International Journal of Neuroscience, 2014; Early Online: 1–6 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.931386

ORIGINAL ARTICLE

Visual-evoked potentials in patients with brain circulatory problems Dorota Pojda-Wilczek

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Ophthalmology Clinic and Department of Ophthalmology, School of Medicine in Katowice, Medical University of Silesia in Katowice, Katowice, Poland Purpose: The aim of this study was to find out if local brain circulatory problems may influence visual-evoked potentials (VEP). Patients and methods: Thirty-eight patients were divided into the following groups: (I) those with hemianopsia or quadrantanopsia and hemiparesis after brain stroke; (II) those with hemianopsia or quadrantanopsia without paresis after brain stroke; and (III) those with amaurosis fugax. The control group consisted of 38 patients. The VEP pattern (PVEP) and flash VEP (FVEP) were examined monocularly using two electrodes placed at O1 and O2 . Latency and amplitude of the N75, P100 and N2, P2 waves were measured. The Newman–Keuls test was used for statistical analysis. Results: In PVEP, no differences between the groups were observed. In FVEP, the mean P2 latency was significantly longer in group I than in group III, and the P2 amplitude was significantly lower in all examined groups when compared with the control group. PVEP and FVEP revealed differences in P latency over 3 ms between brain hemispheres and differences in P amplitude over 30% in all examined groups. In the control group, there were no differences in latency between brain hemispheres and only a small difference in amplitude. Conclusion: Local brain circulatory problems that may lead to brain ischemia cause differences in VEP amplitude and latency between brain hemispheres. Changes in VEPs observed in patients with amaurosis fugax may be considered the result of recurrent brain ischemia. KEYWORDS: evoked potentials visual, cerebral ischemia, stroke, amaurosis fugax

Introduction Cerebral perfusion disturbances can be classified as transient (within 24 h) or persistent according to their duration. These disturbances can be localized and further classified into generalized (transient ischemic attack, cerebral infarct) and local (amaurosis fugax, retinal infarct) categories. Sudden monocular blindness, called amaurosis fugax, is a risk factor for stroke. Interestingly, the analysis of major stroke risk factors by Mead et al. revealed that amaurosis fugax is more closely related to ipsilateral carotid stenosis, whereas cerebral incidents are more significantly correlate with atrial fibrillation [1]. Stroke may lead to scotomas of the visual field and to deterioration in visual acuity. Electrophysiological examinations allow for the objective assessment of visual defects. Ring et al. studied flash visual-evoked potentials (FVEP) in five men after stroke and reported lower

Received 1 December 2013; revised 1 June 2014; accepted 1 June 2014 Correspondence: Dorota Pojda-Wilczek, Huculska 28, 40–736 Katowice, Poland. Tel. +48 608654233. E-mail: [email protected]

cerebral activity on the damaged side, as determined through the asymmetry in the potentials recorded from the left and right hemispheres [2]; there was no asymmetry in their control group. It is very important to find diagnostic examinations that may help understand a patient’s complaints. Relja et al. [3] described a case of persistent visual aura in the right hemifield in a patient with migraines. A brain single photon emission computed tomography (SPECT) with technetium Tc99m hexamethylpropyleneamine oxime (Tc99m-HMPAO) was performed 1 month after the onset of symptoms, while the visual deficit was still significant, and this analysis revealed a decrease in blood perfusion of the left fronto-parieto-occipital and right occipital regions. At the same time, there were no abnormal findings during the neurological and ophthalmological examinations, including visual acuity, color vision, kinetic and computerized perimetry, and ophthalmoscopy. Routine hematological assays, electroencephalography, visual cortical evoked potentials, Doppler ultrasonography of intracranial and extracranial arteries, brain computed tomography and magnetic resonance (MRI) were all normal. Standard VEP with 1

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one electrode above Oz is not useful in such cases. Thus, the examiner should change the conditions in special cases to make the examination more sensitive to local abnormalities. Multichannel or hemifield VEP recording or multifocal VEP should be used in this cases. Cerebrovascular diseases cause a variety of electroencephalography (EEG) abnormalities on the side of the lesion [4–7]. In patients who complain of visual disturbances (transient or persistent scotmas or transient blindness on one side), abnormalities in cortical function obtained by evoked potentials are also expected. Chronic ischemia of the retina or optic nerve may cause a delay in VEP latency, without a loss of visual acuity or visual field [8]. The aim of the current study was to assess whether and to what extent cerebral perfusion disturbances affect VEP.

were averaged. The remaining study conditions were performed as per the recommendations and standards of the ISCEV (International Society for Clinical Electrophysiology of Vision). Latency and amplitude of the negative and positive waves N75, P100 and N2, P2 were measured. Identification of the positive components was first made based on the time range: between 90 and 140 ms for P100, and between 115 and 160 ms for P2 after the onset of stimulation. Negative waves N75 and N2 preceded the positive components. In traces that were difficult to describe, comparison to traces recorded from the opposite hemisphere or fellow eye was found to be helpful. The Newman–Keuls and Fisher exact tests were used for the statistical analysis. Significance was defined as p < 0.05. The following data were analyzed:

Patients and methods

1. Amplitude and latency of the main negative waves (N75, N2) (a) summarized from O1 and O2 . (b) from the stroke hemisphere and from the opposite hemisphere (for groups I and II). 2. Amplitude and latency of main positive waves (P100, P2) (a) summarized from O1 and O2 (b) from the stroke hemisphere and from the opposite hemisphere (for groups I and II) (c) between O1 and O2 in control group. 3. Number of patients in control and examined groups with more than 30% difference in amplitude and 3 ms difference in latency between hemispheres (based on work of Blumhardt and Halliday [9]).

Thirty-eight patients (23 women and 15 men) were divided into three groups. Group I consisted of 14 individuals aged 54–80 (mean age 62) with hemiparesis and visual field defects (hemianopsia or quadrantanopsia) after brain stroke. Group II included 14 patients aged 32–70 (mean age 55) with hemianopsia or quadrantanopsia after stroke, but without neurological residua. Group III included 10 patients, between 15 and 67 years old (mean age 43), with a history of amaurosis fugax (AmF), but without any neurologic or ophthalmic symptoms and with normal MRIs. The control group consisted of 38 patients (21 women, 17 men) aged 55–88 (mean age 73) with initial stages of age-related macular degeneration (AMD). Time after stroke ranged between 6 months and 13 years (mean 2 years). This interval was comparable between groups I and II. Patients in group III noticed 1–4 (mean 2) incidents of AmF. The last incident of AmF occurred from 3 days to 4 months prior to examination (mean 2 weeks). Only eyes with full visual acuity (best corrected visual acuity = 0.0 logMAR) were selected for comparative analysis. For final analysis, the groups included: 22 eyes in group I, 28 eyes in group II, 20 eyes in group III, and 75 eyes in the control group. VEPs were examined using LKC equipment, program UTAS E-2000 with pattern (PVEP) and flash (FVEP) stimulations; the two electrodes (gold cup) placed at O1 and O2 referenced to Fz. Visual potentials were evoked by standard white flashes with a frequency of 1.9 Hz (FVEP) and black-and-white checkerboards with square sizes of 105 and 13 (PVEP). The pattern reversing frequency was 1.9Hz, and the squareto-square contrast was 95%. Monocular, full-field stimulation was used. The refraction errors were corrected to the examination distance (0.7 m), and 80 responses

This study was conducted in accordance with the Declaration of Helsinki.

Results There were no significant differences in the mean negative wave amplitude and latency in PVEP and FVEP (N75, N2) among the patient groups (I, II, III, and control—combined O1 and O2 data), nor between hemispheres (O1 and O2 data separately) within a group. In PVEP, significant differences were present only for stimulations with high angular (105 ) fields. No significant differences for stimulation 13 were found. Therefore, in the following only the analysis of the results of 105 stimulation is discussed. In all study groups, P2 (FVEP) amplitude (combined O1 and O2) was significantly lower than that of the control group. No significant differences in latency (study groups versus control group) were found. Significantly longer P2 latency was found in group I compared with International Journal of Neuroscience

VEP in brain circulatory problems Table 1.

FVEP.

Group

n (O1 and O2 )

Mean P2 amplitude [μV]

I II III control

44 56 40 150

8.8∗∗ 8.2∗ 6.7∗∗ 12.6

SD

Mean P2 latency [ms]

SD

4 4 4.5 6.7

130 126 119 128

19 17.5 16 11

Mean values of the P2 amplitudes and latencies (FVEP) in the examined groups versus the control group. n—number of the results from O1 and O2. ∗ Significant at p < 0.05; ∗∗ significant at p < 0.01. SD—standard deviation.

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Table 2.

PVEP, stimulation size 105 .

Examined group/brain hemisphere I / stroke side I / opposite side II / stroke side II / opposite side Control O1 Control O2

n

Mean P100 amplitude [μV]

SD

Mean P100 latency [ms]

SD

22 22 28 28

4.7∗∗ 6.3∗∗ 5.6∗∗ 7

2 2 3.9 2.5

120∗∗ 113∗∗ 118∗∗ 117∗∗

16 11.2 16 15

75 75

9.4 7.7

3.9 3.3

99 99

6.7 7

Mean values of the P100 amplitudes and latencies in I and II groups versus the control group. ∗∗ Significant at p < 0.01 versus control. n—number of eyes; SD—standard deviation.

the group III (p < 0.05). The mean P2 amplitudes and latencies are presented in Table 1. The combined mean P100 (PVEP) amplitudes and latencies from O1 and O2 did not significantly differ between the groups. The results from the patients after stroke (groups I and II) were split into values from the hemisphere where the stroke was located and the opposite hemisphere. The values were statistically analyzed (Table 2). In control group, no significant differences between hemispheres were found.

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In patients after stroke, P100 (PVEP) amplitude was significantly lower and latency was more delayed than in the control group. In group II, a significant amplitude decrease was observed only on the stroke side. In group I, P100 amplitude on the stroke side was significantly lower (4.7 μV), and the latency was delayed more (120 ms) compared to the ipsilateral side (6.3 μV, 113 ms; p < 0.05). In some patients, only a trace visual response could be recorded on the stroke side. Similarly, the analysis of the FVEP results did not reveal any significant differences between hemispheres. The results for individual patients in all study groups and the control group were analyzed for differences in amplitudes and latencies between hemispheres. A 30% difference in amplitude and 3 ms difference in latency were adopted as the normal limit values. The results are summarized in Table 3. The number of patients with interhemispheral differences was significantly higher in all examined groups versus the control group. The number of patients with P2 amplitude differences between hemispheres were significantly lower in the amaurosis fugax group than in the groups of patients after stroke (p < 0.001). Figure 1 presents samples PVEP and FVEP traces from a healthy person. Figure 2 shows significantly abnormal VEP in the stroke hemisphere of patient from group I.

Discussion Interhemisphere values of amplitude and latency differences used for accepted normal limits were chosen on the basis of our observations and those reported by Blumhardt and Halliday [9]. The correctness of the chosen criteria is shown by only minor differences that were observed in the control group. In a series of 26 patients with homonymous hemianopsia, Blumhardt and Halliday found abnormal asymmetries of P100 amplitudes in only 62% of the patients for the full-field responses but in 81% for the half-field responses [9]. We report similar results for the full-field responses in groups I (68%) and II (70%).

Table 3. The number of eyes with significant interhemispherical differences in the amplitudes (>30%) and latencies (>3 ms) in the study groups.

Group I II III Control ∗∗

Total number of eyes 22 28 20 75

PVEP 105 (P100) amplitude difference (number of eyes) ∗∗

15 19∗∗ 11∗∗ 4

Significant at p < 0.01 versus control.

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% 68 70 55 5

PVEP 105 (P100) latency difference (number of eyes) ∗∗

13 14∗∗ 13∗∗ 0

% 59 50 65 0

FVEP (P2) amplitude difference (number of eyes) ∗∗

18 18∗∗ 7∗∗ 1

% 82 64 35 1.3

FVEP (P2) latency difference (number of eyes) ∗∗

13 20∗∗ 16∗∗ 0

% 59 71 80 0

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Figure 1. VEP of a normal subject with no differences between the brain hemispheres. R—right eye, L—left eye, 01—left brain hemisphere,

and 02—right brain hemisphere.

Figure 2. VEP of a 64-year-old man with an incomplete hemianopsia after ischemic stroke in the right hemisphere of the brain (group I). P100 and P2 amplitudes from the right hemisphere (traces 2 and 4) are lower than those from the left hemisphere (traces 1 and 2). R—right eye, L—left eye, 01—left brain hemisphere, and 02—right brain hemisphere.

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VEP in brain circulatory problems

Longer P100 (PVEP) latency for stimulation with fields 105 was observed in study groups I and II compared with the control group but only in separate analysis of results from O1 and O2 . Taghavy and Hamer, who recorded PVEP with Oz, reported a delay in N80 and P100 latencies and a decrease in P100 amplitude after AmF compared to contralateral eyes [10]. Calleja et al. also described a P100 latency delay with AmF due to severe carotid occlusive disease [11]. Amaurosis fugax may originate from retinal circulatory problems. In this study, P2 amplitude in the AmF was lower (Table 1) than that in the control group. Rate of interhemispheric differences was significantly higher than that in the control group, but lower than that in the stroke group I (Table 3). Therefore, it may be concluded that local hemodynamic disturbances may represent a less advanced stage of brain cerebrovascular disease. Rutgers et al. [12] examined cerebral hemodynamic parameters in patients with transient monocular blindness and patients with hemispheric transient ischemic attacks. The results of their study indicate that there are no cerebral hemodynamic differences between these two groups of patients. Therefore, according to Rutgers [12], AmF may be considered a risk factor for stroke. Abnormal VEP in patients with AmF, especially with interhemispherical asymmetry, may prompt a more profound neurological assessment (magnetic resonance, angiography, Doppler ultrasonography, ocular coherence tomography, etc.), even if visual acuity and perimetry are normal. Diseases of the central nervous system alter the electric activity measured by VEP. In the current study of FVEP the mean P2 amplitude was significantly lower in all examined groups. This result may reflect the generalized abnormalities of the central nervous system. In PVEP, significant differences in P100 amplitudes and latencies were found only in the stroke groups (I and II). In group II, significantly lower P100 amplitudes and longer P100 latencies were observed only in the responses of the stroke hemisphere. Lytaev and Shevchenko examined VEP from patients 1–3 weeks after stroke and found that ischemic stroke significantly influenced the latest waves of VEPs (above 100 ms) [13]. This observation may explain the lack of differences in amplitude and latency of the negative components in the current study. Multichannel multifocal VEP (mfVEP) recording is a new method to detect visual field loss. Klistomer et al. [14] examined patients who had various forms of homonymous or bitemporal field loss from lesions of the posterior visual pathway (tumors, cortical infarcts, injuries, etc.). mfVEP can detect field loss from cortical lesions, but not in some cases of homonymous quadrantanopsia, where the lesion may have been in the extrastriate cortex. This difference supports the idea that  C

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the mfVEP is generated in the V1 striate cortex and that it may thus be able to distinguish between striate and extrastriate lesions. Cortical lesions caused significant differences in mfVEP amplitude between the affected and unaffected hemispheres or quadrants. All hemifield type defects were found to have corresponding mfVEP losses. Only four of seven hemianopias with quadrantanopic type defects showed corresponding mfVEP defects in the same areas. The authors explained this observation based on animal studies provided by Merigan et al. [15]. This study suggested that a quadrantic-type scotoma is more likely to be caused by damage to fiber tracts leading from V1 to the extrastriate areas, than by neuronal damage in the extrastriate areas themselves. In the present study, the absolute values of P2 amplitudes and latencies did not significantly differ between hemispheres. Significant differences in P100 amplitudes between hemispheres were observed after pattern stimulations with square size 105 in group I, where the stroke extent and amplitude loss on stroke side were larger. Differences in the absolute values may depend on the extend of the stroke. Differences between the PVEP and FVEP results may be connected to the origin of these two responses. The VEP represents the response of the visual cortex to stimuli presented in the visual field. Flashes of light stimulate all photoreceptors of the retina, regardless of the patient’s cooperation, fixation, or refractive problems. Responses to pattern stimuli originate in the macular (small checks) and paramacular (large checks) regions. Therefore, this type of stimulation is helpful in the estimation of visual acuity of noncooperative patients. The responses to pattern-reversal stimulus are simple and stable within and between subjects. Response to flashes is enhanced by the background activity of EEG. There are large differences between the FVEP waveforms among the different healthy subjects [16]. The major positive component of PVEP, P100, is generated in the cortical area V1 [17]. The origin of the FVEP components is currently under investigation. The P2 wave is likely generated in the cortical areas V1–V3, and P3 is generated in the area V4. PVEP is sensitive to changes in the central visual field and FVEP is sensitive to changes in the peripheral field. These two stimuli should be used in a complementary manner not as alternative examinations. Currently, the ISCEV standard generally recommends flash stimuli for patients who are unable or unwilling to cooperate for PVEP, and in cases where optical factors, such as media opacities, prevent the valid use of pattern stimuli [18]. Patients with suspected cerebral circulatory disturbances should have PVEP and FVEP performed in a way that enables the individual assessment of the left and right hemispheres. This approach is particularly useful in patients with low visual acuity or in noncompliant

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patients, that is those who do not maintain fixation during perimetry. Electophysiological studies are shorter in duration than perimetry, which is important for elderly patients and those in a poor general condition. Stimuli with high angular values should be chosen for PVEP, as they stimulate relatively large areas of the retina. In the current study, significant differences between hemispheres could be observed with 105 stimulation. The lack of difference after stimulation with smaller stimuli may be explained by our selection of eyes with normal visual acuity, and therefore, preserved central vision. This selection was performed to eliminate VEP abnormalities due to various comorbidities that lead to visual acuity loss. Half-field stimulation requires good fixation control, as patients with hemianopsia often turn their heads to improve their vision. Therefore, performing full-field stimulation is easier. Follow-up VEPs recorded with O1 and O2 lead to detect the long-term functional consequences of stroke are cheaper and easier to perform than imaging and are easier to record than perimetry. For proper interpretation of interhemispherical differences, other possible causes, such as traumas or developmental or perinatal disorders, should be considered. VEP abnormalities are not specific to cerebral perfusion defects and, therefore, must be interpreted using other signs, symptoms, and examination results.

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Conclusion 12.

Local brain circulatory problems, which may lead to brain ischemia, cause differences in VEP amplitudes and latencies between brain hemispheres. Changes in VEP observed in patients with amaurosis fugax may be considered the result of recurrent brain ischemia.

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Declaration of Interest 15.

The author reports no conflict of interest. The author alone is responsible for the content and writing of this paper. The study was supported by the Medical University of Silesia.

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International Journal of Neuroscience

Visual-evoked potentials in patients with brain circulatory problems.

The aim of this study was to find out if local brain circulatory problems may influence visual-evoked potentials (VEP)...
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