Visual evoked potential and its value in the diagnosis of MS

Visual evoked potential

In 1934, Adrian and Matthew noticed potential changes of the occipital EEG can be observed under stimulation of light. Ciganek developed the first nomenclature for occipital EEG components in 1961. During that same year, Hirsch and colleagues recorded a VEP on the occipital lobe (externally and internally), and they discovered amplitudes recorded along the calcarine fissure were the largest. In 1965, Spehlmann used a checkerboard stimulation to describe human VEPs. An attempt to localize structures in the primary visual pathway was completed by Szikla and colleagues. Halliday and colleagues completed the first clinical investigations using VEP by recording delayed VEPs in a patient with retrobulbar neuritis in 1972. A wide variety of extensive research to improve procedures and theories has been conducted from the 1970s to today.

VEP Stimuli

The diffuse light flash stimulus is rarely used due to the high variability within and across subjects. However, it is beneficial to use this type of stimulus when testing infants or individuals with poor visual acuity. The checkerboard and grating patterns use light and dark squares and stripes, respectively. These squares and stripes are equal in size and are presented to one at a time via a television or computer screen.

VEP Electrode Placement

Electrode placement is extremely important to elicit a good VEP response free of artifact. One electrode is placed 2.5 cm above the inion and a reference electrode is placed at Fz. For a more detailed response, two additional electrodes can be placed 5 cm to the right and left of Oz.

VEP Waves

The VEP nomenclature is determined by using capital letters stating whether the peak is positive (P) or negative (N) followed by a number which indicates the average peak latency for that particular wave. For example, P50 is a wave with a positive peak at approximately 50 ms following stimulus onset.

The average amplitude for VEP waves usually falls between 5 and 10 microvolts.

Types of VEP

Some specific VEPs are:

• • Sweep visual evoked potential

  • Binocular visual evoked potential

  • Chromatic visual evoked potential

  • Hemi-field visual evoked potential

  • Flash visual evoked potential

  • LED Goggle visual evoked potential

  • Motion visual evoked potential

• Multifocal visual evoked potential

  • Multi-channel visual evoked potential

  • Multi-frequency visual evoked potential

  • Stereo-elicited visual evoked potential

Visual Evoked Potential

The VEP tests the function of the visual pathway from the retina to the occipital cortex. It measures the conduction of the visual pathways from the optic nerve, optic chiasm, and optic radiations to the occipital cortex. (The author has assumed that the reader is familiar with the anatomy of the optic system.) The most important fact to consider is that, although the axons from the nasal half of the retina decussate at the optic chiasm, the temporal axons do not. Therefore, retrochiasmatic lesions may not be detected by full-field checkerboard stimulation. VEPs are most useful in testing optic nerve function and less useful in postchiasmatic disorders. In retrochiasmatic lesions, the MRI is a more useful test. Partial-field studies may be useful in retrochiasmatic lesions; however, they are not performed routinely in clinical settings. Also note that the macula projects to the occipital pole, while the rest of the retina projects to the mesial calcarine cortex.

The VEP is very useful in detecting an anterior visual conduction disturbance. However, it is not specific with regard to etiology. A tumor compressing the optic nerve, an ischemic disturbance, or a demyelinating disease may cause delay in the P100; only additional clinical history and, often, MRI are needed to uncover the etiology. The usual waveform is the initial negative peak (N1 or N75), followed by a large positive peak (P1 or P100), followed by another negative peak (N2 or N145). Maximum value for P100 is 115 milliseconds (ms) in patients younger than 60 years; it rises to 120 ms thereafter in females and 125 ms in males. Even though published norms are available in the medical literature, each individual laboratory should have its own norms to control for lab-to-lab variability in technique.

The W morphology, in the author's experience, is most often an individual variation, although decreasing the stimulation frequency from the ubiquitous 2 Hz to 1 Hz usually converts the W shape into a conventional P100 peak. Check size and alternation rate are factors in this; the responses can be manipulated to a W or a conventional P100 response by changing these parameters. Large checks tend to produce VEPs similar to those produced by flash stimulation.

Factors influencing VEP

The usual VEPs are evoked by checkerboard stimulation and, because cells of the visual cortex are maximally sensitive to movement at the edges, a pattern-shift method is used with a frequency of 1-2 Hz. The size of the checks affects the amplitude of the waveform and the latency of the P100. In addition, pupillary size, gender, and age all affect the VEP. Visual acuity deterioration up to 20/200 does not alter the response significantly; large checks may be required. In some studies, women have slightly shorter P100 latencies. Sedation and anesthesia abolish the VEP. Some subjects, by "fixating" beyond the plane of stimulation, may alter or suppress P100 altogether.

Certain drugs, such as carbamazepine, prolong VEPs. The effects of carbamazepine and sodium valproate monotherapy on VEPs were studied in 18 epileptic children by Yuksel et al. Pattern-reversal VEPs were determined before administration of the antiepileptic drugs and after 1 year of therapy. The VEP amplitude showed no consistent changes after 1 year of therapy, but VEP P100 latencies were significantly prolonged after 1 year of carbamazepine therapy. The conclusion was that carbamazepine slows down central impulse conduction.^[1]

According to Trip et al, atrophy of the optic nerve was correlated with decreased VEP amplitude.^[2]

Technical aspects

Checkerboard pattern (or less often, flash) is used as stimulation. Responses are collected over Oz, O1, and O2 and with hemifield studies at T5 and T6 electrodes using the standard EEG electrode placement. Monocular stimulation is used to avoid masking of a unilateral conduction abnormality. Sedation should not be used, and note should be taken of medications that the patient is taking regularly. Testing circumstances should be standardized, including seating distance of 70-100 cm from the monitor screen, giving a check size of approximately 30 seconds of visual angle. The vision should be corrected to the extent possible in case of a visual problem. Pupil size and any abnormality should be noted. The P100 waveform is at its maximum in the midoccipital area. Stimulus rates of 1-2 Hz are recommended, and filter setting should be 1- to 200-Hz bandwidth (outside limit is 0.2-300 Hz).

The recommended recording time window (ie, sweep length) is 250 ms; 50-200 responses are to be averaged. A minimum of 2 trials should be given. The responses are averaged and the P100 positive polarity waveform that appears in the posterior head region is analyzed. The mean latency is about 100 ms. Normative data should be assembled on a lab-by-lab basis.

Pitfalls

Check size of 27 seconds of visual angle may result in normal P100 latency in a patient with cortical blindness; smaller checks (ie, 20 seconds of visual angle or less) should be used to demonstrate the abnormality. If cortical blindness is suspected, large checks should not be used.

In conditions such as retinal disease or refractory errors, the amplitude may be smaller and, at very small check sizes, the latency may increase. For this reason proper refraction is of great importance.

Since the VEP measures the pathway from the retina to area 17, a normal P100 does not exclude lesions of the visual pathway beyond area 17. For this reason, the VEP may be normal in patients with the diagnosis of cortical blindness. Note that, in such cases, the VEP is useful, ruling out disease up until area 17 in patients with a normal response. The usefulness of VEP is limited in malingering and hysterical visual loss. It is useful when a normal VEP is recorded, but abnormal responses are of limited diagnostic value in such cases. Baumgartner et al reported that as many as 5 of 15 healthy subjects were able to suppress their pattern VEPs.^[3]

Effects of physiological changes of serum glucose level

Sannita et al evaluated the correlation between amplitude and latencies of the pattern-reversal VEP and serum glucose level in healthy volunteers. Pattern VEP and serum glucose levels were obtained at 2-hour intervals during an 8-hour experimental session. At serum glucose concentrations within the physiological range of variability (55-103 mg/dL), the P100 latency increased with increasing serum glucose level, with a 6.9% estimated latency difference between lower and higher glucose concentrations.^[4]

VEP generator site

The generator site is believed to be the peristriate and striate occipital cortex. Prolongation of P100 latency is the most common abnormality and usually represents an optic nerve dysfunction. VEP is clearly more sensitive than physical examination in detecting optic neuritis. Ikeda et al studied generators of VEP by dipole tracing in the human occipital cortex. Current source generators (dipoles) of human VEP to pattern-onset stimuli were investigated. A visual stimulus, a checkerboard pattern, was presented for 250 ms in each of the 8 quadrants. Central and peripheral parts of each of the 4 quadrant fields were evaluated. The VEPs, consisting of initial positive-late negative waves, were recorded mainly on the occipital region contralateral to stimulated visual fields. The initial positive waves of VEP were divided into 2 components: (1) early component with approximate peak latency of 70-90 ms and (2) late component with approximate peak latency of 100-120 ms.^[5]

The results from these analyses of VEP indicated topographic localization of the dipoles around the calcarine fissure. This was comparable to the retinotopy of the human occipital lobe based on clinicopathologic studies. In order to examine the feasibility of multicenter studies, Brigell et al described the pattern VEP using standardized techniques. They concluded that the peak latency of pattern-reversal VEP is a sensitive measure of conduction delay in the optic nerve caused by demyelination. To establish whether pattern-reversal VEP could be standardized adequately for use as a measure in multicenter therapeutic trials for optic neuropathy or multiple sclerosis (MS), stimulus and recording variables were equated at 4 centers; pattern-reversal VEPs were recorded from 64 healthy subjects and 15 patients with resolved optic neuritis.^[6]

The results showed equivalent latency and amplitude data from all centers, indicating that the VEP test can be standardized satisfactorily for multicenter clinical trials. Further, the authors concluded that the N70 and P100 peak latencies and N70-P100 interocular amplitude difference were sensitive measures of resolved optic neuritis.

Abboud et al studied left-right asymmetry of VEPs in brain-damaged patients. The left-right asymmetry in the potential amplitude on the scalp was studied in patients after stroke by using flash VEP. The VEP amplitude was smaller over the ischemic hemisphere than over the intact hemisphere. This finding indicates that the left-right asymmetry in scalp VEPs of patients after brain damage may be a result of changes in the conductivity of the volume conductor, due to the ischemic region between the source and the electrodes.

Interhemispheric transfer of visual information

Ipata et al assessed interhemispheric visual transfer of information in humans. Estimates of interhemispheric transfer time ranged between 5.77 and 12.54 ms, depending upon the type of component and the location of the electrode sites. More anterior locations yielded shorter values and overall transfer time tended to be 7 ms shorter for the N70 component than for the P100 component.^[7]

Optic neuritis and multiple sclerosis

The VEP characteristically shows an increase in P100 latency of the involved side. The use of steroids in this condition has been controversial. Trauzettel-Klosinski et al observed the effect of oral prednisone on VEP latencies in acute optic neuritis. Forty-eight patients with acute optic neuritis were treated orally either with methylprednisolone (100 mg/day initially, dosage reduction every 3 days; n=15) or with thiamine (100 mg/day; n=33) in the control group, 36 of them in a double-blind procedure. Oral methylprednisolone resulted in a faster improvement in VEP latency in the initial phase but had no benefit after 12 weeks or 12 months.^[8]

Elvin et al used Doppler ultrasonography, MRI, and VEP measurements to study abnormal optic nerve function. VEP assessments were performed in 16 patients. Patients with impairment of visual acuity and a prolonged VEP initially had a more swollen nerve and increased flow resistance in the affected optic nerve. Statistically significant side-to-side differences were found in the optic nerve diameter and in the resistance to flow in the central retinal artery between the affected and unaffected eyes.^[9]

The McDonald criteria has incorporated VEPs into the diagnosis of multiple sclerosis. In patients in whom an insidious neurological progression has occurred, VEPs are recommended in patients with an MRI consisting of 4 or more, but less than 9, T2 lesions consistent with MS.^[10]

Optic neuritis versus ischemic optic neuropathy

Atilla et al found that VEP amplitude decrease was more significant in ischemic optic neuropathy, while optic neuritis showed more significant latency prolongation.^[11]

VEP in adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked metabolic disorder with very long-chain fatty acid (VLCFA) accumulation and multifocal nervous system demyelination, often with early involvement of visual pathways. Kaplan et al found that pattern-reversal VEPs were abnormal in 17% of the men with adrenoleukodystrophy; no evidence indicated that reduction of VLCFA levels improved or retarded visual pathway demyelination.^[12]

Optic neuropathy due to HTLV-1

Yukagawa et al found delayed P100 latencies in 7 of 46 eyes in patients with uveitis due to the virus.^[13]

Idiopathic intracranial hypertension

Kesler et al studied 20 patients with chronic idiopathic intracranial hypertension with VEPs. His group found that 55% of the patients had prolonged VEP. These latencies tended to correlate best with visual field deficits, but other clinical findings were less congruent. The prolongation of the latencies suggested demyelination as the pathogenic process occurring in these individuals.^[14]

Pattern-reversal VEP in classic and common migraine

Shibata et al recorded pattern-reversal VEP to transient checkerboard stimulus in 19 patients with migraine with visual aura (ie, classic migraine), 14 patients with migraine without aura (ie, common migraine) in the interictal period, and 43 healthy subjects. Latencies and amplitudes of pattern-reversal VEPs in each group were analyzed. In patients with classic migraine, P100 amplitude was significantly higher than in healthy subjects, whereas latencies of pattern-reversal VEPs did not differ significantly. No significant differences were noted in latency between the common migraine group and healthy subjects or in latencies and amplitudes of pattern-reversal VEP between the classic migraine and common migraine groups.^[15]

Zgorzalewicz found prolongation of P100 and N145 latencies and reduction in amplitude in migraine patients in one hemisphere.^[16]

These results suggest that patients with classic migraine may have hyperexcitability in the visual pathway during interictal periods and that the increased amplitude of pattern-reversal VEPs after attacks may be due to cortical spreading depression.

Szabela et al found abnormal VEP in 22% of type 2 diabetics.^[17]

With abnormal VEP, some of the differential diagnostic considerations are as follows:

• • Optic neuropathy

  • Optic neuritis

  • Ocular hypertension

  • Glaucoma

  • Diabetes

  • Toxic amblyopia

  • Glaucoma

  • Leber hereditary optic neuropathy

  • Aluminum neurotoxicity

  • Manganese intoxication

  • Retrobulbar neuritis

  • Ischemic optic neuropathy

  • Multiple sclerosis

  • Tumors compressing the optic nerve - Optic nerve gliomas, meningiomas, craniopharyngiomas, giant aneurysms, and pituitary tumors

Normal VEP virtually excludes an optic nerve or anterior chiasmatic lesion.

Clinical usefulness of VEPs includes the following:

• • More sensitive than MRI or physical examination in prechiasmatic lesions

  • Objective and reproducible test for optic nerve function

  • Abnormality persists over long periods of time

  • Inexpensive as compared with to MRI

  • Under certain circumstances, may be helpful to positively establish optic nerve function in patients with subjective complaint of visual loss; normal VEP excludes significant optic nerve disorder

Summary

The VEP is preferable in optic nerve and anterior chiasmatic lesions, while MRI is clearly superior in retrochiasmatic disease. Note that the VEP is nonspecific as to the underlying etiology and pathology.