Advertisement

Documenta Ophthalmologica

, Volume 139, Issue 2, pp 83–97 | Cite as

Visual evoked and event-related brain potentials in HIV-infected adults: a longitudinal study over 2.5 years

  • Jana SzanyiEmail author
  • Jan Kremlacek
  • Zuzana Kubova
  • Miroslav Kuba
  • Pavel Gebousky
  • Jaroslav Kapla
  • Juraj Szanyi
  • Frantisek Vit
  • Jana Langrova
Original Research Article

Abstract

Purpose

The aim of this neurophysiological study was to monitor changes in the visual and cognitive function of HIV-infected patients treated with combination antiretroviral therapy.

Methods

Eleven adult Czech HIV+ patients, with a mean age of 35 years and CD4 cell count ≥ 230 × 106 cells/L of blood at the time of enrollment, underwent four to six examinations over the course of 2.5 years to evaluate pattern-reversal and motion-onset visual evoked potentials (P-VEPs and M-VEPs), visually driven oddball event-related potentials (ERPs) and Montreal Cognitive Assessments. In addition to evaluating the intraindividual change in the observed parameters, we also compared patient data to data from eleven age- and gender-matched controls.

Results

We did not find any significant differences in P-VEPs between the patients and controls or in the paired comparison of the first and last visit. The only significant finding for P-VEPs was a linear trend in prolongation of the 20′ P-VEP P100 peak time. In M-VEPs, we found a significant intergroup difference in the N160 peak time recorded during the first visit for peripheral M-VEPs only. During the last visit, all N160 peak times for patients differed significantly from those of the control group. The only intervisit difference close to the level of significance was for peripheral M-VEPs, which confirmed the trend analysis. No significant differences between patients and controls were found in the ERPs, but the P300 peak time showed a significant difference between the first and last visits, as confirmed by the trend. Patient reaction time was not significantly delayed at the first visit; however, it was prolonged with time, as confirmed by the trend.

Conclusion

Our aim was to evaluate whether antiretroviral treatment in HIV+ patients is sufficient to preserve brain visual function. The optic nerve and primary visual cortex function tested by the P-VEPs seem to be preserved. The prolongation of the M-VEPs suggests an individually detectable decline in CNS function, but these changes did not show a progression during the follow-up. From a longitudinal perspective, the trends in peak time prolongation of the 20′ P-VEP, peripheral M-VEP, ERP and reaction time suggest a faster decline than that caused by aging in healthy populations, as previously described in a cross-sectional study.

Keywords

Human immunodeficiency virus (HIV) Visual evoked potentials (VEPs) Motion-onset VEP Pattern-reversal VEP Event-related potentials (ERPs) 

Introduction

Human immunodeficiency virus (HIV) reaches the central nervous system (CNS) early in the infection and manifests in various ways in the visual pathway and its cortical projections [1, 2]. After the introduction and widespread use of combination antiretroviral therapy (cART), the frequency of CNS opportunistic infections has dramatically decreased, but less aggressive levels of HIV-associated inflammatory and neurodegenerative pathology have persisted in the brain despite the use of antiretroviral treatment [3, 4, 5]. The effectiveness of antiretroviral therapy is usually evaluated by blood tests, such as CD4+ lymphocyte counts and plasma HIV RNA levels. Nevertheless, an important question remains as to whether antiretroviral treatment is sufficient to preserve brain function, especially in patients treated for many years. Electrophysiological examination, such as visual evoked potentials (VEPs) and event-related potentials (ERPs), provides information about visual processing in the brain and is one of the ways by which this question can be addressed.

Alternating black/white checkerboards are widely used to activate the primary visual area, and the elicited pattern-reversal VEPs (P-VEPs) can detect optic nerve pathology via P100 peak time prolongation and amplitude reduction. Before the cART era, many studies reported prolonged and reduced P-VEP components, even in the early stages of HIV infection [2, 6, 7, 8, 9, 10]. The initiation of cART has reduced the risk of impaired optic nerve function due to opportunistic infection in HIV-infected populations; therefore, the occurrence of P-VEP pathology has been substantially reduced, as confirmed in our previous study of this problem [11].

The specific motion-onset VEPs (M-VEPs) reflect activity in the magnocellular system and the dorsal stream of the visual pathway. M-VEPs are characterized by the motion-onset-specific negative peak, N160, in the extrastriate temporo-occipital and parietal cortices [12]. Our previous study described subclinical dysfunction in this system, as detected by M-VEPs in five out of 16 neurologically asymptomatic, virally suppressed HIV patients [11].

A milder form of HIV-associated neurocognitive disorder (HAND) remains common in the HIV-infected population despite effective cART [13, 14, 15]. Event-related potentials are sensitive markers that correlate with cognitive decline as reflected in prolongation of the P300 (P3b) peak time and reduction in its amplitude. ERPs are a useful screening tool, as they can detect early neurocognitive involvement in HIV+ subjects [16, 17, 18].

To our knowledge, no longitudinal neurophysiological studies have followed the development of functional changes at various levels of visual information processing, such as primary visual cortex and associate visual motion processing cortex, and cognitive processing in HIV subjects on cART. Therefore, the goal of the current study was to monitor virally suppressed, neurologically asymptomatic HIV patients undergoing cART by using pattern-reversal VEPs, motion-onset VEPs and visual ERPs as potential additional neuro-ophthalmological screening methods. We also explored whether electrophysiological changes correlated with other clinical parameters.

Methods

Patients

The participants were recruited from the Department of Infectious Diseases of the Faculty Hospital in Hradec Kralove in the Czech Republic. Eleven of the original 16 neurologically asymptomatic HIV+ patients from our previous study, seven males and four females, were included in the present study after excluding patients with neuro-ophthalmological manifestation and cognitive impairment [11]. These 11 patients were examined 4–6 times at 6-month intervals. The study started in June 2013 and lasted two and a half years. The demographic and clinical characteristics of the enrolled patients, including age, gender, duration of HIV infection, number of CD4 cells, HIV RNA copies in plasma, Centers for Disease Control and Prevention score, Montreal Cognitive Assessment results during follow-up and type of antiretroviral therapy, are shown in Tables 1 and 2. The duration of HIV infection at the time of inclusion in the study was estimated based on the date of the first positive HIV antibody test and ranged from 1.2 to 18.7 years. Patient mean age at inclusion was 35 years. All patients had ≥ 230 × 106 CD4 cells/L of blood and a viral load ≤ 117,000 HIV RNA copies/mL of blood at the time of enrollment.
Table 1

Demographic and clinical characteristics of the observed patients

Pt.

Duration of HIV (years)

No of CD4 cells × 106/L

HIV RNA copies in plasma

0

1

2

3

4

5

6

0

1

2

3

4

5

6

1

1.9

450

460

350

340

430

390

430

23,000

4390

793

718

654

3530

0

2

8.0

350

350

540

460

520

590

740

107,000

0

0

0

0

0

0

3

1.2

350

350

620

770

570

770

840

13,000

13,000

35

0

0

0

0

4

7.1

680

720

 

1004

1340

 

1160

107,000

< 20

 

< 20

< 20

 

< 20

5

7.2

700

710

690

800

640

720

670

1880

6200

1060

10,000

8280

7770

9170

6

3.0

10

530

500

550

810

 

940

280,000

< 20

394

< 20

20

 

< 20

7

2.9

540

750

800

740

830

690

780

8590

7840

14,000

3770

10,100

28,200

31,400

8

18.7

810

230

80

110

60

 

70

3000

117,000

289,000

34,000

34,500

 

1300

9

5.2

750

1550

1780

1670

1860

2880

 

2870

< 20

0

0

0

< 20

 

10

7.4

250

580

880

520

660

  

100,000

< 20

0

20

< 20

  

11

4.0

330

870

880

1280

1130

 

1150

137,000

30

57

20

23

 

0

Column 0: No. of CD4 cells and HIV RNA copies at the time of the first positive HIV antibody test

Columns 1–6: No. of blood CD4 cells and presence of HIV RNA copies in plasma at six individual visits during a longitudinal study over 2.5 years at 6-month intervals at the appropriate time with VEP examination

Table 2

Demographic and clinical characteristics of the observed patients

Pt.

Gender (M/F)

Age (years)

CDC

MoCA (max 30 points)

CART

VEP findings

   

1

2

3

4

5

6

1

M

24

A1

28

30

29

28

29

26

T + P

0

2

F

27

B2

28

28

30

30

29

29

K + C

M-VEP

3

F

32

C2

30

29

30

30

30

28

K + KI

0

4

F

32

B1

29

 

28

28

 

27

T + K

0

5

M

33

A1

30

30

30

30

30

30

sine

P-VEP

6

M

34

C3

30

29

30

28

 

30

K + KI

M-VEP

7

M

36

A1

29

30

30

30

30

28

Sine

M-VEP

8

F

38

B2

30

30

30

30

 

30

T + A

M-VEP

9

M

38

B1

26

26

29

29

25

 

P + KI

0

10

M

42

A2

30

30

30

30

  

E + T

P + M-VEP

11

M

50

A2

29

29

29

29

 

29

T + K

0

F, female; M, male; CDC, Centers for Disease Control and Prevention (classification system for HIV infection); MoCA, Montreal Cognitive Assessment; cART, combination antiretroviral therapy; T, TRUVADA (nucleoside/nucleotide reverse transcriptase inhibitor); K, KALETRA (protease inhibitor); KI, KIVEXA (nucleoside reverse transcriptase inhibitor); E, EFAVIRENZ (non-nucleoside reverse transcriptase inhibitor); C, COMBIVIR (nucleoside reverse transcriptase inhibitor); P, PREZISTA (protease inhibitor); A, ATAZANAVIR (protease inhibitor); and P-VEP and M-VEP, pattern-reversal and motion-onset visual evoked potentials

Counts of CD4 T-cells were determined by using a Cytomics FC500 flow cytometer (Beckman Coulter, Brea, California, USA). Quantitative measurement of HIV viremia was performed by a COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, version 2.0 (F. Hoffmann-La Roche, Basel, Switzerland), which was used as an in vitro nucleic acid amplification test to quantitate human immunodeficiency virus type 1 RNA in human EDTA plasma. For all patients, the HIV disease staging classification according to the Centers for Disease Control and Prevention (CDC) was periodically evaluated but remained unchanged during the study (A1-C3) [19]. At the beginning of the study, three patients, Nos. 1, 5 and 7, had not undergone any treatment for HIV; however, patient No. 1 started cART during the study between the fifth and sixth VEP examinations. At the time these patients were diagnosed, the guidelines of the International AIDS Society-USA Panel advised starting cART in symptomatic patients and in patients with a CD4 cell count below 350 × 106 CD4 cells/L or a viral load above 50,000–100,000 copies/mL of blood [20]. Eight HIV patients had been taking antiretroviral medication for at least 2 months prior to participation in the study. All patients treated with cART incorporated a combination of different groups of antiretroviral medicines into one complete regimen (see Table 2).

Control subjects

The control group consisted of eleven volunteers who did not suffer from any neurological disease, and none were being treated by any medication that would influence CNS function. They were selected to match the patient group according to age, gender and visual acuity results. Control subjects displayed a Montreal Cognitive Assessment (MoCA) result between 27 and 30 points.

In the longitudinal follow-up of HIV patients, every patient served as his/her own control.

Electrophysiological examination

The electrophysiological examination consisted of measuring VEPs and ERPs. Two types of visual stimuli were used to elicit VEPs, pattern-reversal and motion-onset stimuli, with the aim of testing the function of two subsystems of the visual pathway and their cortical projections. Patients were examined four to six times every 6 months in the Electrophysiological Laboratory at Charles University in Prague—Faculty of Medicine in Hradec Kralove. The stimuli were presented on a 21″ computer monitor (Electron 22blue IV, LaCie Ltd., France) subtending 37° × 28° of the visual field from a 0.6-m viewing distance, and the average stimulus luminance was 17 cd/m2. The monitor was driven using a Visual Stimulus Generator 2/5 (CRS Ltd., UK) at a 105-Hz vertical refresh frequency. Correct fixation on the stimulus field center was monitored via a near-infrared CCD camera. Monocular VEPs and binocular ERPs were recorded from six unipolar derivations using the right earlobe as a reference. Four derivations from the midline (Oz, Pz, Cz, and Fz) and two lateral derivations (Ol and Or, which were 5 cm to the left and right of the Oz position) were used to cover areas with maximum amplitudes for both VEPs and ERPs.

Forty single sweeps for VEPs and twenty for target ERPs were averaged. We selected a lower number of sweeps than that generally used because we achieved sufficient signal-to-noise ratio by suppressing technical and physiological noise. To a large degree, we eliminated any electromagnetic noise by recording in a Faraday cage. Physiological noise was reduced by instructing the subject to attentively follow the stimuli and not to move and by setting the chair in a comfortable position to reduce subject muscle tension. A medical doctor monitored the VEP/ERP recording online and repeated the recording in cases of questionable reliability.

Information on visual acuity was obtained by the Landolt C test. A trained assistant administered a monocular test at the beginning of every electrophysiological examination.

Pattern-reversal VEPs

For the pattern-reversal VEPs, the stimuli consisted of a black and white checkerboard (96% contrast, according to Michelson), with check element sizes of 40′ (40′ P-VEPs) and 20′ (20′ P-VEPs), that reversed at a frequency of 2 rev/s.

The P100 peak time and interpeak amplitudes were evaluated in the Oz derivation.

Motion-onset VEPs

Motion-onset stimuli consisted of low-contrast (10%, sinusoid modulation) gray concentric circles that randomly expanded/contracted (radial motion). We recorded three variants of M-VEPs to radial motion onset. For an overview of stimuli appearance and their timing, see Fig. 1:
  1. (A)

    full-field M-VEPs (FF M-VEPs) to stimuli comprising 37° × 28° of the central visual field;

     
  2. (B)

    peripheral M-VEPs (M20° M-VEPs) to the stimulus field outside the central 20°; and

     
  3. (C)

    central M-VEPs (C8° M-VEPs) to stimuli in the central 8° of the visual field.

     
Fig. 1

Stimuli for motion-onset VEPs. Three variants of the radial motion-onset stimuli were used: A full-field stimulus comprising 37° × 28° of the central visual field; B peripheral stimulus with structure outside the central 20°; and C stimulus in the central 8° of the visual field. In all these variants, a low-contrast structure of concentric circles moved radially in an expanding or contracting way, as depicted by the white arrows. The timing of the stimuli is plotted in the bottom of figure (D); the radial motion (200 ms) was interleaved by 1 s of the stationary pattern, as illustrated in the middle column. The VEP origin was synchronized to the motion-onset event. A detailed description of the stimuli has been previously published [21]

All moving stimuli had the same timing parameters: 200 ms of motion that was followed by a 1-s interstimulus interval (stationary pattern) [12, 21].

The N160 peak time and interpeak amplitudes were collected from one of the lateral occipital or parietal leads [22].

Visual oddball ERPs

The ERPs were recorded during an oddball test, in which the white letter X (frequent, nontarget stimulus, probability of 75%) and Arabic digits 1–9 (rare, target stimulus with a probability of 25%) appeared pseudorandomly in the center (2.8° × 3.3°) of the black stimulus field (average luminance of 1 cd/m2) with a red fixation square (0.4° × 0.4°). The letter X or a digit was displayed for 500 ms, followed by a blank screen for 500 ms. Patients were instructed to react to the appearance of a digit by pressing a joystick to assess reaction time (RT). For the ERPs, 20 epochs to target stimuli and 20 randomly selected epochs to nontarget stimuli (both of 1000 ms duration with a sampling frequency of 250 Hz) were averaged for each condition. The epochs with artifacts, most often related to blinking, were manually rejected.

In the ERPs to rare stimuli, the P3b (designated as P300 in the following text) peak time and interpeak amplitudes were measured from either the Pz or Cz leads, whichever yielded the maximum P300 interpeak amplitude.

Cognitive questionnaire evaluation

The Montreal Cognitive Assessment (MoCA) was used as a screening instrument for cognitive function evaluation. It assesses different cognitive domains such as attention and concentration, executive function, memory, language, visuoconstructional skills, conceptual thinking, calculations and orientation [23]. The maximum score of the MoCA is 30 points, and a score of ≤ 25 is considered to indicate cognitive impairment. Three versions of the MoCA were used during the course of the study to prevent practice effects. A trained assistant administered the test at the end of every electrophysiological examination (Table 2).

Statistical analysis

The data were statistically processed with R software version 3.2 [24], using the “nortest” and “psych” packages.

Because patients with neurological symptoms or monocular impairment were not included in our study, the monocular VEP responses were averaged and statistically processed to keep the number of observations equal to the number of subjects.

Based on the Anderson–Darling test for the normality of the data, parametric or nonparametric tests were used. To examine the differences between the age- and gender-matched groups, the Wilcoxon rank sum test or Student’s t test was used; to assess intervisit differences, we used Student’s paired test or the Wilcoxon signed rank test.

For each patient, we evaluated the linear slope of the drop in amplitudes or prolongation of peak times over the follow-up period using regression analysis. We evaluated whether the slope (designated as a trend in the subsequent text) was significantly different from zero among the patients. We determined the relationship between significant trends and clinical markers (CD4 cells, HIV copies, visual acuity and CDC score) using Spearman’s or Pearson’s test.

Effects were considered statistically significant if the probability level (p) was below an alpha level of 0.05. When appropriate, the probability level was corrected for multiple comparisons by a Holm–Bonferroni adjustment.

Results

P-VEPs

Table 3 lists the median, lower and upper quartile of electrophysiological parameters and visual acuity of controls and patients during the first and last visits. For both check element sizes, we did not find any significant differences between the patient and control groups in the P100 peak time (p > 0.101) or its interpeak amplitude (p > 0.243) recorded at the first or last visit. A paired comparison of the first and last visits did not show a significant difference in amplitudes (p > 0.923). For the P100 peak time of the 20′ P-VEPs, the prolongation (1.0 [0.5 3.5] ms–median [lower and upper quartile], p = 0.057) was close to significance but not for 40′ P-VEPs (p = 0.473). A more comprehensive analysis of the trend, including all points recorded during the follow-up, showed a significant trend (1.0 [0.6 1.3] ms/year, p = 0.002) for the 20′ P-VEPs P100 peak time (see Fig. 2, which illustrates the significant prolongation trend in the 20′ P-VEPs P100 peak time over the follow-up period). Table 4 shows the statistical significance and power of the intergroup tests, paired comparison and trend analysis of electrophysiological parameters, visual acuity and MoCA results.
Table 3

Descriptive statistics of electrophysiological parameters and visual acuity of controls and patients at the first and last visit. The observations represent the averages of monocular examinations

 

HIV first visit

Median [lower; upper quartile]

HIV last visit

Median [lower; upper quartile]

Controls

Median [lower; upper quartile]

40′ P-VEP P100

Peak time (ms)

108.0 [105.5; 112.0]

110.0 [106.0; 113.0]

106.0 [104.0; 110.0]

40′ P-VEP A (µV)

9.9 [6.6; 12.6]

10.5 [7.8; 12.6]

12.4 [9.3; 13.6]

20′ P-VEP P100

Peak time (ms)

109.0 [108.0; 113.5]

111.0 [109.0; 115.5]

111.0 [105.0; 116.0]

20′ P-VEP A (µV)

10.9 [7.6; 12.3]

11.0 [9.0; 12.5]

13.4 [11.0; 15.1]

FF M-VEP N160

Peak time (ms)

166.0 [157.0; 182.0]

165.0 [161.5; 179.5]**

158.0 [151.0; 161.0]

FF M-VEP A (µV)

12.0 [6.6; 15.0]

11.7 [6.7; 13.4]

10.7 [10.5; 12.6]

M20° M-VEP N160

Peak time (ms)

171.0 [169.0; 178.0]*

175.0 [167.0; 190.5]*

160.0 [157.0; 163.0]

M20° M-VEP A (µV)

9.6 [6.6; 14.9]

10.1 [6.4; 12.4]

10.9 [9.1; 12.1]

C8° M-VEP N160

Peak time (ms)

173.0 [164.5; 190.5]

179.0 [163.5; 188.0]*

164.0 [157.0; 167.0]

C8° M-VEP A (µV)

8.2 [4.7; 10.8]

8.7 [4.3; 9.3]

8.8 [7.7; 9.6]

P300 peak time (ms)

368.0 [338.0; 378.0]

368.0 [344.0; 388.0]

376.0 [372.0; 384.0]

P300 A (µV)

18.3 [11.6; 19.7]

17.2 [15.3; 23.0]

18.0 [14.1; 24.7]

Reaction time (ms)

336.0 [326.0; 360]

352.0[342.0; 370.0]*

320 [300.0; 340.0]

Visual acuity

1.00 [0.69; 1.00]

1.00 [0.70;.1.00]

0.80 [0.67;.1.00]

A, corresponding interpeak average amplitude described in “Methods” section; 40′ P-VEP, pattern-reversal stimulation with an element size of 40′; 20′ P-VEP, pattern-reversal stimulation with an element size of 20′; FF M-VEP, full-field gray circles with randomly expanding/contracting motion; M20° M-VEP, gray circles with randomly expanding/contracting motion outside the central 20°; C8° M-VEP, gray circles with randomly expanding/contracting motion in the central 8° of the visual field; P300, oddball test with a white letter X (nontarget stimulus, probability of 75%) and white Arabic digits 1–9 (target stimulus with probability of 25%), appearing pseudorandomly in the center of a black stimulus field; visual acuity obtained by the Landolt C test as expressed in decimal values

A star symbol marks comparisons between patients and controls that reached statistical significance (*~ p < 0.05; **~ p < 0.01). All significant comparisons are also printed in bold

Fig. 2

Individual data from HIV patients for the observed parameters that exhibited a significant trend over the follow-up period: A relative 20′ P-VEP P100 peak time change, B relative M20° M-VEP N160 peak time change, C relative P300 peak time change, D relative reaction time change and E relative CD4 change. The data were normalized by subtracting values at the first visit from those of subsequent visits for each patient. The solid black line depicts the group median slope, and the dashed and dotted curves show 95% and 99% confidence intervals. In the plots of P100, N160 and P300 relative peak time, the gray line presents a control trend described by Kuba et al. [25]

Table 4

Overview of the statistical significance of the tests used

 

HIV first visit vs Controls

HIV last visit vs Controls

HIV last visit vs first visit

Trends

40′ P-VEP P100

Peak time (ms)

p = 0.138 pwr = 0.34

Student’s t test

p = 0.101 pwr = 0.4

Student’s t test

p = 0.473 pwr = 0.11

Student’s paired t test

p = 0.577 pwr = 0.08

Wilcoxon rank sum test

40′ P-VEP A (µV)

p = 0.345 pwr = 0.16

Student’s t test

p = 0.323 pwr = 0.17

Student’s t test

p = 0.938 pwr = 0.05

Student’s paired t test

p = 0.837 pwr = 0.05

Student’s t test

20′ P-VEP P100

Peak time (ms)

p = 0.705 pwr = 0.07

Wilcoxon rank sum test

p = 0.265 pwr = 0.21

Student’s t test

p = 0.057 pwr = 0.52

Wilcoxon signed rank test

p = 0.002** pwr = 0.92

Student’s t test

20′ P-VEP A (µV)

p = 0.271 pwr = 0.2

Student’s t test

p = 0.243 pwr = 0.22

Student’s t test

p = 0.923 pwr = 0.05

Student’s paired t test

p = 0.684 pwr = 0.07

Student’s t test

FF M-VEP N160

Peak time (ms)

p = 0.065 pwr = 0.5

Student’s t test

p = 0.009** pwr = 0.81

Wilcoxon rank sum test

p = 0.422 pwr = 0.13

Wilcoxon signed rank test

p = 0.175 pwr = 0.27

Wilcoxon rank sum test

FF M-VEP A (µV)

p = 0.843 pwr = 0.05

Student’s t test

p = 0.375 pwr = 0.15

Student’s t test

p = 0.233 pwr = 0.23

Student’s paired t test

p = 0.071 pwr = 0.44

Student’s t test

M20° M-VEP N160

Peak time (ms)

p = 0.037* pwr = 0.6

Wilcoxon rank sum test

p = 0.019* pwr = 0.72

Wilcoxon rank sum test

p = 0.070 pwr = 0.49

Student’s paired t test

p = 0.048* pwr = 0.52

Student’s t test

M20° M-VEP A (µV)

p = 0.825 pwr 0.06

Student’s t test

p = 0.432 pwr = 0.13

Student’s t test

p = 0.113 pwr = 0.38

Student’s paired t test

p = 0.051 pwr = 0.51

Student’s t test

C8° M-VEP N160

Peak time (ms)

p = 0.076 pwr = 0.46

Student’s t test

p = 0.023* pwr = 0.68

Student’s t test

p = 0.686 pwr = 0.07

Student’s paired t test

p = 0.638 pwr = 0.07

Wilcoxon rank sum test

C8° M-VEP A (µV)

p = 0.800 pwr = 0.06

Student’s t test

p = 0.300 pwr = 0.19

Student’s t test

p = 0.144 pwr = 0.33

Student’s paired t test

p = 0.180 pwr = 0.26

Student’s t test

P300 peak time (ms)

p = 0.104 pwr = 0.4

Student’s t test

p = 0.275 pwr = 0.2

Student’s t test

p = 0.034* pwr = 0.62

Student’s paired t test

p = 0.027* pwr = 0.62

Student’s t test

P300 A (µV)

p = 0.268 pwr = 0.21

Student’s t test

p = 0.699 pwr = 0.07

Wilcoxon rank sum test

p = 0.309 pwr = 0.18

Student’s paired t test

p = 0.765 pwr = 0.06

Wilcoxon rank sum test

Reaction time (ms)

p = 0.278 pwr = 0.2

Student’s t test

p = 0.017* pwr = 0.73

Student’s t test

p = 0.046* pwr = 0.57

Student’s paired t test

p = 0.032* pwr = 0.60

Wilcoxon rank sum test

Visual acuity

p = 0.547 pwr = 0.09

Wilcoxon rank sum test

p = 0.508 pwr = 0.1

Wilcoxon rank sum test

p = 1 pwr = 0.05

Wilcoxon signed rank test

p = 0.689 pwr = 0.07

Student’s t test

MoCA

p = 0.383 pwr = 0.14

Wilcoxon rank sum test

p = 0.186 pwr = 0.28

Wilcoxon rank sum test

p = 0.138 pwr = 0.34

Wilcoxon signed rank test

p = 0.193 pwr = 0.25

Wilcoxon rank sum test

Table arrangement is similar to Table 3. Abbreviations are consistent with those of Table 3; MoCA, Montreal Cognitive Assessment. The intergroup comparison between the patient’s first visit and the controls is listed in the first column. The intergroup comparison between the patient’s last visit and the controls is listed in the second column. The within-subject comparison of the patient’s first and last visits is in the third column, and the trends over all follow-ups are depicted in the last column. The table lists type I error (p) and 1type II error (pwr) for all tests. The differences were considered statistically significant if the probability level (p) was below an alpha level of 0.05. A star symbol marks the statistical significance of the tests used (*~ p < 0.05; **~ p < 0.01). All significant comparisons are also printed in bold

Our laboratory norm for the P100 peak time was exceeded only twice in 232 monocular VEPs throughout the whole course of the follow-up study. These two abnormal findings for 40′ P-VEPs were in one eye in patient No. 5 (P100 peak time 126 ms, interocular difference 24 ms) during the second visit, with complete recovery at the next four visits (peak time average 110 ms, interocular difference average 4 ms), and in patient No. 10 (P100 peak time 134 ms, interocular difference 18 ms) at the last visit.

M-VEPs

We did not find any significant differences between patients and controls in the N160 interpeak amplitudes of all M-VEP types during the first (p > 0.800) or last visit (p > 0.300). For the N160 peak time, we found a significant intergroup difference during the first visit for peripheral M-VEPs only (p = 0.037). All the M-VEPs recorded in patients during the last visit differed significantly from those of the control group (p < 0.023). There were no differences in M-VEPs between the beginning and end of follow-up for amplitudes (p > 0.113) or N160 peak times of central and full-field M-VEPs (p > 0.422) (see Table 4). However, the intervisit difference in peripheral M-VEPs (6.0 [− 2.5 10.0] ms) was close to the level of significance (p = 0.070), which confirmed the trend analysis (1.9 [− 0.1 3.7] ms/year, p = 0.048). (Figure. 2 shows the significant trend of the peripheral M-VEPs N160 peak time over the follow-up.)

M-VEP latency values above the laboratory limit were observed in 84 out of 348 monocular responses in five out of 11 patients recorded during the study. Among the five patients who showed abnormal M-VEP results, No. 8 had binocular N160 peak prolongations of expanding/contracting macular stimulation only during the third VEP examination with complete recovery during the following visits. Patient No. 6 initially showed normal M-VEPs and later displayed binocular worsening of some motion responses, but during the last visit, the N160 peak times of the majority of responses returned to normal (for details, see Fig. 3). The remaining three patients, Nos. 2, 7 and 10, who exhibited abnormal binocular M-VEPs since inclusion in this study and were infected with HIV for 2.9–8 years displayed prolonged N160 peak times in all motion variants. These patients showed transient worsening of the M-VEP measures and subsequent transient improvement of some responses during the observation period.
Fig. 3

An example of the electrophysiological responses over five visits (patient No. 6). The black lines indicate the upper borders (M + 2.5 SD) of the peak time norm with respect to the age of the subject, except the line in the last column, which represents reaction time median (352 ms). Abbreviations are consistent with those in Table 3. Monocular pattern-reversal VEPs (40′ and 20′) with stable P100 peak times during the monitoring period are plotted in the first two columns. Motion-onset VEPs are graphed in the next three columns. Initially, normal FF M-VEP responses displayed gradual prolongation of N160 peak times during the third and fourth visits in the left eye, and they partially returned to normal during the last visit. Normal M20° M-VEP responses during the first two visits were followed by binocular gradual prolongation of the N160 peak times during the next two visits, and complete recovery appeared during the last visit. The C8° M-VEPs N160 peak times prolonged during the third and fourth visits, which were more highly expressed in the right eye, and they returned to the norm at the last visit. Binocular visual oddball ERP—P300 peak times, which were relatively stable during follow-up, at the first visit 380 ms, last visit 388 ms, and reaction time (first visit 368 ms, last visit 352 ms) are depicted in the last two columns

Visual ERPs

We did not find any significant differences between the patient and control groups in either the P300 peak times (p > 0.104) or the amplitudes (p > 0.268), and the laboratory norm for the P300 peak time was not exceeded during follow-up. Comparison of the P300 peak time difference (8.0 [12.0 2.0] ms) between the first and last visits showed a significant difference (p = 0.034), which was consistent with the trend analysis (see the significant trend of the P300 peak time in Fig. 2 and Tables 3, 4) of the P300 peak prolongation (3.3 [0.6 5.8] ms/year, p = 0.027).

Behavioral results

We did not find any differences in visual acuity between groups (p > 0.508) or in the trend analysis (0.00 [− 0.01 0.03] –/year, p = 0.689), nor did we find intraindividual differences (p = 1). Patient reaction time was not significantly delayed (p = 0.278) compared to that of controls at the first visit; however, it was prolonged at the end of follow-up (p = 0.017), which also confirmed the trend analysis (6.4 [0.31 11.5] ms/year, p = 0.032). (Figure. 2 shows the significant trend of reaction time, and Tables 3, 4 present the relevant statistics.)

Montreal Cognitive Assessment

The cognitive results using the MoCA did not differ between patients and controls (p > 0.186), between the first and last visits of the HIV patients (p = 0.138) or the trend (0.00 [− 0.01 0.00] points/year, p = 0.193) (Table 4). We did not find any pathology with only one exception; patient No. 9 received a score of 25/30 points at the last visit, the borderline value of the normal limit, but his ERP peak time and reaction time did not differ from the previous examination.

Clinical parameters

Among the observed clinical parameters, only CD4 cell counts showed a statistically significant trend over time (116 [− 11 176] CD4 cells/year, p = 0.046) (Fig. 2). The number of copies of HIV RNA did not differ in trend between the first and last visit examinations (p > 0.477).

Evoked potentials and clinical parameters

A Spearman rank correlation test of the electrophysiological parameters with statistically significant trends (20′ P-VEP P100 peak time, peripheral M-VEP N160 peak time, P300 peak time and reaction time) did not show any statistically significant relationship (p > 0.221) with visual acuity, CD4 cell count, HIV RNA copies in plasma or CDC score.

Discussion

Summary

We did not find any obvious changes in the pattern-reversal VEPs in HIV+ patients during the course (2.5 years) of the follow-up study. Our findings strongly support the widely accepted proposition that HIV patients on cART therapy have a substantially reduced risk of opportunistic infection involvement, so optic nerve function seems to be preserved. Although P100 peak latencies were in the normal range, their trend over the follow-up period of 1.0 [0.6 1.3] ms/year was approximately threefold higher than the dependence observed by Kuba et al. [25] of 0.3 [0.2 0.3] ms/year in a cross-sectional study over an age span of 15–85 years. Such a comparison is not straightforward since our results arose from longitudinal observation; however, the difference is so distinct that it is worth investigating in a future study.

The most pronounced electrophysiological changes observed involved the function of the magnocellular system and/or the dorsal stream of the visual pathway. Our results suggest that optic nerve axons or motion-onset specific areas V3/V3A and MT of the temporo-occipital and parietal cortices could be affected. These CNS changes manifested mainly as a transient worsening of the M-VEP results and a subsequent improvement in some responses during the observation period without a clearly apparent gradual progression of M-VEP abnormalities. One potential explanation for this progression of CNS changes is that low-level viral replication or indirect inflammatory processes may lead to a slight dysregulation of neuronal responses, and/or it could be a manifestation of cART neurotoxicity or the effect of other substances on brain metabolic function [26, 27, 28].

Among HIV-infected patients, cognitive impairment was and is one of the most feared complications. The ERP results in this study did not show significant differences between patient and control groups; however, we would point out that the diagnostic use of ERPs is limited by the fact that even in normal subjects; P300 latencies display high interindividual variability. For clinical use, a longitudinal evaluation of P300 peak latencies might be more promising in capturing and monitoring pathology or evaluating a therapy effect in individual patients.

This idea was supported by the significant difference observed in P300 peak time between the first and last visits and by the P300 peak time trend analysis. In the aforementioned cross-sectional study [25], cognitive processing was more strongly influenced by aging than were the “lower” levels of the visual system, and despite its high variability, P300 peak time increased 2.0 [1.7 2.3] ms/year. Findings in HIV patients suggested a faster slowing of the P300 peak time (3.3 [0.6 5.8] ms/year) than that caused by aging in a healthy population; however, this trend is not as distinct as that of the P100 and N160 peak times (see Fig. 2). In HIV-infected patients, functional disproportion among different brain regions was also reported by Ances et al. [29] and Wilson et al. [30].

Our observation of the P300 peak time trend seemingly contradicts findings by Samuelsson et al. in a prospective study following 28 HIV patients for up to 7 years [31]. They observed no auditory P300 peak time deterioration in their group. We extracted P300 peak latencies from Fig. 1 in Samuelsson et al. [31] (see Fig. 4 left plot [A], which depicts a reconstruction of Fig. 1 from their original paper), and we analyzed these data for a P300 peak time trend. Using our analysis approach, we found a similar significant relationship with a stronger decline of 4.6 [2.6 8.0] ms/year (p = 0.002) (see Fig. 4 right plot [B] for the group trend in their data).
Fig. 4

Left plot A depicts a reconstruction of Fig. 1 from Samuelsson et al. [31]. The P300 peak times were recorded in an auditory oddball paradigm for 18 HIV patients. The right plot B shows the same data in a relative representation similar to our study, with the group trend as a solid black line. The gray line represents the control group trend described by Kuba et al. [25]

These results show that cognitive decline might be present despite cART. Future studies with appropriate long-term monitoring of HIV patients and controls are needed to test this hypothesis. In addition, the neuroimaging results regarding ongoing brain volume loss in HIV+ individuals despite cART are not consistent. Although brain volume loss was observed in some studies [32, 33, 34], it was not observed in others [35].

In contrast to our ERP results, which did not show significant differences between patients and controls, auditory ERP studies of virally suppressed HIV patients by Polich and Basho [36] and Chao et al. [17] suggest that cognitive impairment in HIV patients on retroviral medication is evident as a longer P3a peak time, and Chao et al. also indicate that P3b peak time and amplitudes are reduced compared to those of the control subjects. We speculate that such differences might be due to the variations in demographic and clinical characteristics among study populations. Moreover, a comparison between our study, which focused on the visual pathway and visual information processing, and the results of previous articles using auditory ERP examination is limited.

The comparison of reaction time differences between the first and last visits showed significant prolongation, which confirmed the trend analysis. Reaction time slowing during the monitoring period points to hand agility deterioration, which is a well-known feature of psychomotor dysfunction in the HIV+ population [37, 38].

When compared to our population norm, the one borderline finding on the MoCA (25/30 points in patient No. 9) without concurrent changes in ERP peak time and reaction time indicated that psychological testing provides different information about cognitive processing than does electrophysiological examination (see Tables 2, 4). The lack of a trend in MoCA scores during the follow-up study contrasts with the significant trend in the ERP and reaction time results and suggests that electrophysiological parameters may be more sensitive in diagnosing subtle changes in CNS function [39].

The lack of a correlation between visual acuity, CD4 cell count, HIV RNA copies in plasma and CDC score on one side and VEP and ERP parameters on the other side suggests that these electrophysiological examinations provide some additional information to the commonly used clinical parameters. The lack of correlation between clinical and electrophysiological parameters in our HIV group could also be explained by the fact that patients did not have severe immunosuppression. For example, Polich et al. [16] described an increase in the P300 peak time with increased HIV viral load, but for most patients in our study, this parameter was at or near zero during the monitoring period (see Table 1).

Conclusion

The goal of this longitudinal study was to monitor the function of the visual pathway and visual cortex in virally suppressed HIV+ patients by using pattern-reversal VEPs, motion-onset VEPs and visual ERPs.

The P-VEPs did not indicate optic nerve dysfunction during the observation period. The first individually detectable decline in CNS function observed in five out of 11 HIV+ patients was impairment in the magnocellular system and/or the dorsal stream of the visual pathway. Similar results for high motion-onset VEP sensitivity in the visual pathway and CNS functional changes have previously been reported by our laboratory [12, 40, 41].

Longitudinal evaluation revealed changes in VEPs, ERPs and reaction time, suggesting an accelerated aging process in the visual system and cognitive processing with a decline in psychomotor speed.

Limitations

The limited number of patients examined and the wide range in duration of HIV infection are shortcomings of this study. Unfortunately, the actual duration of infection was known for only a small number of patients, and the duration of infection was derived in most subjects from the first positive HIV antibody test. An electroretinogram (ERG), pattern ERG, multifocal ERG and fundoscopic examination was performed only once, at the end of the longitudinal study, in six out of 11 patients (patient Nos. 2, 3, 5, 6, 7 and 8) with completely normal results. The remaining patients were not willing to undergo this relatively long and burdensome examination.

Notes

Acknowledgements

Supported by Charles University in Prague, Czech Republic, project Progress Q40/07.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest for any of the authors. The authors have nothing to disclose. J.S., J.K., Z.K., M.K., P.G., J.S., F.V. and J.L. were supported by a grant from Charles University in Prague, Czech Republic - Progress Q40/07.

Statement of human rights

The experiment was performed only on humans and was procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation. The Ethical Committee of the University Hospital in Hradec Kralove gave ethical approval. All experiments were conducted in accordance with the Declaration of Helsinki.

Informed consent

Informed consent for the electrophysiological examination was obtained from each subject.

Statement on the welfare of animals

No animals were used in this study.

Ethical approval

The Ethical Committee of the University Hospital in Hradec Kralove gave ethical approval. All experiments were conducted in accordance with the Declaration of Helsinki.

References

  1. 1.
    Jabs DA (1995) Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 93:623–683Google Scholar
  2. 2.
    Mwanza J-C, Nyamabo LK, Tylleskär T, Plant GT (2004) Neuro-ophthalmological disorders in HIV infected subjects with neurological manifestations. Br J Ophthalmol 88:1455–1459.  https://doi.org/10.1136/bjo.2004.044289 CrossRefGoogle Scholar
  3. 3.
    Price RW, Spudich S (2008) Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197:S294–S306.  https://doi.org/10.1086/533419 CrossRefGoogle Scholar
  4. 4.
    Valcour V, Sithinamsuwan P, Letendre S, Ances B (2011) Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep 8:54–61.  https://doi.org/10.1007/s11904-010-0070-4 CrossRefGoogle Scholar
  5. 5.
    Schouten J, Cinque P, Gisslen M et al (2011) HIV-1 infection and cognitive impairment in the cART era: a review. Aids 25:561–575.  https://doi.org/10.1097/QAD.0b013e3283437f9a CrossRefGoogle Scholar
  6. 6.
    Malessa R, Heuser-Link M, Brockmeyer N et al (1989) Evoked potentials in neurologically asymptomatic persons during the early stages of HIV infection. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb 20:257–266Google Scholar
  7. 7.
    Farnarier G, Somma-Mauvais H (1990) Multimodal evoked potentials in HIV infected patients. Electroencephalogr Clin Neurophysiol Suppl 41:355–369Google Scholar
  8. 8.
    Somma-Mauvais H, Farnarier G (1992) Evoked potentials in HIV infection. Neurophysiol Clin 22:369–384.  https://doi.org/10.1016/S0987-7053(05)80095-4 CrossRefGoogle Scholar
  9. 9.
    Pierelli F, Soldati G, Zambardi P et al (1993) Electrophysiological study (VEP, BAEP) in HIV-1 seropositive patients with and without AIDS. Acta Neurol Belg 93:78–87Google Scholar
  10. 10.
    Malessa R, Agelink MW, Diener H-C (1995) Dysfunction of visual pathways in HIV-1 infection. J Neurol Sci 130:82–87.  https://doi.org/10.1016/0022-510X(95)00002-J CrossRefGoogle Scholar
  11. 11.
    Szanyi J, Kremlacek J, Kubova Z et al (2017) Pattern- and motion-related visual evoked potentials in HIV-infected adults. Doc Ophthalmol 134:45–55.  https://doi.org/10.1007/s10633-016-9570-x CrossRefGoogle Scholar
  12. 12.
    Kuba M, Kubová Z, Kremláček J, Langrová J (2007) Motion-onset VEPs: characteristics, methods, and diagnostic use. Vision Res 47:189–202.  https://doi.org/10.1016/j.visres.2006.09.020 CrossRefGoogle Scholar
  13. 13.
    Clifford DB (2008) HIV-associated neurocognitive disease continues in the antiretroviral era. Top HIV Med 16:94–98Google Scholar
  14. 14.
    Heaton RK, Franklin DR, Ellis RJ et al (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17:3–16.  https://doi.org/10.1007/s13365-010-0006-1 CrossRefGoogle Scholar
  15. 15.
    Clifford DB, Ances BM (2013) HIV-associated neurocognitive disorder. Lancet Infect Dis 13:976–986.  https://doi.org/10.1016/S1473-3099(13)70269-X CrossRefGoogle Scholar
  16. 16.
    Polich J, Ilan A, Poceta JS et al (2000) Neuroelectric assessment of HIV: EEG, ERP, and viral load. Int J Psychophysiol 38:97–108.  https://doi.org/10.1016/S0167-8760(00)00133-1 CrossRefGoogle Scholar
  17. 17.
    Chao LL, Lindgren JA, Flenniken DL, Weiner MW (2004) ERP evidence of impaired central nervous system function in virally suppressed HIV patients on antiretroviral therapy. Clin Neurophysiol 115:1583–1591.  https://doi.org/10.1016/j.clinph.2004.02.015 CrossRefGoogle Scholar
  18. 18.
    da Silva AC, Pinto FR, Matas CG (2007) Long latency auditory evoked potentials in adults with HIV/Aids. Pro Fono 19:352–356CrossRefGoogle Scholar
  19. 19.
    Ward JW, Slutsker L, Buehler JW, Jaffe HW, Berkelman RL (1993) revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 41:1–19Google Scholar
  20. 20.
    Hammer SM, Eron JJ, Reiss P et al (2008) Antiretroviral treatment of adult HIV infection. JAMA 300:555.  https://doi.org/10.1001/jama.300.5.555 CrossRefGoogle Scholar
  21. 21.
    Kremlácek J, Kuba M, Kubová Z, Chlubnová J (2004) Motion-onset VEPs to translating, radial, rotating and spiral stimuli. Doc Ophthalmol 109:169–175CrossRefGoogle Scholar
  22. 22.
    Kuba M, Kubova Z (1992) Visual evoked potentials specific for motion onset. Doc Ophthalmol 80:83–89CrossRefGoogle Scholar
  23. 23.
    Valcour VG (2011) Evaluating cognitive impairment in the clinical setting: practical screening and assessment tools. Top Antivir Med 19:175–180Google Scholar
  24. 24.
    R Core Team (2018) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/
  25. 25.
    Kuba M, Kremláček J, Langrová J et al (2012) Aging effect in pattern, motion and cognitive visual evoked potentials. Vision Res 62:9–16.  https://doi.org/10.1016/j.visres.2012.03.014 CrossRefGoogle Scholar
  26. 26.
    González-Scarano F, Martín-García J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81.  https://doi.org/10.1038/nri1527 CrossRefGoogle Scholar
  27. 27.
    Garveya LJ, Pavese N, Politis M et al (2014) Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS.  https://doi.org/10.1097/01.aids.0000432467.54003.f7 Google Scholar
  28. 28.
    Cysique LA, Brew BJ (2009) Neuropsychological functioning and antiretroviral treatment in HIV/AIDS: a review. Neuropsychol Rev.  https://doi.org/10.1007/s11065-009-9092-3 Google Scholar
  29. 29.
    Ances BM, Vaida F, Yeh MJ et al (2010) HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 201:336–340.  https://doi.org/10.1086/649899 CrossRefGoogle Scholar
  30. 30.
    Wilson TW, Heinrichs-Graham E, Becker KM et al (2015) Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV-infected older adults. Hum Brain Mapp 36:897–910.  https://doi.org/10.1002/hbm.22674 CrossRefGoogle Scholar
  31. 31.
    Samuelsson K, Pirskanen-Matell R, Bremmer S et al (2006) The nervous system in early HIV infection: a prospective study through 7 years. Eur J Neurol 13:283–291.  https://doi.org/10.1111/j.1468-1331.2006.01173.x CrossRefGoogle Scholar
  32. 32.
    Cardenas VA, Meyerhoff DJ, Studholme C et al (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15:324–333.  https://doi.org/10.1080/13550280902973960 CrossRefGoogle Scholar
  33. 33.
    Thompson PM, Dutton RA, Hayashi KM et al (2005) Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline. Proc Natl Acad Sci USA 102:15647–15652.  https://doi.org/10.1073/pnas.0502548102 CrossRefGoogle Scholar
  34. 34.
    Kuper M, Rabe K, Esser S et al (2011) Structural gray and white matter changes in patients with HIV. J Neurol 258:1066–1075.  https://doi.org/10.1007/s00415-010-5883-y CrossRefGoogle Scholar
  35. 35.
    Sanford R, Ances BM, Meyerhoff DJ et al (2018) Longitudinal trajectories of brain volume and cortical thickness in treated and untreated primary human immunodeficiency virus infection. Clin Infect Dis.  https://doi.org/10.1093/cid/ciy362 Google Scholar
  36. 36.
    Polich J, Basho S (2002) P3a and P3b auditory ERPs in HIV patients receiving anti-viral medication. Clin Electroencephalogr 33:97–101CrossRefGoogle Scholar
  37. 37.
    DeVaughn S, Müller-Oehring EM, Markey B et al (2015) Aging with HIV-1 infection: motor functions, cognition, and attention—a comparison with Parkinson’s disease. Neuropsychol Rev 25:424–438.  https://doi.org/10.1007/s11065-015-9305-x CrossRefGoogle Scholar
  38. 38.
    Ogunrin AO, Odiase FE, Ogunniyi A (2007) Reaction time in patients with HIV/AIDS and correlation with CD4 count: a case-control study. Trans R Soc Trop Med Hyg 101:517–522.  https://doi.org/10.1016/j.trstmh.2006.10.002 CrossRefGoogle Scholar
  39. 39.
    Kim WJ, Ku NS, Lee YJ et al (2016) Utility of the Montreal Cognitive Assessment (MoCA) and its subset in HIV-associated neurocognitive disorder (HAND) screening. J Psychosom Res 80:53–57.  https://doi.org/10.1016/j.jpsychores.2015.11.006 CrossRefGoogle Scholar
  40. 40.
    Kubová Z, Szanyi J, Langrová J et al (2006) Motion-onset and pattern-reversal visual evoked potentials in diagnostics of neuroborreliosis. J Clin Neurophysiol 23:416–420.  https://doi.org/10.1097/01.wnp.0000218241.95542.4f CrossRefGoogle Scholar
  41. 41.
    Kubová Z, Kremláček J, Vališ M et al (2010) Visual evoked potentials to pattern, motion and cognitive stimuli in Alzheimer’s disease. Doc Ophthalmol 121:37–49.  https://doi.org/10.1007/s10633-010-9230-5 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathological PhysiologyCharles University - Faculty of Medicine in Hradec KraloveHradec KraloveCzech Republic
  2. 2.Department of Infectious DiseasesFaculty Hospital in Hradec KraloveHradec KraloveCzech Republic
  3. 3.Department of Epidemiology, Faculty of Military Health SciencesUniversity of Defence in Hradec KraloveHradec KraloveCzech Republic

Personalised recommendations