This is the first study to functionally assess the afferent visual pathway using the multifocal VEP in patients with RIS. The findings of this work are significant given the current interest in understanding the physiopathological mechanisms associated with demyelinating lesions in the early stages of MS. Our results suggest that neuroaxonal damage in the afferent visual pathway is present in these early stages of MS.
In our study, we demonstrated that our patients exhibited significant alterations in the interocular and monocular analysis of amplitudes (47.6%) of electrical signals from multifocal VEP, suggesting the presence of subclinical axonal degeneration processes in the afferent visual pathway in RIS. Changes in the amplitudes of multifocal VEP are a highly sensitive biomarker of the functional integrity of visual pathway axons.15
Additionally, our patients showed a significant delay in the interocular and monocular analysis of latencies (38%) of signals from multifocal VEP, suggesting the early presence of demyelination processes in the afferent visual pathway in RIS. Myelin plays a crucial role in trophic support and protects axons against the aggression of inflammatory mediators and immune cells in MS.16 These defects in myelin sheaths are initially subclinical but expose axons, making them more vulnerable to degenerative processes. Delayed latencies of signals from VEP are a good indicator of demyelination processes in the visual pathway, and their severity correlates with the extent of elongation of bioelectrical signal latencies.17–19 Changes in latencies often do not associate with any obvious clinical visual dysfunction in these early phases. In lesions of the afferent visual pathway, we observe concurrent phenomena of demyelination and axonal degeneration, and it can be challenging to separate the effect of both processes on VEP signals. Normalization of latency values over time indicates the effect of active remyelination processes in the visual system. Amplitudes can also recover in these early stages as conduction is unblocked, provided that axons are not damaged.8 Experimental evidence suggests that a significant proportion of ganglion cell axons can be critically damaged in these early episodes of subclinical acute inflammation in the visual pathway.9,10 This axonal damage will degenerate slowly and progressively, both retrogradely and anterogradely, and sometimes, this axonal damage takes a considerable time to manifest clinically.11 Multifocal VEP technology has the advantage of early identification of functional defects in the afferent visual pathway before they are clinically observed or detected by other structural or psychophysical diagnostic techniques.12
Very few studies have assessed the afferent visual pathway with conventional Visual Evoked Potentials in patients with RIS, and none have used multifocal technology.20,21 Gabelic et al.22 observed a significant elongation of latencies of conventional VEP responses in 14% (4/24) of their RIS patient cohort. Another prospective study with RIS patients did not yield conclusive data due to the small sample size.23 Similarly, in a multicenter and longitudinal study, Lebrun et al.,2009 24 observed altered conventional VEP in 53% of patients with RIS. In this study, conventional VEP were associated with the number of hyperintense lesions in T2 mode and gadolinium-enhancing lesions on MRI, as well as pathological cerebrospinal fluid, serving as a predictive factor for clinical progression to MS. However, in a smaller study with 20 RIS patients, Knier et al.25 did not observe any abnormalities in conventional VEPs. Our results closely align with those observed by Lebrun et al.24 where the evaluation of multifocal VEP in two thirds of our RIS patients revealed abnormalities at the baseline. It is interesting to note that studies using conventional VEP exhibited considerable variability in results, potentially attributed to various factors: i) in our clinical experience, very few centers conduct high-quality visual neurophysiology tests following ISCEV protocols, as evident in the graphs and tables published in these articles; ii) the studied patient cohorts were relatively small and included individuals with different risk profiles.
The multifocal VEP has demonstrated a generally good correlation with conventional VEP. However, the multifocal technology offers a distinct advantage by simultaneously and independently stimulating and analyzing multiple regions of the visual field. This capability enables the identification of subtle alterations that may go unnoticed by the aggregated single signal of cVEP.26 Using the multifocal VEP, Pérez-Rico et al. 27 observed abnormal amplitudes and latencies in 48% and 23%, respectively, of patients with CIS. Similarly, Blanco et al. 12 have found anomalous amplitudes and latencies in 70% and 74%, respectively, of MS patients, regardless of a history of optic neuritis. Klistorner et al.28 have also demonstrated a correlation between the P100 wave of conventional and multifocal VEP in patients with optic neuritis. The multifocal VEP can detect a greater number of abnormal responses and have higher diagnostic sensitivity for detecting small peripheral lesions and defects in the upper visual field. Similarly, Laron et al.29 found that multifocal VEP exhibit greater sensitivity in identifying minor visual field abnormalities compared to automated static perimetry and optical coherence tomography in MS, regardless of whether they have a history of optic neuritis.
At the 24-month follow-up, 23.8% (5/21) of our RIS patient cohort clinically converted to either CIS or MS. These findings align with published data.30–34 Recent studies have indicated that two-thirds of patients diagnosed with RIS will exhibit radiological progression, and one-third will experience a symptomatic first demyelinating neurological event, either CIS or MS, within the initial five years of follow-up.31 By the ten-year mark, half of patients diagnosed with RIS will transition to advanced forms of the demyelinating process.35,24 Notably, 12% of RIS patients will progress to primary progressive MS, more frequently observed in males, at older ages, and with a higher number of spinal cord lesions on MRI.30
Several factors have been associated with an increased risk of developing a first clinical event in RIS, including younger age at diagnosis, presence of spinal cord lesions 31,36, high lesion burden in T2 mode37, gadolinium-enhancing lesions36, and infratentorial lesions on MRI, along with the presence of oligoclonal bands and/or elevated immunoglobulin G index in cerebrospinal fluid.36–39 Additionally, altered conventional VEP have been linked to an elevated risk of clinical conversion19.
In our study, the reduction in amplitudes and latency delay of multifocal VEP responses in patients with RIS were significantly associated with an elevated risk of conversion to CIS or MS at the two-year follow-up. Additionally, within our RIS patient group, a diagnosis age younger than 37 years was significantly associated with a higher risk of clinical conversion to CIS or MS at the two-year follow-up. However, we did not observe associations between variables from MRI or cerebrospinal fluid and the risk of clinical conversion, contrary to findings in previous studies. 41 This lack of observation was expected, given that our sample was not optimized to detect these associations, nor was it the primary focus of this study.
This study is subject to several limitations that warrant discussion. Firstly, the cohort of patients with RIS recruited for this study was relatively small. Despite this, the sample proved sufficient to detect significant changes in multifocal VEP in RIS, correlating with an increased risk of conversion to MS. However, the sample size was inadequate to identify changes in MRI. Addressing this limitation necessitates larger patient cohorts, prompting the consideration of multicenter studies. Given the challenge of recruiting an ample number of RIS patients within a reasonable timeframe at a single hospital center, multicenter collaboration becomes essential. 37–40
Moreover, the follow-up duration for patients in this study was limited to a relatively short two-year period. While this timeframe sufficed to observe changes in mfVEP results, the natural history of this disease suggests that an extended follow-up may reveal more conversions. Studies with follow-up periods of five to ten years are currently under consideration for RIS. Unfortunately, due to the unavailability of specific image analysis software at that time, we were unable to conduct volumetric analysis of lesions observed in the MRI at our hospital's Radiology Department. Such volumetric analysis would have allowed for the assessment of cerebral atrophy and quantitative characteristics of MRI-observed lesions. 36–39
The statistical analysis in this study involved selecting one eye per patient. Although some studies with small population samples choose to include both eyes, this approach requires more complex statistical techniques such as generalized estimating equations. There are additional neurological variables that were not explored in our study but could be valuable in future investigations. Notably, cognitive disorders have been found to be common in RIS patients, impacting neuropsychological functions such as memory, complex attention, information processing speed, and executive functions. 40
Furthermore, the technology of multifocal VEP is not widely adopted in clinical practice within our environment. For many years, our center was the sole facility equipped with multifocal VEP equipment in our country. Conducting these recordings demands time and specialized knowledge. Nevertheless, in recent years, several commercial visual neurophysiology teams have integrated the option to perform multifocal VEP alongside conventional potentials, enhancing clinical experience with this technology.
In summary, the observed abnormalities in amplitudes and latencies of responses in multifocal VEP in RIS subjects indicate frequent and early involvement of the afferent visual pathway in the preclinical stages of MS. This suggests that multifocal VEP could emerge as a particularly useful tool in clinical practice for the diagnosis and objective monitoring of demyelinating processes in their early phases. Studying the afferent visual pathway through multifocal VEP in patients with RIS provides an opportunity to uncover etiopathogenic mechanisms of this disease before the onset of clinical signs. This represents a novel diagnostic technique capable of detecting axonal and/or demyelinating lesions in the optic nerve during the preclinical stages of MS.