Pituitary DOI 10.1007/s11102-014-0613-6
Comparison of multifocal visual evoked potential, static automated perimetry, and optical coherence tomography findings for assessing visual pathways in patients with pituitary adenomas Nidan Qiao • Yichao Zhang • Zhao Ye • Ming Shen • Xuefei Shou • Yongfei Wang Shiqi Li • Min Wang • Yao Zhao
•
Ó Springer Science+Business Media New York 2014
Abstract Background There have been no studies investigating the correlation between structural [thickness of the retinal nerve fiber layer (RNFL) as determined by optical coherence tomography (OCT)] and functional [Humphrey visual field (HVF) or visual evoked potential (VEP) amplitude] measures of optic nerve integrity in patients with pituitary adenomas (PA). Methods Patients with PAs were recruited between September 2010 and September 2013. OCT, standard automated perimetry (SAP), and multifical VEP (mfVEP) were performed. Agreement between OCT, SAP, and mfVEP values in classifying eyes/quadrants was determined using AC1 statistics. Pearson’s correlation was used to examine relationships between structural and functional data. Results In total, 88.7 % of the eyes tested showed abnormal SAP findings and 93.7 % showed abnormal mfVEP findings. Only 14.8 % of the eyes showed abnormal OCT findings. The agreement between SAP and mfVEP findings was 88.9 % (AC1 = 0.87). The agreement
Nidan Qiao and Yichao Zhang have contributed equally to this work. N. Qiao Y. Zhang Z. Ye M. Shen X. Shou Y. Wang S. Li Y. Zhao (&) Shanghai Pituitary Tumor Center, Department of Neurosurgery, HuaShan Hospital, Shanghai Medical College, Fudan University, 12# Middle Wulumuqi Road, Shanghai 200040, China e-mail: [email protected] M. Wang (&) Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai 200031, China e-mail: [email protected]
between OCT and mfVEP findings was 24.2 % (AC1 = -0.52), and that between OCT and SAP findings was 21.5 % (AC1 = -0.56). The correlation values between RNFL thickness and the functional measurements were -0.601 for the mfVEP score (P = 0.000) and -0.441 for the SAP score (P = 0.000). The correlation between the mfVEP and SAP scores was -0.617 (P = 0.000). Conclusions mfVEP, SAP, and OCT provided complementary information for detecting visual pathway abnormalities in patients with PAs. Good agreement was demonstrated between SAP and mfVEP and quantitative analysis of structure–function measurements revealed a moderate correlation. Keywords
mfVEP SAP OCT Visual function
Introduction Pituitary adenomas (PAs) are one of the most common types of brain tumors, accounting for 15 % of all intracranial neoplasms [1]. Visual disturbances are noted when the tumor grows beyond the sella and compresses the optic nerve. Typical neuro-ophthalmic features include progressive bilateral slow and asymmetric deterioration in visual field defects and optic disc changes. Static automated perimetry (SAP) assessments, such as the Humphrey visual field (HVF) test, provide a subjective measure of visual function that is considered to be the clinical ‘‘gold standard’’ for documenting loss of visual sensitivity. However, in the clinical setting, patients are not always cooperative and attentive well, resulting in unreliable perimetry readings. Multifocal visual evoked potential (mfVEP) is a relatively new technical approach for assessing the integrity of the visual pathway that eliminates
123
Pituitary
the subjectivity and patient learning process required for static automated perimetry. VEP testing for PAs has been used to assess subjects presenting with initial visual disturbances. However, the clinical usefulness of full-field VEP is limited by the fact that it provides a summed response of all neuronal elements stimulated. Recent developments using multifocal stimulation techniques have uncovered a new methodology for assessing visual function. mfVEP testing is beginning to show promise for the management of patients with glaucoma [2, 3], and interesting findings are becoming available from studies of patients with ischemic optic neuropathy and optic neuritis [4, 5]. Peripapillary retinal nerve fiber layer (RNFL) thickness has been proposed as a structural marker of axonal loss in the optic nerve. The RNFL will show retrograde degeneration following damage to the optic nerve or the optic tract in the brain. The most widely used method to measure RNFL thickness is optical coherence tomography (OCT), which utilizes the echo time delay of back-scattered light using an interferometer and a low-coherence light to perform cross-sectional imaging of the retina [6]. Strong associations between structural (thickness of RNFL as determined by OCT) and functional (HVF or amplitude of VEP) measures of optic nerve integrity in patients with optic neuritis or multiple sclerosis have been demonstrated in several studies [7, 8]. However, there have been no studies assessing the correlation between structural and functional measures of optic nerve integrity in PA patients. Therefore, the purpose of this study was to compare the sensitivity of mfVEP for detecting abnormalities in the visual pathway of PA patients with the sensitivities of static automated perimetry, HVF testing, and/or imaging of the nerve fiber layer with OCT.
Methods Subjects This study had a cross-sectional design. The procedures followed the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. Patients with PAs were recruited from Huashan Hospital between September 2010 and September 2013. PA was confirmed by pathology. Patients underwent a thorough ophthalmic examination by experienced ophthalmologists, which included pupil, anterior, and posterior segment examination. Patients with other ocular diseases were excluded. SAP was performed using the Humphrey 750 Visual Field Analyzer (Zeiss-Humphrey Systems, Dublin, CA, USA) and a central 30-2 threshold protocol. Fixation loss
123
was less than 20 %. The false positive error rate was less than 20 % and the false negative error rate was less than 20 %. To allow a comparison of visual-field sensitivity to the mfVEP responses, estimates of sensitivity for each sector of the multifocal stimulus were obtained from the visual field values (total deviation). These estimates were obtained using a computer (MATLAB software; The Mathworks, Natick, MA, USA). mfVEP recordings were obtained using VERIS system (Electro-Diagnostic Imaging, San Mateo, CA, USA). The stimulus was a 60-sector, cortically scaled dartboard pattern with a mean luminance of 66 cd/m2 and a Michelson contrast of 95 %. The dartboard pattern reversed at a frame rate of 75 Hz. Patients were instructed to fixate on the center of the dartboard pattern (marked with an ‘X’) with their best refractive correction in place, and eye position was monitored continuously by the examiner via the camera display provided in the VERIS system. Three recording channels were connected to gold cup electrodes. For the midline channel, electrodes were placed 4 cm above the inion (active), at the inion (reference), and on the earlobe (ground). For the other two active channels, the same ground and reference electrodes were used, but the active electrode was placed 1 cm up and 4 cm lateral to the inion on either side. Two 7-min recordings from each eye were obtained, and averaged responses were used. The channel providing the best recording for each sector was selected during the analysis as the ‘‘best channel response.’’ The analyses were performed with programs written in MATLAB. For each sector, monocular amplitude (MAMP), interocular amplitude (IAMP), monocular latency (MLAT), and interocular latency (ILAT) were calculated by comparing the amplitude or latency of the mfVEP from a particular sector of the stimulus array to the mean and standard deviation of the Portland normative data for the corresponding location, and assigning a probability value. The RNFL was assessed by RTVue (Optovue, Fremont, CA, USA) using a three-dimensional disc and optic nerve head (ONH) protocols. The OCT reports measurements for four sectors: superior, temporal, nasal, and inferior.
Topographic correspondence between SAP, OCT, and mfVEP Topographical correlations between SAP, OCT, and mfVEP were estimated based on a previous study that examined the anatomical relationships between the visual field and regions of the ONH and was used earlier in glaucoma research [9]. The SAP and mfVEP were divided into four quadrants corresponding to the four-quadrant output of the OCT (Fig. 1). The nasal sector was excluded
Pituitary Fig. 1 A topographic map relating quadrants from OCT measurements and the corresponding quadrants from the SAP and mfVEP tests. For patients tested with the SAP 30-2 paradigm, only the areas corresponding to the 24-2 map were analyzed
from topographic comparisons due to limited representation on the SAP and mfVEP tests.
Table 1 Global measurements of SAP, OCT and mfVEP
Criteria used to define total abnormality for each technique
Left
1.97
92.65
0.85
Right Total
1.68 1.83
92.58 92.62
0.77 0.81
To assess overall mfVEP performance, we defined an eye as abnormal if MAMP and IAMP probability plots met the following criteria: at least five adjacent points with P \ 0.05 and at least four adjacent points with P \ 0.01. The visual field was defined as abnormal if the mean deviation of the total deviation plot had a P \ 0.05. The OCT result was defined as being abnormal if the overall RNFL thickness was significantly thinner than norms provided by the instrument (P \ 0.05). Criteria used to define abnormal quadrants for each technique OCT: RFNL thickness of that quadrant was significantly thinner than the norms (P \ 0.05). SAP: at least two adjacent test points in a quadrant depressed by P \ 0.01, or at least three adjacent points depressed by P \ 0.05 with one of the points depressed by P \ 0.01. HVF inferior and superior sector clusters could not include more than one peripheral rim test location. mfVEP: a quadrant was defined as abnormal if MAMP met the following cluster criteria: at least two adjacent test points in a quadrant depressed by P \ 0.01, or at least three adjacent points depressed by P \ 0.05. Severity of field involvement was also analyzed using the probability plots displayed on the reports. HVF data was analyzed using total deviation probability plots. Each probability point was assigned a numerical value (P [ 5 % = 0; P \ 5 % = 1; P \ 2 % or P \ 1 % = 2; and P \ 0.5 % = 3). The numerical values were then averaged, giving a total severity score for each quadrant ranging from 0 to 3. The mfVEP report displayed a similar probability plot for amplitude deviation, and these points were assigned
SAP score
OCT RNFL thickness (lm)
mfVEP score
SAP static automated perimetry, OCT optic coherence tomography, RNFL retinal nerve fiber layer, mfVEP multifocal visual evoked potential
Table 2 Percent of eyes being defined as abnormal Percent of abnormal
SAP (%)
OCT (%)
mfVEP (%)
Temporal
88.5
27.9
95.2
Superior Inferior
95.3 89.9
7.8 9.2
64.0 77.6
Total
88.7
14.8
93.7
SAP static automated perimetry, OCT optic coherence tomography, mfVEP multifocal visual evoked potential
numerical values and averaged for each quadrant, again giving a severity score for each quadrant ranging from 0 to 2 (P [ 5 % = 0; P \ 5 % = 1; and P \ 1 % = 2). Statistics analysis Statistical analysis was performed using SPSS 11.0 for Windows (SPSS Inc, Chicago, IL, USA). The Student’s t test was used to compare means. Agreement between OCT, SAP, and mfVEP in classifying eyes/quadrants are presented as AC1 statistics. Pearson’s correlation was used to examine relationships between structural and functional data.
Results Global measurements of SAP, OCT, and mfVEP The averaged SAP score, RNFL thickness measured by OCT, and mfVEP scores are shown in Table 1.
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Pituitary Table 3 Total agreement between OCT, SAP and mfVEP Normal
Abnormal
Agreement
AC1
Normal
4 (3.4 %)
4 (3.4 %)
88.9 %
0.87
Abnormal
9 (7.7 %)
100 (85.5 %)
Normal
14 (11.3 %)
94 (75.8)
24.2 %
-0.52
Abnormal
0 (0.0 %)
16 (12.9 %)
8 (6.6 %) 95 (78.5 %)
0 (0.0 %) 18 (14.9 %)
21.5 %
-0.56
mfVEP SAP
mfVEP OCT
OCT SAP Normal Abnormal
AC1 agreement coefficient, SAP static automated perimetry, OCT optic coherence tomography, mfVEP multifocal visual evoked potential
Table 4 Topographic agreement between OCT, SAP and mfVEP
Fig. 2 Abnormal monocular amplitude plot. a Left eye. b Right eye. Sectors marked in black indicate no significant difference from the normative database. Colored sectors denote significantly reduced amplitudes. Saturated color: P \ 0.01; desaturated color: P \ 0.05
Agreement (AC1)
mfVEP versus SAP
mfVEP versus OCT
OCT versus SAP
Temporal
89.8 % (0.88)
31.4 % (-0.31)
34.4 % (-0.28)
Superior
65.0 % (0.48)
42.4 % (-0.05)
11.6 % (-0.77)
Inferior
76.9 % (0.69)
31.4 % (-0.34)
18.2 % (-0.64)
AC1 agreement coefficient, SAP static automated perimetry, OCT optic coherence tomography, mfVEP multifocal visual evoked potential
Abnormality detected by SAP, OCT, and mfVEP The performance of SAP, OCT, and mfVEP for detecting abnormalities in the visual pathway of patients with PAs and the percent of eyes defined as abnormal by each of the three tests are reported in Table 2. In total, 88.7 % of the eyes tested were defined as abnormal on SAP and 93.7 % were defined as abnormal on mfVEP. Conversely, only 14.8 % of the eyes showed abnormal findings on OCT. Examples of abnormal eyes are shown in Fig. 2. Table 2 also illustrates the percentage of quadrants identified as abnormal by each test; the number of abnormal quadrants was high for SAP and mfVEP. The temporal sector was the most affected on both OCT and mfVEP tests. For SAP, no statistical significance between the three sectors was observed. Agreement between mfVEP, SAP, and OCT The mfVEP results reported 88.7 % of eyes as abnormal compared with 93.2 % using SAP (Table 3). The agreement between the two tests was 88.9 % (AC1 = 0.87).
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However, agreement between OCT and SAP tests was only 21.5 % (AC1 = –0.56). Similarly, agreement between OCT and mfVEP was only 24.2 % (AC1 = –0.52). Topographic agreement between OCT, SAP, and mfVEP was also analyzed (Table 4). Agreement between the quadrants for the two functional tests ranged from 65.0 to 89.8 %, which is much higher than the agreement between OCT and mfVEP or agreement between OCT and SAP. Quantitative comparisons between OCT, mfVEP, and SAP In addition to qualitative analysis, relationships between OCT RNFL thickness, mfVEP score, and SAP score were studied quantitatively using Pearson’s correlation analysis. The correlation between OCT RNFL thickness and the functional measurements were as follows: –0.601 for mfVEP score (P = 0.000) and –0.441 for SAP score (P = 0.000). The correlation between mfVEP and SAP scores was –0.617 (P = 0.000).
Pituitary
Discussion Studies evaluating structure—function relationships are important both for diagnosis and follow-up of patients with a range of visual pathway diseases. In this study, we examined the relationship between structural and functional measures of optic nerve dysfunction in patients with PAs. Compared with SAP, mfVEP has the advantage of being an objective test of local visual function and does not require patients to make a decision; some patients with PAs may have cognitive dysfunction [10, 11], which adversely affects their performance on the SAP test. The multifocal nature of our electrophysiological examination permitted topographic evaluation and comparisons of these three measures. The ability of mfVEP to detect abnormalities was confirmed by assessment of abnormal eyes. For instance, MAMP plot was abnormal in 93.7 % of the eyes, whereas the temporal quadrant made it possible to identify 95.2 % of eyes as abnormal. SAP identified abnormalities in up to 88.7 % of eyes. Therefore, our results indicate that mfVEP may be used as a complementary method for quantifying visual function loss. In agreement with previous reports on patients with optic neuritis and multiple sclerosis [7, 8, 12, 13], we found that functional tests (mfVEP and SAP) detected more abnormalities in patients with PAs than the structural test. This result was expected because (1) mfVEP detects demyelination while the OCT does not; and (2) OCT measurements are limited to the posterior visual pathway assessed at the retinal level, whereas the functional tests measure integrity of both the anterior and posterior visual pathways. The OCT will not detect or underestimate the defects when retrograde axonal degeneration is partial or not significant, which is very common in patients with PAs. The largest visual field reduction was observed in the temporal quadrants on both mfVEP and OCT. This was in accordance with clinical and pathological studies indicating a particular susceptibility of the temporal bundle fibers for damage in patients with PAs. In most PA patients with visual dysfunction, the most severe compression was at the center of the optic chiasm, which comes from the temporal quadrants. The agreement between the two functional tests (SAP and mfVEP) was stronger than the agreement between the structural and individual functional tests. This is in accordance with previous studies on optical neuritis and multiple sclerosis [7, 8]. In the present study, we also evaluated the topographical relationship between OCT, mfVEP, and SAP. The agreement between SAP and mfVEP was the largest in the temporal quadrant. This is likely due to the fact that the majority of the patients suffered from temporal quadrant disturbance. Agreement between SAP and OCT
or between mfVEP and OCT in patients with PA was limited by the fact that SAP and mfVEP measure the function of the entire visual pathway, whereas OCT only measures retinal ganglion complex axonal integrity. Mild compression of the optic chiasm may only lead to initial demyelination without significant axonopathy. However, with tumor growth, retrograde degeneration of ganglion cells may occur. Our quantitative analysis of the structure–function measurements revealed a moderate correlation. Though agreement between SAP and OCT or between mfVEP and OCT in patients with PA was limited, their correlation reached statistical significance. In general, the more severe the optic chiasm compression due to the tumor, the more severe the SAP or mfVEP readings and the thinner the RNFL. To our knowledge, this is the first study to investigate the relationship between mfVEP, SAP, and OCT in patients with PAs. However, it is important to acknowledge some limitations of our study. For instance, this was a crosssectional study that did not address the important issue of test–retest variability. A functional test, such as mfVEP or SAP, is more likely to be affected by physiological factors, such as fatigue and drug effects, than a structural test, such as OCT. Future studies should evaluate test repeatability in patients with PAs, and compare test utility longitudinally. Furthermore, there were limitations with respect to directly comparing mfVEP to SAP, as the two modalities are different types of measurements; for instance, SAP is a threshold test, whereas mfVEP is a supra-threshold or summed-input test. Moreover, the mfVEP is a measure of the amplitude of a gross electrical response, whereas SAP is a behaviorally determined threshold measure.
Conclusions In conclusion, mfVEP, SAP, and OCT provide complementary information for detecting visual pathway abnormalities in patients with PAs. The largest reduction was observed in temporal quadrant. Moreover, good agreement was demonstrated between SAP and mfVEP and quantitative analysis of the structure–function measurements revealed a moderate correlation. Conflict of interest
None.
References 1. Mete O, Asa SL (2012) Clinicopathological correlations in pituitary adenomas. Brain Pathol 22:443–453 2. Boonchai W, Vivienne CG, Fabio NK, Tomas MG, Jeffrey ML, Robert R, Donald CH (2009) A method to detect progression of
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glaucoma using the multifocal visual evoked potential technique. Doc Ophthalmol 118:139–150 Mousa MF, Cubbidge RP, Al-Mansouri F, Bener A (2014) Evaluation of hemifield sector analysis protocol in multifocal visual evoked potential objective perimetry for the diagnosis and early detection of glaucomatous field defects. Korean J Ophthalmol 28(1):49–65 Jayaraman M, Gandhi RA, Ravi P, Sen PL (2014) Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy. Indian J Ophthalmol 62(3):299–304 Brecelj J (2014) Visual electrophysiology in the clinical evaluation of optic neuritis, chiasmal tumours, achiasmia, and ocular albinism: an overview. Doc Ophthalmol 129(2):71–84 Ml Jacob, Raverot G, Jouanneau E, Borson-Chazot F, Perrin G, Rabilloud M, Tilikete C, Bernard M, Vighetto A (2009) Predicting visual outcome after treatment of pituitary adenomas with optical coherence tomography. Am J Ophthalmol 147(1):64–70 Klistorner A, Arvind H, Garrick R, Graham SL, Paine M, Yiannikas C (2010) Interrelationship of optical coherence tomography and multifocal visual-evoked potentials after optic neuritis. Invest Ophthalmol Vis Sci 51(5):2770–2777 Laron M, Cheng H, Zhang B, Schiffman JS, Tang RA, Frishman LJ (2012) Comparison of multifocal visual evoked potential, standard automated perimetry and optical coherence tomography
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in assessing visual pathway in multiple sclerosis patients. Mult Scler. 16(4):412–426 Garway-Heath DF, Poinoosawny D, Fitzke FW (2000) Mapping the visual field to the optic disc in normal tension glaucoma eyes. Ophthalmology 107(10):1809–1815 Psaras T, Milian M, Hattermann V, Gerlach C, Honegger J (2011) Executive functions recover earlier than episodic memory after microsurgical transsphenoidal resection of pituitary tumors in adult patients: a longitudinal study. J Clin Neurosci. 18(10): 1340–1345 Brummelman P, Elderson MF, Dullaart RP, van den Bergh AC, Timmer CA, van den Berg G, Koerts J, Tucha O, Wolffenbuttel BH, van Beek AP (2011) Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy. Clin Endocrinol (Oxf). 74(4): 481–487 Punjabi OS, Stamper RL, Bostrom AG, Han Y, Lin SC (2008) Topographic comparison of the visual function on multifocal visual evoked potentials with optic nerve structure on heidelberg retinal tomography. Ophthalmology 115(3):440–446 Danesh-Meyer HV, Carroll SC, Gaskin BJ, Gao A, Gamble GD (2006) Correlation of the multifocal visual evoked potential and standard automated perimetry in compressive optic neuropathies. Invest Ophthalmol Vis Sci 47(4):1458–1463
Comparison of multifocal visual evoked potential, static automated perimetry, and optical coherence tomography findings for assessing visual pathways in patients with pituitary adenomas Nidan Qiao • Yichao Zhang • Zhao Ye • Ming Shen • Xuefei Shou • Yongfei Wang Shiqi Li • Min Wang • Yao Zhao
•
Ó Springer Science+Business Media New York 2014
Abstract Background There have been no studies investigating the correlation between structural [thickness of the retinal nerve fiber layer (RNFL) as determined by optical coherence tomography (OCT)] and functional [Humphrey visual field (HVF) or visual evoked potential (VEP) amplitude] measures of optic nerve integrity in patients with pituitary adenomas (PA). Methods Patients with PAs were recruited between September 2010 and September 2013. OCT, standard automated perimetry (SAP), and multifical VEP (mfVEP) were performed. Agreement between OCT, SAP, and mfVEP values in classifying eyes/quadrants was determined using AC1 statistics. Pearson’s correlation was used to examine relationships between structural and functional data. Results In total, 88.7 % of the eyes tested showed abnormal SAP findings and 93.7 % showed abnormal mfVEP findings. Only 14.8 % of the eyes showed abnormal OCT findings. The agreement between SAP and mfVEP findings was 88.9 % (AC1 = 0.87). The agreement
Nidan Qiao and Yichao Zhang have contributed equally to this work. N. Qiao Y. Zhang Z. Ye M. Shen X. Shou Y. Wang S. Li Y. Zhao (&) Shanghai Pituitary Tumor Center, Department of Neurosurgery, HuaShan Hospital, Shanghai Medical College, Fudan University, 12# Middle Wulumuqi Road, Shanghai 200040, China e-mail: [email protected] M. Wang (&) Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai 200031, China e-mail: [email protected]
between OCT and mfVEP findings was 24.2 % (AC1 = -0.52), and that between OCT and SAP findings was 21.5 % (AC1 = -0.56). The correlation values between RNFL thickness and the functional measurements were -0.601 for the mfVEP score (P = 0.000) and -0.441 for the SAP score (P = 0.000). The correlation between the mfVEP and SAP scores was -0.617 (P = 0.000). Conclusions mfVEP, SAP, and OCT provided complementary information for detecting visual pathway abnormalities in patients with PAs. Good agreement was demonstrated between SAP and mfVEP and quantitative analysis of structure–function measurements revealed a moderate correlation. Keywords
mfVEP SAP OCT Visual function
Introduction Pituitary adenomas (PAs) are one of the most common types of brain tumors, accounting for 15 % of all intracranial neoplasms [1]. Visual disturbances are noted when the tumor grows beyond the sella and compresses the optic nerve. Typical neuro-ophthalmic features include progressive bilateral slow and asymmetric deterioration in visual field defects and optic disc changes. Static automated perimetry (SAP) assessments, such as the Humphrey visual field (HVF) test, provide a subjective measure of visual function that is considered to be the clinical ‘‘gold standard’’ for documenting loss of visual sensitivity. However, in the clinical setting, patients are not always cooperative and attentive well, resulting in unreliable perimetry readings. Multifocal visual evoked potential (mfVEP) is a relatively new technical approach for assessing the integrity of the visual pathway that eliminates
123
Pituitary
the subjectivity and patient learning process required for static automated perimetry. VEP testing for PAs has been used to assess subjects presenting with initial visual disturbances. However, the clinical usefulness of full-field VEP is limited by the fact that it provides a summed response of all neuronal elements stimulated. Recent developments using multifocal stimulation techniques have uncovered a new methodology for assessing visual function. mfVEP testing is beginning to show promise for the management of patients with glaucoma [2, 3], and interesting findings are becoming available from studies of patients with ischemic optic neuropathy and optic neuritis [4, 5]. Peripapillary retinal nerve fiber layer (RNFL) thickness has been proposed as a structural marker of axonal loss in the optic nerve. The RNFL will show retrograde degeneration following damage to the optic nerve or the optic tract in the brain. The most widely used method to measure RNFL thickness is optical coherence tomography (OCT), which utilizes the echo time delay of back-scattered light using an interferometer and a low-coherence light to perform cross-sectional imaging of the retina [6]. Strong associations between structural (thickness of RNFL as determined by OCT) and functional (HVF or amplitude of VEP) measures of optic nerve integrity in patients with optic neuritis or multiple sclerosis have been demonstrated in several studies [7, 8]. However, there have been no studies assessing the correlation between structural and functional measures of optic nerve integrity in PA patients. Therefore, the purpose of this study was to compare the sensitivity of mfVEP for detecting abnormalities in the visual pathway of PA patients with the sensitivities of static automated perimetry, HVF testing, and/or imaging of the nerve fiber layer with OCT.
Methods Subjects This study had a cross-sectional design. The procedures followed the tenets of the Declaration of Helsinki, and written informed consent was obtained from all participants. Patients with PAs were recruited from Huashan Hospital between September 2010 and September 2013. PA was confirmed by pathology. Patients underwent a thorough ophthalmic examination by experienced ophthalmologists, which included pupil, anterior, and posterior segment examination. Patients with other ocular diseases were excluded. SAP was performed using the Humphrey 750 Visual Field Analyzer (Zeiss-Humphrey Systems, Dublin, CA, USA) and a central 30-2 threshold protocol. Fixation loss
123
was less than 20 %. The false positive error rate was less than 20 % and the false negative error rate was less than 20 %. To allow a comparison of visual-field sensitivity to the mfVEP responses, estimates of sensitivity for each sector of the multifocal stimulus were obtained from the visual field values (total deviation). These estimates were obtained using a computer (MATLAB software; The Mathworks, Natick, MA, USA). mfVEP recordings were obtained using VERIS system (Electro-Diagnostic Imaging, San Mateo, CA, USA). The stimulus was a 60-sector, cortically scaled dartboard pattern with a mean luminance of 66 cd/m2 and a Michelson contrast of 95 %. The dartboard pattern reversed at a frame rate of 75 Hz. Patients were instructed to fixate on the center of the dartboard pattern (marked with an ‘X’) with their best refractive correction in place, and eye position was monitored continuously by the examiner via the camera display provided in the VERIS system. Three recording channels were connected to gold cup electrodes. For the midline channel, electrodes were placed 4 cm above the inion (active), at the inion (reference), and on the earlobe (ground). For the other two active channels, the same ground and reference electrodes were used, but the active electrode was placed 1 cm up and 4 cm lateral to the inion on either side. Two 7-min recordings from each eye were obtained, and averaged responses were used. The channel providing the best recording for each sector was selected during the analysis as the ‘‘best channel response.’’ The analyses were performed with programs written in MATLAB. For each sector, monocular amplitude (MAMP), interocular amplitude (IAMP), monocular latency (MLAT), and interocular latency (ILAT) were calculated by comparing the amplitude or latency of the mfVEP from a particular sector of the stimulus array to the mean and standard deviation of the Portland normative data for the corresponding location, and assigning a probability value. The RNFL was assessed by RTVue (Optovue, Fremont, CA, USA) using a three-dimensional disc and optic nerve head (ONH) protocols. The OCT reports measurements for four sectors: superior, temporal, nasal, and inferior.
Topographic correspondence between SAP, OCT, and mfVEP Topographical correlations between SAP, OCT, and mfVEP were estimated based on a previous study that examined the anatomical relationships between the visual field and regions of the ONH and was used earlier in glaucoma research [9]. The SAP and mfVEP were divided into four quadrants corresponding to the four-quadrant output of the OCT (Fig. 1). The nasal sector was excluded
Pituitary Fig. 1 A topographic map relating quadrants from OCT measurements and the corresponding quadrants from the SAP and mfVEP tests. For patients tested with the SAP 30-2 paradigm, only the areas corresponding to the 24-2 map were analyzed
from topographic comparisons due to limited representation on the SAP and mfVEP tests.
Table 1 Global measurements of SAP, OCT and mfVEP
Criteria used to define total abnormality for each technique
Left
1.97
92.65
0.85
Right Total
1.68 1.83
92.58 92.62
0.77 0.81
To assess overall mfVEP performance, we defined an eye as abnormal if MAMP and IAMP probability plots met the following criteria: at least five adjacent points with P \ 0.05 and at least four adjacent points with P \ 0.01. The visual field was defined as abnormal if the mean deviation of the total deviation plot had a P \ 0.05. The OCT result was defined as being abnormal if the overall RNFL thickness was significantly thinner than norms provided by the instrument (P \ 0.05). Criteria used to define abnormal quadrants for each technique OCT: RFNL thickness of that quadrant was significantly thinner than the norms (P \ 0.05). SAP: at least two adjacent test points in a quadrant depressed by P \ 0.01, or at least three adjacent points depressed by P \ 0.05 with one of the points depressed by P \ 0.01. HVF inferior and superior sector clusters could not include more than one peripheral rim test location. mfVEP: a quadrant was defined as abnormal if MAMP met the following cluster criteria: at least two adjacent test points in a quadrant depressed by P \ 0.01, or at least three adjacent points depressed by P \ 0.05. Severity of field involvement was also analyzed using the probability plots displayed on the reports. HVF data was analyzed using total deviation probability plots. Each probability point was assigned a numerical value (P [ 5 % = 0; P \ 5 % = 1; P \ 2 % or P \ 1 % = 2; and P \ 0.5 % = 3). The numerical values were then averaged, giving a total severity score for each quadrant ranging from 0 to 3. The mfVEP report displayed a similar probability plot for amplitude deviation, and these points were assigned
SAP score
OCT RNFL thickness (lm)
mfVEP score
SAP static automated perimetry, OCT optic coherence tomography, RNFL retinal nerve fiber layer, mfVEP multifocal visual evoked potential
Table 2 Percent of eyes being defined as abnormal Percent of abnormal
SAP (%)
OCT (%)
mfVEP (%)
Temporal
88.5
27.9
95.2
Superior Inferior
95.3 89.9
7.8 9.2
64.0 77.6
Total
88.7
14.8
93.7
SAP static automated perimetry, OCT optic coherence tomography, mfVEP multifocal visual evoked potential
numerical values and averaged for each quadrant, again giving a severity score for each quadrant ranging from 0 to 2 (P [ 5 % = 0; P \ 5 % = 1; and P \ 1 % = 2). Statistics analysis Statistical analysis was performed using SPSS 11.0 for Windows (SPSS Inc, Chicago, IL, USA). The Student’s t test was used to compare means. Agreement between OCT, SAP, and mfVEP in classifying eyes/quadrants are presented as AC1 statistics. Pearson’s correlation was used to examine relationships between structural and functional data.
Results Global measurements of SAP, OCT, and mfVEP The averaged SAP score, RNFL thickness measured by OCT, and mfVEP scores are shown in Table 1.
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Pituitary Table 3 Total agreement between OCT, SAP and mfVEP Normal
Abnormal
Agreement
AC1
Normal
4 (3.4 %)
4 (3.4 %)
88.9 %
0.87
Abnormal
9 (7.7 %)
100 (85.5 %)
Normal
14 (11.3 %)
94 (75.8)
24.2 %
-0.52
Abnormal
0 (0.0 %)
16 (12.9 %)
8 (6.6 %) 95 (78.5 %)
0 (0.0 %) 18 (14.9 %)
21.5 %
-0.56
mfVEP SAP
mfVEP OCT
OCT SAP Normal Abnormal
AC1 agreement coefficient, SAP static automated perimetry, OCT optic coherence tomography, mfVEP multifocal visual evoked potential
Table 4 Topographic agreement between OCT, SAP and mfVEP
Fig. 2 Abnormal monocular amplitude plot. a Left eye. b Right eye. Sectors marked in black indicate no significant difference from the normative database. Colored sectors denote significantly reduced amplitudes. Saturated color: P \ 0.01; desaturated color: P \ 0.05
Agreement (AC1)
mfVEP versus SAP
mfVEP versus OCT
OCT versus SAP
Temporal
89.8 % (0.88)
31.4 % (-0.31)
34.4 % (-0.28)
Superior
65.0 % (0.48)
42.4 % (-0.05)
11.6 % (-0.77)
Inferior
76.9 % (0.69)
31.4 % (-0.34)
18.2 % (-0.64)
AC1 agreement coefficient, SAP static automated perimetry, OCT optic coherence tomography, mfVEP multifocal visual evoked potential
Abnormality detected by SAP, OCT, and mfVEP The performance of SAP, OCT, and mfVEP for detecting abnormalities in the visual pathway of patients with PAs and the percent of eyes defined as abnormal by each of the three tests are reported in Table 2. In total, 88.7 % of the eyes tested were defined as abnormal on SAP and 93.7 % were defined as abnormal on mfVEP. Conversely, only 14.8 % of the eyes showed abnormal findings on OCT. Examples of abnormal eyes are shown in Fig. 2. Table 2 also illustrates the percentage of quadrants identified as abnormal by each test; the number of abnormal quadrants was high for SAP and mfVEP. The temporal sector was the most affected on both OCT and mfVEP tests. For SAP, no statistical significance between the three sectors was observed. Agreement between mfVEP, SAP, and OCT The mfVEP results reported 88.7 % of eyes as abnormal compared with 93.2 % using SAP (Table 3). The agreement between the two tests was 88.9 % (AC1 = 0.87).
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However, agreement between OCT and SAP tests was only 21.5 % (AC1 = –0.56). Similarly, agreement between OCT and mfVEP was only 24.2 % (AC1 = –0.52). Topographic agreement between OCT, SAP, and mfVEP was also analyzed (Table 4). Agreement between the quadrants for the two functional tests ranged from 65.0 to 89.8 %, which is much higher than the agreement between OCT and mfVEP or agreement between OCT and SAP. Quantitative comparisons between OCT, mfVEP, and SAP In addition to qualitative analysis, relationships between OCT RNFL thickness, mfVEP score, and SAP score were studied quantitatively using Pearson’s correlation analysis. The correlation between OCT RNFL thickness and the functional measurements were as follows: –0.601 for mfVEP score (P = 0.000) and –0.441 for SAP score (P = 0.000). The correlation between mfVEP and SAP scores was –0.617 (P = 0.000).
Pituitary
Discussion Studies evaluating structure—function relationships are important both for diagnosis and follow-up of patients with a range of visual pathway diseases. In this study, we examined the relationship between structural and functional measures of optic nerve dysfunction in patients with PAs. Compared with SAP, mfVEP has the advantage of being an objective test of local visual function and does not require patients to make a decision; some patients with PAs may have cognitive dysfunction [10, 11], which adversely affects their performance on the SAP test. The multifocal nature of our electrophysiological examination permitted topographic evaluation and comparisons of these three measures. The ability of mfVEP to detect abnormalities was confirmed by assessment of abnormal eyes. For instance, MAMP plot was abnormal in 93.7 % of the eyes, whereas the temporal quadrant made it possible to identify 95.2 % of eyes as abnormal. SAP identified abnormalities in up to 88.7 % of eyes. Therefore, our results indicate that mfVEP may be used as a complementary method for quantifying visual function loss. In agreement with previous reports on patients with optic neuritis and multiple sclerosis [7, 8, 12, 13], we found that functional tests (mfVEP and SAP) detected more abnormalities in patients with PAs than the structural test. This result was expected because (1) mfVEP detects demyelination while the OCT does not; and (2) OCT measurements are limited to the posterior visual pathway assessed at the retinal level, whereas the functional tests measure integrity of both the anterior and posterior visual pathways. The OCT will not detect or underestimate the defects when retrograde axonal degeneration is partial or not significant, which is very common in patients with PAs. The largest visual field reduction was observed in the temporal quadrants on both mfVEP and OCT. This was in accordance with clinical and pathological studies indicating a particular susceptibility of the temporal bundle fibers for damage in patients with PAs. In most PA patients with visual dysfunction, the most severe compression was at the center of the optic chiasm, which comes from the temporal quadrants. The agreement between the two functional tests (SAP and mfVEP) was stronger than the agreement between the structural and individual functional tests. This is in accordance with previous studies on optical neuritis and multiple sclerosis [7, 8]. In the present study, we also evaluated the topographical relationship between OCT, mfVEP, and SAP. The agreement between SAP and mfVEP was the largest in the temporal quadrant. This is likely due to the fact that the majority of the patients suffered from temporal quadrant disturbance. Agreement between SAP and OCT
or between mfVEP and OCT in patients with PA was limited by the fact that SAP and mfVEP measure the function of the entire visual pathway, whereas OCT only measures retinal ganglion complex axonal integrity. Mild compression of the optic chiasm may only lead to initial demyelination without significant axonopathy. However, with tumor growth, retrograde degeneration of ganglion cells may occur. Our quantitative analysis of the structure–function measurements revealed a moderate correlation. Though agreement between SAP and OCT or between mfVEP and OCT in patients with PA was limited, their correlation reached statistical significance. In general, the more severe the optic chiasm compression due to the tumor, the more severe the SAP or mfVEP readings and the thinner the RNFL. To our knowledge, this is the first study to investigate the relationship between mfVEP, SAP, and OCT in patients with PAs. However, it is important to acknowledge some limitations of our study. For instance, this was a crosssectional study that did not address the important issue of test–retest variability. A functional test, such as mfVEP or SAP, is more likely to be affected by physiological factors, such as fatigue and drug effects, than a structural test, such as OCT. Future studies should evaluate test repeatability in patients with PAs, and compare test utility longitudinally. Furthermore, there were limitations with respect to directly comparing mfVEP to SAP, as the two modalities are different types of measurements; for instance, SAP is a threshold test, whereas mfVEP is a supra-threshold or summed-input test. Moreover, the mfVEP is a measure of the amplitude of a gross electrical response, whereas SAP is a behaviorally determined threshold measure.
Conclusions In conclusion, mfVEP, SAP, and OCT provide complementary information for detecting visual pathway abnormalities in patients with PAs. The largest reduction was observed in temporal quadrant. Moreover, good agreement was demonstrated between SAP and mfVEP and quantitative analysis of the structure–function measurements revealed a moderate correlation. Conflict of interest
None.
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