Continuing Education Activity

Visual evoked potentials (VEPs) represent a valid electrophysiological tool in neurological pathologies. VEPs are the expression of the electrical activity of the visual pathways up to the optic nerve to the calcarine cortex. These potentials provide a non-invasive exploration method of the functionality of the human visual system through detecting neuronal pool activity responding to stimuli independently of the consciousness and attention state of the patient. VEPs have a clinical application in ophthalmological retinal pathology and neurological pathology related to the optic nerve and/or brain. VEPs have been used as an alternative method to assess visual acuity in non-verbal infants and adults with low intellectual abilities or potential malingerers and for surgical intra-operative monitoring. This activity describes the role of this instrumental examination in the diagnosis and follow-up of neurological and ophthalmological pathologies by the interprofessional team.

Objectives:

• Describe the main type of VEPs used in studying neurological pathologies affecting the visual pathways.
• Identify the main degenerative disease explored by VEPs.
• Explain VEPs alterations in multiple sclerosis.
• Summarize the technical principles of VEPs.

Introduction

Visual evoked potentials (VEP)s represent a valid electrophysiological tool in neurological pathologies. VEPs are the expression of the electrical activity of the visual pathways up to the optic nerve to the calcarine cortex.[1]

These potentials provide a non-invasive exploration method of the functionality of the human visual system through detecting neuronal pool activity responding to stimuli independently of the consciousness and attention state of the patient. The measurement of VEP is made possible by applying electrodes on the scalp in the occipital region and administering visual stimuli in a patient with open eyes.[1][2] 

Depending on the characteristics of the stimulus, pattern visual evoked potentials can provide different information on the functionality of the various sectors of the visual field and the integrity of the optical pathways. This type of instrumental exploration has a clinical application in ophthalmological retinal pathology and neurological pathology related to the optic nerve and/or brain (inflammatory, atrophic, toxic, tumoral, and genetic disease). VEPs has been used as an alternative method to assess visual acuity in non-verbal infants and adults with low intellectual abilities or potential malingering.[3][4][5]

Function

Technical Notions

The main type of VEPs used in studying neurological pathologies affecting the visual pathways is VEP structured with a stimulation model (pattern-VEP or P-VEP). Generally, it is a "reversal" pattern (reversal-P-VEP), in which the light and dark elements of the model are organized to form a chessboard or bars. The stimuli are reversed, allowing contrast variations with constant average luminance. Another type of VEP with an "onset-offset" pattern (onset-offset-P-VEP) is based on a visual stimulus that appears and disappears in a sequence always characterized by a constant average luminance.

VEPs that use a diffuse flash stimulus (flash-VEP or F-VEP) characterized by a variation in brightness, however, have a rather limited field of application in the field of neurological pathologies affecting the visual pathways considering that this testing method offers extremely variable responses in the normal individuals and are less sensitive than P-VEP. Furthermore, P-VEPs allow for the selection of characteristics for the most suitable stimulus in the clinical analysis of the different components of the visual system, which can be activated differently according to the spatial, temporal, chromatic, and contrast properties of the image.[6][7] (See Figures of instrumentation, testing, stimulator, and results of VEPs)

The spatial frequency (SF) of a pattern stimulus measures how many times the contrast of an image changes from the minimum to the maximum value in a degree of visual angle, which is then measured in cycles per degree (c / d), where 1 c / g corresponds to the complete alternation from a light element to a dark one in a degree of visual angle.

The size of the bar (w) can be calculated by the formula: w = 60/2f, where w is expressed in arc minutes and f is the SF expressed in c/d. If instead of bars, the model used is a chessboard, the dimensions of the chessboards are measured in arc minutes of the degree of visual angle. The different SFs permit the exploration of the different sectors of the visual field by stimulating the different neuronal systems of the visual pathway physiologically.[8] 

The electrophysiological response obtained with a potential depends on the luminance of the stimulus, the contrast between the two stimuli (luminance difference), and the temporal frequency. P-VEP amplitude increases linearly with increasing contrast and disappears for contrasts equal to or less than 10% when the difference between light and dark elements is no longer recognizable. If VEPs are recorded according to an offset/onset stimulus, the background luminance of the offset stimulus must be identical to that of the structured stimulus (onset stimulus).

The contrast (C) between the elements of the pattern corresponds to the difference in luminance between the light and dark elements and is expressed in percentage values. The electrophysiological response obtained with a P-VEP depends on the temporal frequency, that is, on the speed with which the pattern appears or disappears (onset-off-set-P-VEP) or with which the elements of the model reverse their position (reversal-P-VEP). The variation of the temporal frequency with which the elements reverse each other at low frequencies (<4 Hz) is considered a "transient" type response, while at high frequencies (>4 Hz), the response type is defined as a "steady state."[9]

In the reversal-P-VEP,  low stimulation FTs (between 1 Hz and 4 Hz) are currently used, allowing precise recording from the occipital cortex. This electrophysiological response is known as "transient" response. The "transient" potential of the reversal-P-VEP consists of three deflections of the electrical signal with an alternating polarity of reproducible latency and morphology, in which it is possible to recognize a positive main component with a latency of about 100 ms (potential P 100), preceded and followed by two negative components, with a latency of about 70 to 75 ms (potential N 75) and 130 to 145 ms (potential N 140) respectively. The positive component P100 represents the most stable and repeatable response of this P-potential, recordable on all scalp regions that correspond to the occipital cortex, with its maximum amplitude along the midline, at the inion.

Numerous studies have identified P100 as the electrical correlate of the activity of the primary visual cortex. For lesions of the optic pathways with cortical saving, it is still possible to record an intact P100. The other two negative components of the potential (N140 and N70) could instead have generators at the level of the striatal cortex (N70) and extra-striatal (N140), which tend not to be useful in clinical practice.[9][10][11] (See Figures of VEPs results)

Applications

In a routine clinical setting, the P-VEP stimulation pattern is obtained through the simultaneous stimulation of the two visual hemifields on the sides of the fixation center (whole-field stimulation) while the recording electrodes are positioned on the occipital scalp at Oz (International Electroencephalographic System 10-20) and on two symmetrical points placed laterally 5 to 7 cm away from the central one.

The potentials recorded by the laterally placed electrodes are generally variable and less represented; therefore, amplitude and latency parameters are regularly acquired considering the central electrode. The evaluations of the morphology, amplitude, and above all, the latency (retino-cortical conduction time) of the P100 potential represent the fundamental element for the electrophysiological study of the integrity of the optical pathways, especially at the pre-chiasmatic level.

The reduction of the sensitivity of the visual field due to damage to the retro-orbital nerve structures (optic nerve) determines alterations of the P-PEV that are reflected as a decrease in amplitude and/or in a lengthening of the latency time of the different components that make up the potential. The variations in amplitude and latency of PEVs represent precisely the electrophysiological correlate of different pathological phenomena that affect the optical pathways.

The topographic position, size, and degree of the campimetric deficit strictly condition any anomalies detected in the analysis of the P-PEV. Lesions of the optic nerve associated with relative scotomas in the macular area can cause significant alterations of the P-VEP recorded by the scalp, while an absolute scotoma, even if extensive but localized in the peripheral region of the visual field, can modify the P-VEP in a minimal or even null way.[12]

Clinical Significance

P-VEPs represent a sensitive indicator of abnormalities in the integrity of the entire visual system, which can be the subject of demyelinating or axonal pathologies. Depending on the type of pathogenetic mechanism, P-VEPs can signal the presence of demyelination phenomena, expressed by changes in latency and an increase in retinol-cortical conduction time, as well as indicating the existence of axonal damage evidenced by alterations in the amplitude and morphology of the acquired responses. According to these principles, P-VEPs are used to diagnose pre-chiasmatic, chiasmatic, and retrochiasmatic neurological pathologies.[13][14][15]

Neuropthalmological Field

VEPs are used in the field of neuro-ophthalmology for several clinical applications, which include: the quantification and monitoring of functional damage in optical neuropathies of different inflammatory, demyelinating, compressive, ischemic, traumatic, hereditary, degenerative, and/or toxic-metabolic origin; the differential diagnosis between optic nerve pathologies and retinal pathologies through the use of results associated with functional examinations of the retina; and, in the distinction between cortical blindness and malingering.[16][17][18]

Neurological Field

Multiple sclerosis is an inflammatory disease of the white matter characterized by a multifocal involvement of the brain's white matter. The clinical manifestations are very variable in relation to the localization and extent of demyelination outbreaks; however, the lesions seem to have a preferential distribution in some areas of the central nervous system. In more than 20% of cases, the symptom of the onset of the disease is optic neuritis, and over 50% of patients have a clinical episode of optic neuritis. Studies have sown that VEP latency and optical coherence tomography retinal nerve layer thickness measurements correlated with disability measurements and can be useful in the management of these patients.[19] The early clinical signs of MS could identify "benign" phenotypes, characterized by an almost complete recovery of vision and retinal sensibility loss in the acute phase.[20][21] 

In demyelinating pathologies of the optic nerve, P-VEPs show a delay in the latency of responses, often in the absence of significant alterations of the amplitude related to the decrease in patients'  visual acuity. The latency alterations of the P-VEP could persist for a long time, even after the full recovery of visual acuity. It is sometimes possible to observe the delay of the latency of the P-PEV also in the contralateral eye. This alteration type can reveal the presence of sub-clinical alterations of the conduction of the impulse along the optic nerve,  even before clinical signs or symptoms of nerve involvement manifest.[22]

In the ischemic neuropathy of the optic nerve, anterior ischemic optic neuropathy or AION is due to infarction of the laminar or laminar portion of the optic nerve head caused by occlusion of the short ciliary posteriors arteries. The clinical onset of this alteration is generally unexpected, without pain, and the loss of vision can progress for many days. Studies have shown VEPs useful in the management of these patients.[23]

The campimetry deficit is typically altitudinal and may involve the central fixation area, which justifies the severe loss of visual acuity. Regarding VEP alterations, it is possible to observe a pre-dominant alteration that turns out to be the marked reduction in the amplitude of P100 associated with a poor modification of latency.[24]

The cause of optic nerve compression is frequent optic pathway gliomas of pediatric age. The clinical onset is characterized by a gradual loss of vision without orbital pain, which may even be asymptomatic for a long time. An early clinical diagnosis and an accurate follow-up of patients with compressive neuropathy of the optic nerve, especially in the presence of meningiomas or gliomas, is of fundamental importance to improve the therapeutic approach based on surgical resection and/or radiotherapy procedures.[25] In these cases, PEVs consistently exhibit a de-synchronized P100 of low amplitude with an evident latency delay.[26]

Concerning neurodegenerative diseases, the study VEPs do not typically have a diagnostic role. These testing methods, however, can offer the possibility of investigating the physio- and pathophysiological mechanisms and the involvement of the different neurotransmission systems involved in the pathogenesis of these morbid conditions in a refined and non-invasive way. 

Leber optic neuropathy (LON) and Kjer-type dominant optic neuritis (DON) are the most common hereditary forms of primary retinal ganglion cell disease. LON typically presents a progressive loss of bilateral vision not associated with orbital tissue and is linked to mitochondrial mutations. In these cases, P-VEPs are markedly delayed, but relative maintenance of P100 morphology is possible in the initial stages of the disease.

Alterations in the P100 amplitude are related to the stage and clinical form of the disease. Alterations of P-PEVs are generally preceded by the reduction of the amplitude or even by the lack of reproducibility of the N95 potential.[27] 

In Friedrich's Ataxia, PEVs are used to assess the evolution of visual function in this neurodegenerative disease, which tends to be abnormal in two-thirds of patients. The delayed latency and the increased amplitude of wave p100 is the most frequent electrophysiological alteration in this pathology.[28][29]

Other Issues

Surgical Intraoperative Monitoring

In the last few years, VEPs have been considered for intraoperative monitoring of visual function using several protocols; however, current literature and clinical evidence in this field are very limited. The use of total intravenous anesthesia, the introduction of light-emitting diode technology, electroretinography, and electroencephalography have increased the reliability of VEP neuromonitoring by enhancing the technique’s reproducibility and interpretability and working to make it more reliable and easier to integrate it into the operative workflow.

Recent studies have applied these tools in orbital and transsphenoidal surgery.[30][31][32] (See Figures of intraoperative surgical monitoring with VEPs)

Enhancing Healthcare Team Outcomes

VEP application requires an interprofessional team of healthcare professionals, including nurses, neurophysiopathology technicians, neurologists, and ophthalmologists. This team is fundamental for correctly applying this tool both in the clinical field and in intraoperative surgical monitoring. VEPs are regularly used in diagnosing pre-chiasmatic, chiasmatic, and retrochiasmatic neurological pathologies.[13] [Level 3]

In this scenario, the neurophysiopathology technician provides for the preparation and control of the instrumentation of the equipment it is equipped with and fully manages to collect and optimize the various diagnostic methods on which, upon request, it must draw up a descriptive report from the technical aspect. (level I)

Recent studies have applied VEPs in orbital and transsphenoidal surgery but without standardized protocols and homogeneous results.[30][31][32] [Level 3]

An interprofessional team that provides an integrated approach to patient care and comprehensive diagnostic management can help achieve the best possible outcomes. Collaboration, multidisciplinary shared decision-making, and open communication between team members are key elements for a proper diagnosis and a good outcome. The interprofessional care provided to the patient must use an integrated care pathway combined with an evidence-based approach to planning and evaluating all joint activities.[33] The earlier signs and symptoms of a complication are identified, the better the prognosis and outcome. [Level 3]