported a correlation between volume of OR lesions and latency delay in the fellow eyes of MS patients (Klistorner et al., 2013). Findings of this study also concur with our previous report demonstrating that latency prolongation and amplitude decline 12 months after acute ON were proportional to the risk of MS (Klistorner et al., 2009). Likewise, full-field VEP studies (Jones and Brusa, 2003) also suggested that the cause of the observed asymptomatic deterioration of VEP latency in unaffected eyes of MS patients is a demyelination process in the posterior visual pathway. Therefore, to analyze the effect of acute ON on the amplitude and latency of the mfVEP, the potential effect of retro-chiasmal damage has to be eliminated. Assuming that retro-chiasmal damage influences both eyes similarly, its effect can be removed by subtracting values of the fellow eye from ON eye. Consequently, performed inter-eye asymmetry analysis showed no difference in amplitude reduction, recovery and residual deficit between patients who converted to CDMS and patients who remained at high risk or low risk of conversion to MS, indicating similar degree of inflammation caused by acute ON for all three groups. This is also supported by high (and very similar) correlation between residual amplitude of the mfVEP and RNFL thickness in all three groups and by the similar inter-eye asymmetry of the RNFL thickness between the groups. Results of the inter-eye latency analysis also revealed a similar picture, suggesting that the demyelinating effect of the acute ON is MS-independent. While several studies have reported a shorter latency in eyes with acute ON as part of mono-symptomatic disease (analogous to LR group) as compared to MS-related ON (Alshuaib, 2000; Fredericksen and Petrera, 1999; Samsen et al., 2007), none of them assessed potential effect of retro-chiasmal pathology by analyzing inter-eye asymmetry. Our data, however, indicates that retrochiasmal demyelination is the major factor contributing to amplitude and latency differences between MS and non-MS patients. Another important aspect of this study is a demonstration of an early predictive power of mfVEP amplitude in post-ON axonal loss. The amplitude reduction predicted a significant portion of the final axonal loss as early as 3 months. The early association of mfVEP amplitude with the degree of post-inflammatory neuronal loss may suggest possible role of the electrophysiological measure as a potential functional surrogate marker in neuro-protective trials. The limitation of this study is its retrospective design in regards to conversion to CDMS. Therefore, a significant number of patients in the HR group and some patients in the LR group are in reality MS patients, who, due to limited follow-up time, have not yet demonstrated evidence of conversion to CDMS. Another limitation is the use of time-domain OCT. Since there is a low incidence of ON in Australia, the enrolment process took several years and started at the time when spectral-domain OCT machines were not yet available. However, we believe that for the purpose of the current study resolution of time-domain OCT was adequate. In conclusion, we demonstrated significant recovery of the amplitude and shortening of the latency during 12 months
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follow-up period, which was fastest within the first 3 months after acute episode. We also showed high predictive value of mfVEP amplitude in consecutive axonal loss as early as 3 months after acute ON. Our result suggested presence of the progressive retrochiasmal inflammatory demyelination in patients with MS-related disease. Acknowledgements This work was supported by King Saud University [grant number 7861359], Save Neuron grants from Novartis, Sydney Medical Foundation [grant number E34], and Sydney Hospital Foundation. The sponsors had no role in collection, analysis and interpretation of data or in the writing of the manuscript. Conflict of interest statement: The authors declare that there is no conflict of interest. References Alshuaib WB. Progression of visual evoked potential abnormalities in multiple sclerosis and optic neuritis. Electromyogr Clin Neurophysiol 2000;40:243–52. Beck RW, Trobe JD, Moke PS, Gal RL, Xing D, Bhatti MT, et al. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 2003;121:944–9. Blakemore W, Chari D, Gilson J, Crang A. Modelling large areas of demyelination in the rat reveals the potential and possible limitations of transplanted glial cells for remyelination in the CNS. Glia 2002;38:155–68. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, et al. The window of therapeutic opportunity in multiple sclerosis. J Neurol 2006;253:98–108. Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM. Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis. Brain 2001;124:1813–20. Fraser C, Klistorner A, Graham S, Garrick R, Billson F, Grigg J. Multifocal visual evoked potential latency analysis: predicting progression to multiple sclerosis. Arch Neurol 2006a;63:847. Fraser CL, Klistorner A, Graham SL, Garrick R, Billson FA, Grigg JR. Multifocal visual evoked potential analysis of inflammatory or demyelinating optic neuritis. Ophthalmology 2006b;113:315–23. e312. Fredericksen JL, Petrera J. Serial visual evoked potentials in 90 untreated patients with acute optic neuritis. Surv Ophthalmol 1999;44(Suppl 1):S54–62. Halliday A, McDonald W, Mushin J. Delayed visual evoked response in optic neuritis. Lancet 1972;299:982–5. Hickman SJ, Toosy AT, Miszkiel KA, Jones SJ, Altmann DR, MacManus DG, et al. Visual recovery following acute optic neuritis – a clinical, electrophysiological and magnetic resonance imaging study. J Neurol 2004;251:996–1005. Hood DC, Odel JG, Zhang X. Tracking the recovery of local optic nerve function after optic neuritis: a multifocal VEP study. Invest Ophthalmol Vis Sci 2000a;41:4032–8.
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Hood DC, Zhang X, Greenstein VC, Kangovi S, Odel JG, Liebmann JM, et al. An interocular comparison of the multifocal VEP: a possible technique for detecting local damage to the optic nerve. Invest Ophthalmol Vis Sci 2000b;41:1580–7. Hornabrook RS, Miller D, Newton MR, MacManus DG, du Boulay GH, Halliday AM, et al. Frequent involvement of optic radiation in patients with acute isolated optic neuritis. Neurology 1992;42:77–9. Jones SJ, Brusa A. Neurophysiological evidence for long-term repair of MS lesions: implications for axon protection. J Neurol Sci 2003;206:193–8. Klistorner AI, Graham SL, Grigg JR, Billson FA. Multifocal topographic visual evoked potential: improving objective detection of local visual field defects. Invest Ophthalmol Vis Sci 1998;39:937–50. Klistorner A, Fraser C, Garrick R, Graham S, Arvind H. Correlation between full-field and multifocal VEPs in optic neuritis. Doc Ophthalmol 2008;116:19–27. Klistorner A, Arvind H, Nguyen T, Garrick R, Paine M, Graham S, et al. Fellow eye changes in optic neuritis correlate with the risk of multiple sclerosis. Mult Scler 2009;15:928–32. Klistorner A, Arvind H, Garrick R, Yiannikas C, Paine M, Graham SL. Remyelination of optic nerve lesions: spatial and temporal factors. Mult Scler 2010;16:786–95. Klistorner A, Garrick R, Barnett MH, Graham SL, Arvind H, Sriram P, et al. Axonal loss in non-optic neuritis eyes of patients with multiple sclerosis linked to delayed visual evoked potential. Neurology 2013;15:242–5. Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 2006;129:3165–72. Plant GT, Kermode AG, Turano G, Moseley IF, Miller DH, MacManus DG, et al. Symptomatic retrochiasmal lesions in multiple sclerosis: clinical features, visual evoked potentials and magnetic resonance imaging. Neurology 1992;42:68–76. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘‘McDonald Criteria’’. Ann Neurol 2005;58:840–6. Prineas J, Barnard R, Kwon E, Sharer L, Cho ES. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 1993;33:137–51. Raz N, Chokron S, Ben-Hur T, Levin N. Temporal reorganization to overcome monocular demyelination. Neurology 2013;81:702–9. Rosenblatt MA, Behrens MM, Zweifach PH, Forman S, Odel JG, Duncan CM, et al. Magnetic resonance imaging of optic tract involvement in multiple sclerosis. Am J Ophthalmol 1987;104:74–9. Samsen P, Chuenkongkaew WL, Masayaanon P, Chirapapaisan N, Ruangvaravate N, Loket S. A comparative study of visual evoked potentials in optic neuritis and optic neuritis with multiple sclerosis. J Med Assoc Thai 2007;90:313–8. Sorensen TL, Frederiksen JL, Bronnum-Hansen H, Petersen HC. Optic neuritis as onset manifestation of multiple sclerosis. Neurology 1999;53:473–8. Trip SA, Schlottmann PG, Jones SJ, Altmann DR, Garway-Heath DF, Thompson AJ, et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005;58:383–91. Trip SA, Schlottmann PG, Jones SJ, Li W-Y, Garway-Heath DF, Thompson AJ, et al. Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy. Neuroimage 2006;31:286–93. Weinstock-Guttman B, Baier M, Stockton R, Weinstock A, Justinger A, Munschauer F, et al. Pattern reversal visual evoked potential as a measure of visual pathway pathology in multiple sclerosis. Mult Scler 2003;9:529–34.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Multifocal VEP assessment of optic neuritis evolution Daniah Alshowaeir a,b,⇑,1, Con Yannikas c,d, Raymond Garrick e, Anneke Van Der Walt f, Stuart L. Graham g, Clare Fraser a, Alexander Klistorner a,h a
Department of Ophthalmology, University of Sydney, Sydney, Australia Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia c Concord Hospital, Sydney, Australia d Department of Neurology, Royal North Shore Hospital, Sydney, Australia e Department of Neurology, St Vincent Hospital, Sydney, Australia f Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia g Department of Ophthalmology, Macquarie University, Sydney, Australia h Australian School of Advanced Medicine, Macquarie University, Sydney, Australia b
a r t i c l e
i n f o
Article history: Accepted 11 November 2014 Available online 20 November 2014 Keywords: Optic neuritis Multiple sclerosis mfVEP Demyelination Axonal loss
h i g h l i g h t s Recovery of amplitude and shortening of latency was fastest within the first 3 months. Multi-focal visual evoked potentials amplitude is an early predictor of post-optic neuritis axonal loss. The apparent more severe involvement of optic neuritis eyes in multiple sclerosis subgroup may be
due to subclinical inflammation along the visual pathway.
a b s t r a c t Objective: To evaluate multifocal visual evoked potentials (mfVEP) changes in optic neuritis (ON) and fellow eyes during first year after the attack. Methods: Eighty-seven patients and twenty-five controls were examined. Patients were classified as multiple sclerosis (MS) group, high risk (HR) or low risk (LR) groups for conversion to MS. mfVEP recordings and retinal nerve fiber layer (RNFL) thickness were analyzed. Results: Recovery of amplitude and shortening of latency was fastest within the first 3 months. The largest amplitude reduction and longest latency delay of the ON eye were recorded in the MS group. This was accompanied by deterioration of both parameters in fellow eyes (p < 0.03). mfVEP remained stable in fellow eyes of the LR group. Inter-eye asymmetry showed similar amount of amplitude reduction and latency delay in all three groups. RNFL thickness strongly correlated with mfVEP amplitude as early as 3 months after ON (R2 = 0.6, p = 0.001). Conclusion: mfVEP amplitude is an early predictor of post-ON axonal loss. The apparent more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. Significance: Severity of amplitude reduction and latency delay after episode of ON is not MS-related. Retro-chiasmal demyelination is a possible factor contributing to amplitude and latency differences between MS and non-MS patients. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Optic neuritis (ON) is a common form of inflammatory demyelination in the central nervous system. ON is often associated with ⇑ Corresponding author at: Save Sight Institute, Sydney Eye Hospital, 8 Macquarie Street, Sydney, NSW 2000, Australia. E-mail address: [email protected] (D. Alshowaeir). 1 Address: P.O. Box 4337, Sydney, NSW 2001, Australia.
multiple sclerosis (MS) and is the presenting symptom in approximately 20% of MS patients (Sorensen et al., 1999). However, in a significant proportion of patients ON remains a single demyelinating episode of unknown, probably viral, etiology, so called Clinically Isolated Syndrome (CIS). In contrast with most demyelinating brain lesions, the effect of the disease on the optic nerve is clinically apparent and quantifiable by objective means. Visual Evoked Potentials (VEP) was developed as an objective means of functional assessment of
http://dx.doi.org/10.1016/j.clinph.2014.11.010 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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the integrity of the visual pathway in ON (Halliday et al., 1972). However, the full-field VEP is limited by the fact that it provides a summed response of all neuronal elements stimulated and is greatly dominated by the macular region due to its cortical overrepresentation. Being the vector sum of numerous differently oriented dipoles, the waveform of the full-field VEP is prone to unpredictable change depending on the part of the nerve/visual field affected. This can lead to detection of apparent rather than real latency delay and waveform distortion (Klistorner et al., 2008). The multifocal VEP is a topographic recording of optic nerve function with measurement of amplitude and latency from locally derived VEP responses. This technique minimize limitations of full-field recording by providing simultaneous, but independent stimulation of a plurality of visual field locations, which reduces waveform’s cancelation and macular over-representation (Klistorner et al., 1998). The current study provides a comprehensive mfVEP evaluation of the evolution of optic neuritis during the first 12 months after the attack using mfVEP. The pattern of amplitude and latency change of ON eyes, fellow eyes and conversion to MS were examined. We also investigated any association between mfVEP parameters and the long-term axonal loss. The study represents an extension of previous work (Fraser et al., 2006a,b) examining larger sample size and assessing changes in the fellow eye to provide a better understanding of mfVEP changes and the time frame of their occurrence. 2. Methodology 2.1. Subjects Ninety-eight subjects were recruited with clinically diagnosed typical acute unilateral ON. No participants had a history of previous demyelinating events. Exclusion criteria were an atypical presentation, involvement of the other eye or other ophthalmic conditions that could affect either the mfVEP or ocular coherence tomography (OCT) measurements. Patients had a brain and spine magnetic resonance imaging (MRI) within 2 weeks of the ON attack and at least one follow up MRI within next 12 months. Diagnosis of clinically definite multiple sclerosis (CDMS) was made by a neurology consultant based on revised McDonald Criteria for multiple sclerosis (Polman et al., 2005). mfVEP recordings were performed at 1, 3, 6 and 12 months from the onset of ON. OCT was performed at 12 months. Twenty-five aged and gender matched healthy subjects were recruited as controls. Approval was obtained from the Human Research Ethics Committee of the University of Sydney (protocol No. 745). Informed consent was obtained from all participants. 2.2. Methods 2.2.1. mfVEP recording and analysis Multifocal VEP testing was performed using Accumap (ObjectiVision Pty. Ltd., Sydney, Australia), described elsewhere (Klistorner et al., 2009). In order to accurately follow the evolution of the latency after the ON attack, only eyes that had at least 75% of traces with sufficient amplitude at 1 month were included. To determine sufficient amplitude, software automatically calculate signal to noise ratio (SNR) at each segment of the stimulated visual field. The signal was considered non-recordable in segments where amplitude of the response was less than 1.96 times of the noise level (determined as Standard Deviation of the trace within the interval 400–1000 ms) (Klistorner et al., 2010).
Mean values of both amplitude and latency were calculated by averaging the amplitude and latency of the individual sectors (Fig. 1). 2.3. OCT recording and analysis OCT was performed using Stratus OCT-3 scanner (Stratus; Carl Zeiss Meditec, Inc., Dublin, CA, USA). The fast retinal nerve fibre layer (RNFL) protocol was used. The mean total RNFL thickness was assessed. Latency Z-scores were calculated for each patient using following formula:
ðPatient’s latency mean normal latencyÞ=Normal latency standard deviation A Z-score greater than 1.96 was classified as latency delay. 2.4. Asymmetry analysis Inter-eye asymmetry of both amplitude and latency of the mfVEP and inter-eye asymmetry of RNFL thickness has been calculated and analyzed. The inter-eye asymmetry was calculated as a difference between fellow and ON eyes and was expressed in volts, milliseconds and micrometers for mfVEP amplitude, latency and RNFL thickness respectively. Inter-eye asymmetry has been used extensively in studies of both mfVEP and RNFL thickness and has proved to be more sensitive in detection of abnormality as well as revealing relationships between various measures compared to absolute values (Hood et al., 2000b; Trip et al., 2005, 2006; Klistorner et al., 2010). 2.5. Statistical analysis Statistical analysis was performed using SPSS 21.0 software. To evaluate the pattern of amplitude and latency change over time, we tested the trend of change with mixed model repeated measure analysis using the visits as a continuous variable. One-way ANOVA was used to assess difference between groups. p-Value of 60.05 was considered statistically significant. 3. Results 3.1. Demographic and clinical characteristics of participants Ninety-eight acute ON patients were recruited. Subsequently, 11 ON patients were excluded from analysis (9 due to recurrent ON, 1 due to noisy traces and 1 due to presence of a maculopathy). At presentation, 27/87 patients without other demyelinating MRI lesions were classified as low risk (LR) for developing MS. 60/ 87 patients had brain and/or spinal cord demyelinating lesions on MRI, but did not meet the criteria for a diagnosis of CDMS. This group was considered high-risk group (HR) for MS (Beck et al., 2003). During regular clinical follow up after the attack (range 1–4 years), 38 patients converted to CDMS with 36/60 (60%) from HR group and 2/27 (7%) from LR group. Demographic and clinical characteristics of the study participants are summarized in Table 1. There was no significant difference between groups with respect to age (p = 0.6, one-way ANOVA). 3.2. Amplitude of mfVEP in ON eyes 3.2.1. Entire study cohort As expected there was a significant reduction of amplitude at 1 month in ON eyes compared to fellow eyes and controls (1.2E07 ± 4.3E08, 1.9E07 ± 4E08, 2.4E07 ± 3.6E08 V for
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Fig. 1. mfVEP of a patient with left eye optic neuritis showing localized amplitude reduction centrally with latency delay at more peripheral locations.
Table 1 Demographic and clinical characteristics of the study participants.
Number of subjects Mean age Male:female ratio
Controls
Patients converted to MS
Patients remained at HR
Patients remained at LR
25 35.9 ± 11.2 6:19
38 34.4 ± 10.5 9:29
24 33.9 ± 8.3 6:18
25 36.5 ± 11.3 9:16
Abbreviations: MS, multiple sclerosis; HR, high risk; LR, low risk.
ON, fellow eyes, and controls respectively, one-way ANOVA p < 0.0001, post hoc Tukey test p < 0.0001). During the study period, amplitude recovered significantly (p < 0.01, mixed model repeated measure analysis). The largest amplitude improvement was seen within the first 3 months (Fig. 2a). Although amplitude continued to improve slowly after 3 months, the change was not significant (p = 0.47, mixed model analysis repeated measure analysis). At the 12-month time-point, the final amplitude remained significantly reduced compared to both normal controls and fellow eyes (p < 0.0001, one-way ANOVA, post hoc Tukey test p < 0.0001).
3.2.2. Group analysis Separate analysis of LR, HR and MS patients revealed similar trend for all three groups with a significant difference between the ON eye versus fellow eyes and controls (Table 2 and Fig. 2a). Mean amplitude of MS group was less than the HR and LR groups throughout the study period, but this difference did not reach statistical significance at any time point. The largest improvement in amplitude in all 3 groups was seen within the first 3 months (p = 0.03, 0.05, 0.02 for MS, HR, and LR respectively) with modest, but not significant improvement
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Fig. 2. (a) Amplitude changes during the study period in the ON eyes in patients’ groups. (b) Latency recovery during study period in ON eyes. Bars show standard error of the mean ( – entire study cohort, triangles – LR, squares – HR, and diamonds – MS group).
Table 2 Statistical difference of amplitude of the optic neuritis eyes compared to fellow eyes and normal controls at 1 and 12 months. (One-way ANOVA, post hoc Tukey test.)
Table 3 Z-scoresa of latency for ON eyes and fellow eyes according to their subgroups. Subgroup
Affected eye
MS HR LR
At 1st month
At 12th month
Fellow eye
Controls
Fellow eye
Controls
p < 0.001 p < 0.001 p < 0.001
p < 0.001 p < 0.001 p < 0.001
p < 0.001 p = 0.007 p = 0.008
p < 0.001 p < 0.001 p < 0.001
MS HR LR Total
Abbreviations: MS, multiple sclerosis; HR, high risk; LR, low risk. a
afterward (p = 0.5, 0.3, 0.6 mixed model repeated measure analysis for MS, HR, and LR respectively). 3.3. Latency of mfVEP in ON eyes 3.3.1. Entire study cohort Fifty-seven eyes (MS-24, HR-18, LR-15) had at least 75% of traces with sufficient amplitude at 1 month and were suitable for analysis. ON eyes had a substantial mfVEP latency delay at 1 month when compared to controls and fellow eyes (p < 0.0001, one-way ANOVA, post hoc Turkey test p < 0.0001). A significant trend of latency recovery was observed during the study period (p < 0.001 mixed model repeated measure analysis) (Fig. 2b). Average rate of latency recovery was 1.33 ms/month between 1 and 3 months, which declined between 3 and 6 months to 0.76 ms/month and slowed to 0.33 ms/month between 6 and 12 months. There was still a significant residual latency delay at 12 months in comparison to controls and fellow eyes (157.9 ± 8.3, 145.6 ± 6.7, 141 ± 5.1 ms for ON, fellow eyes and controls respectively, p < 0.0001 one way-ANOVA-post hoc test). 3.3.2. Group analysis Affected eyes in all groups showed significant latency delay in comparison to controls and fellow eyes throughout the study period p 6 0.003. All three groups follow similar trend of latency recovery (p < 0.001 mixed model repeated measure analysis for each group) (Fig. 2b). The LR group had less latency delay throughout the study period. There was a significant difference in latency delay between LR group and MS and HR groups at 3 months (p = 0.01, one-way ANOVA, Tukey post hoc analysis p = 0.01 for MS and p = 0.05 for HR respectively) and 6 months (p = 0.01 one-way ANOVA, Tukey post hoc analysis p = 0.01 for MS and p = 0.05 for HR respectively) and the tendency for statistical significance at 12 months (p = 0.057, one-way ANOVA).
ON eye
Fellow eye
Z-score P 2 at 1 month
Z-score > 2 at 12 months
Z-score > 2 at 12 months
21/24 (88%) 17/18 (94%) 9/15 (62%) 47/57 (82%)
17/24 (71%) 13/18 (72%) 5/15 (36%) 35/57 (61%)
9/24 (38%) 4/18 (22%) 0/15 (0%) 13/57 (23%)
Z-score less than 1.96 classified as normal latency.
Analysis of the latency Z-scores also revealed that a smaller proportion of LR group ON eyes were abnormal as compared to MS and HR groups (Table 3). 3.4. Retinal nerve fiber thickness analysis At 12 months, RNFL thickness of the entire cohort was significantly reduced in ON eyes in comparison to fellow eyes (84 ± 16 vs. 103 ± 11 lm p = 0.0001). This reduction was similar between the three studied groups (p = 0.46, one-way ANOVA). To assess predictive power of mfVEP amplitude on long-term axonal loss, the inter-eye asymmetry of mfVEP amplitude at every time point was compared with the final inter-eye asymmetry of the RNFL thickness. A high degree of correlation between mfVEP amplitude and RNFL thickness was seen as early as 3 months after the attack, and this marginally increased with time. Separate analysis for each group was also performed. A similar trend was observed for all groups. The correlation by 3 months was already strong and moderately improved with time (Table 4). 3.5. Amplitude of mfVEP in fellow eyes 3.5.1. Entire study cohort The fellow eyes demonstrated lower amplitude in comparison to controls (p < 0001, one-way ANOVA) at all time points. There was no significant change of the amplitude throughout the study period (p = 0.5, mixed model repeated measure analysis). 3.5.2. Group analysis The amplitude in the fellow eye was significantly lower in all three groups, however the LR group demonstrated less amplitude reduction compared to HR and MS groups (p < 0.01 for all). Amplitude of the fellow eye in the LR group remained stable during the follow-up period, while progressive amplitude reduction in the fellow eye was seen in the MS group with difference
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R2 of inter-eye asymmetry of amplitude over time vs. 12 month inter-eye asymmetry of RNFL thickness. 1 month
Total MS HR LR
0.28 0.27 0.29 0.29
3 months p < 0.001 p = 0.0008 p = 0.006 p = 0.005
0.59 0.63 0.59 0.49
6 months p < 0.001 p < 0.001 p < 0.001 p < 0.001
0.61 0.6 0.71 0.65
12 months p < 0.001 p < 0.001 p < 0.001 p < 0.001
0.71 0.73 0.75 0.68
p < 0.001 p < 0.001 p < 0.001 p < 0.001
Fig. 3. (a) Amplitude changes during study period in fellow eyes. (b) Latency changes during study period in fellow eyes. Bars show standard error of the mean ( – entire study cohort, triangles – LR group, squares – HR, and diamonds – MS).
Fig. 4. (a) Amplitude inter-eye asymmetry changes during study period. (b) Latency delay inter-eye asymmetry during study period in patients groups. Bars show standard error of the mean (MS group are shown in diamond, HR in square, and LR group in triangle).
between MS and LR groups reaching significance at 6 months (p = 0.01, one-way ANOVA, post hoc p = 0.02) and at 12 months (p = 0.02, one-way ANOVA, post hoc p = 0.03) (Fig. 3a). 3.6. Latency of mfVEP in fellow eyes 3.6.1. Entire study cohort Latency of the fellow eye was not significantly delayed at the first visit in comparison to the controls (p = 0.17). However, a slow, but consistent increase in latency was seen during the study period. By 3 months the latency delay reached significance (p = 0.03), and this continued to increase during subsequent visits (p = 0.02, and 0.018 in the 6 and 12 month visits Fig. 3b). 3.6.2. Group analysis There was no significant difference between the latency of each individual group and normal controls at 1 month (p = 0.2, one-way ANOVA). By 3 months, however, the MS group displayed significant latency delay compared to controls (p = 0.024, one-way ANOVA, p = 0.023 Tukey post hoc). This trend continued at 6 and 12 months
(p = 0.018, one-way ANOVA, p = 0.013 Tukey post hoc and 0.01 one-way ANOVA, p = 0.01 Tukey post hoc respectively) (Fig. 3b). While latency delay of the fellow eye in HR group increased over time, it was not statistically significant. The latency of the LR group remained stable. Z-score analysis of the fellow eyes revealed abnormal latency in more than third of patients who converted to MS, but none of patients from LR group (Table 3). 3.6.3. Asymmetry analysis Inter-eye asymmetry analysis of the amplitude demonstrated no difference between groups at any time point (ANOVA p = 0.6, 0.3, 0.3, 0.4 for 1, 3, 6 and 12 months respectively) (Fig. 4a), suggesting that the difference in amplitude between the groups is likely due to retro-chiasmal damage. In addition, all three groups demonstrated very similar latency recovery trend (Fig. 4b). There was less latency asymmetry in LR group compared to MS and HR groups, which, however, did not reach statistical significance at any time points (p = 0.2. 0.07, 0.18, 0.29 for 1, 3, 6, and 12 month respectively, one way-ANOVA) (Fig. 4b).
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4. Discussion This report provides prospectively acquired, longitudinal mfVEP data over 12 months of patients presenting with ON as clinically isolated syndrome. The study demonstrated that both amplitude and latency of the mfVEP are grossly abnormal at the early stage of ON. While amplitude of the mfVEP improves considerably during the first year after acute ON, the majority of the recovery occurred within the first 3 months. These results are similar to those reported for full-field VEPs (Jones and Brusa, 2003). This pattern of amplitude recovery is also in line with visual acuity, which demonstrates rapid improvement of vision within early post-acute period (Hickman et al., 2004; Hood et al., 2000a). Similar to amplitude, the speed of latency recovery was fastest during the first 3 months. It is believed that latency shortening after ON is mostly due to the process of remyelination. Remyelination occurs most efficiently during the early post-acute stage, where cells engaging in the formation of new myelin sheaths are frequently observed (Prineas et al., 1993). The environment for successful remyelination may be severely altered afterward (Coles et al., 2006). Thus, the significant latency recovery during the first few months after the attack supports the concept of ‘window of opportunity’ as being fundamentally important for the success of remyelination (Blakemore et al., 2002; Coles et al., 2006). Spontaneous remyelination, which is an early and frequent phenomenon in MS, is often incomplete (Patrikios et al., 2006; Prineas et al., 1993). Our results confirm this, as we showed significant residual latency delay even 12 months after acute ON. This chronically persisting latency delay has been demonstrated in multiple studies and remains the major hallmark of previous ON (Weinstock-Guttman et al., 2003). In this study, patients were divided into those who converted to CDMS and those who remained at high risk or low risk of conversion to the disease. Overall, the group analysis demonstrated smaller amplitude and longer latency in ON eyes of MS patients compared to LR patients. However, the progressive deterioration of both amplitude and latency in the fellow eyes of MS group, and to a lesser extent HR group suggests that the apparent more severe involvement of ON eyes in those subgroups is due to superimposed burden of subclinical inflammatory demyelinating activity along the posterior visual pathway. Hence, the severe involvement of ON of MS group is indirectly a reflection of lesion load and disease burden at presentation and not related to the difference in remyelination pattern between MS and LR groups. The latency of the fellow eye in LR group did not differ from the latency of normal controls and was stable throughout the study period. However, there was a clearly visible trend of latency increase in the fellow eye of MS group. The difference between MS and controls reached statistical significance by 3 months and continued to increase thereafter. Latency of the fellow eye in HR group also demonstrated tendency to increase, although not to the same extent as patients in the MS group. Delayed latency in fellow eyes of ON patients has been suggested as a part of central adaptive mechanism at the cortical level to compensate for delayed cortical visual input from ON eyes (Raz et al., 2013). The fact that fellow eyes of LR subgroup in this study did not show significant latency delay argues against this suggestion. Since both ON and fellow eyes appear to be involved, it is reasonable to assume that this pathological process is occurring in a post-chiasmal location. Optic tract (OT) and optic radiation (OR) are two potential sites of such retro-chiasmal lesions. Lesions of the optic tract, however, are rare in MS (Plant et al., 1992; Rosenblatt et al., 1987). Furthermore, it is unlikely for the acute inflammation of the OT to be missed clinically due to its small
diameter and supposedly preferential damage of small central fibers (Evangelou et al., 2001), which would result in an acute binocular visual deficit. On the other hand, OR lesions, are very common in MS (Hornabrook et al., 1992) and are often clinically silent. This apparent clinical ‘invisibility’ is due to a wide spread of OR fibers, and non-preferential distribution of the lesions, which cause rather small and more peripherally located visual field defects, easily missed by patients. However, since mfVEP covers a significant part of the visual field (48°), demyelinating lesions of the OR are likely to cause amplitude reduction and latency delay for both ON and fellow eyes. Consistent with this, we have recently reported a correlation between volume of OR lesions and latency delay in the fellow eyes of MS patients (Klistorner et al., 2013). Findings of this study also concur with our previous report demonstrating that latency prolongation and amplitude decline 12 months after acute ON were proportional to the risk of MS (Klistorner et al., 2009). Likewise, full-field VEP studies (Jones and Brusa, 2003) also suggested that the cause of the observed asymptomatic deterioration of VEP latency in unaffected eyes of MS patients is a demyelination process in the posterior visual pathway. Therefore, to analyze the effect of acute ON on the amplitude and latency of the mfVEP, the potential effect of retro-chiasmal damage has to be eliminated. Assuming that retro-chiasmal damage influences both eyes similarly, its effect can be removed by subtracting values of the fellow eye from ON eye. Consequently, performed inter-eye asymmetry analysis showed no difference in amplitude reduction, recovery and residual deficit between patients who converted to CDMS and patients who remained at high risk or low risk of conversion to MS, indicating similar degree of inflammation caused by acute ON for all three groups. This is also supported by high (and very similar) correlation between residual amplitude of the mfVEP and RNFL thickness in all three groups and by the similar inter-eye asymmetry of the RNFL thickness between the groups. Results of the inter-eye latency analysis also revealed a similar picture, suggesting that the demyelinating effect of the acute ON is MS-independent. While several studies have reported a shorter latency in eyes with acute ON as part of mono-symptomatic disease (analogous to LR group) as compared to MS-related ON (Alshuaib, 2000; Fredericksen and Petrera, 1999; Samsen et al., 2007), none of them assessed potential effect of retro-chiasmal pathology by analyzing inter-eye asymmetry. Our data, however, indicates that retrochiasmal demyelination is the major factor contributing to amplitude and latency differences between MS and non-MS patients. Another important aspect of this study is a demonstration of an early predictive power of mfVEP amplitude in post-ON axonal loss. The amplitude reduction predicted a significant portion of the final axonal loss as early as 3 months. The early association of mfVEP amplitude with the degree of post-inflammatory neuronal loss may suggest possible role of the electrophysiological measure as a potential functional surrogate marker in neuro-protective trials. The limitation of this study is its retrospective design in regards to conversion to CDMS. Therefore, a significant number of patients in the HR group and some patients in the LR group are in reality MS patients, who, due to limited follow-up time, have not yet demonstrated evidence of conversion to CDMS. Another limitation is the use of time-domain OCT. Since there is a low incidence of ON in Australia, the enrolment process took several years and started at the time when spectral-domain OCT machines were not yet available. However, we believe that for the purpose of the current study resolution of time-domain OCT was adequate. In conclusion, we demonstrated significant recovery of the amplitude and shortening of the latency during 12 months
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follow-up period, which was fastest within the first 3 months after acute episode. We also showed high predictive value of mfVEP amplitude in consecutive axonal loss as early as 3 months after acute ON. Our result suggested presence of the progressive retrochiasmal inflammatory demyelination in patients with MS-related disease. Acknowledgements This work was supported by King Saud University [grant number 7861359], Save Neuron grants from Novartis, Sydney Medical Foundation [grant number E34], and Sydney Hospital Foundation. The sponsors had no role in collection, analysis and interpretation of data or in the writing of the manuscript. Conflict of interest statement: The authors declare that there is no conflict of interest. References Alshuaib WB. Progression of visual evoked potential abnormalities in multiple sclerosis and optic neuritis. Electromyogr Clin Neurophysiol 2000;40:243–52. Beck RW, Trobe JD, Moke PS, Gal RL, Xing D, Bhatti MT, et al. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 2003;121:944–9. Blakemore W, Chari D, Gilson J, Crang A. Modelling large areas of demyelination in the rat reveals the potential and possible limitations of transplanted glial cells for remyelination in the CNS. Glia 2002;38:155–68. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, et al. The window of therapeutic opportunity in multiple sclerosis. J Neurol 2006;253:98–108. Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM. Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis. Brain 2001;124:1813–20. Fraser C, Klistorner A, Graham S, Garrick R, Billson F, Grigg J. Multifocal visual evoked potential latency analysis: predicting progression to multiple sclerosis. Arch Neurol 2006a;63:847. Fraser CL, Klistorner A, Graham SL, Garrick R, Billson FA, Grigg JR. Multifocal visual evoked potential analysis of inflammatory or demyelinating optic neuritis. Ophthalmology 2006b;113:315–23. e312. Fredericksen JL, Petrera J. Serial visual evoked potentials in 90 untreated patients with acute optic neuritis. Surv Ophthalmol 1999;44(Suppl 1):S54–62. Halliday A, McDonald W, Mushin J. Delayed visual evoked response in optic neuritis. Lancet 1972;299:982–5. Hickman SJ, Toosy AT, Miszkiel KA, Jones SJ, Altmann DR, MacManus DG, et al. Visual recovery following acute optic neuritis – a clinical, electrophysiological and magnetic resonance imaging study. J Neurol 2004;251:996–1005. Hood DC, Odel JG, Zhang X. Tracking the recovery of local optic nerve function after optic neuritis: a multifocal VEP study. Invest Ophthalmol Vis Sci 2000a;41:4032–8.
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