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Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function
Schizophrenia Research xxx (xxxx) xxx
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Optical coherence tomography of the retina in schizophrenia: Interdevice agreement and relations with perceptual function Margaret Miller a, b, c, 1, Vance Zemon c, Rachel Nolan-Kenney a, e, Laura J. Balcer a, d, e, Donald C. Goff b, f, Michelle Worthington b, 2, Lisena Hasanaj a, Pamela D. Butler b, f, * a
Department of Neurology, New York University School of Medicine, New York, NY, USA Department of Psychiatry, New York University School of Medicine, New York, NY, USA Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY, USA d Department of Ophthalmology, New York University School of Medicine, New York, NY, USA e Department of Population Health, New York University School of Medicine, New York, NY, USA f Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 April 2019 Received in revised form 18 October 2019 Accepted 21 October 2019 Available online xxx
Background: Optical coherence tomography (OCT) studies have demonstrated differences between people with schizophrenia and controls. Many questions remain including the agreement between scanners. The current study seeks to determine inter-device agreement of OCT data in schizophrenia compared to controls and to explore the relations between OCT and visual function measures. Methods: Participants in this pilot study were 12 individuals with schizophrenia spectrum disorders and 12 age- and sex-matched controls. Spectralis and Cirrus OCT machines were used to obtain retinal nerve fiber layer (RNFL) thickness and macular volume. Cirrus was used to obtain ganglion cell layer þ inner plexiform layer (GCL þ IPL) thickness. Visual function was assessed with low-contrast visual acuity and the King-Devick test of rapid number naming. Results: There was excellent relative agreement in OCT measurements between the two machines, but poor absolute agreement, for both patients and controls. On both machines, people with schizophrenia showed decreased macular volume but no difference in RNFL thickness compared to controls. No between-group difference in GCL þ IPL thickness was found on Cirrus. Controls showed significant associations between King-Devick performance and RNFL thickness and macular volume, and between low-contrast visual acuity and GCL þ IPL thickness. Patients did not show significant associations between OCT measurements and visual function. Conclusions: Good relative agreement suggests that the offset between machines remains constant and should not affect comparisons between groups. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device. © 2019 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia Optical coherence tomography Retina Visual Perception
1. Introduction The retina has been described as a “window to the brain” (Silverstein et al., 2018; Chu et al., 2012) because it is part of the central nervous system and, like the brain, develops from the neuroectoderm. Thinning of retinal tissue has been observed in
* Corresponding author. Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY, 10962, USA. E-mail address: [email protected] (P.D. Butler). 1 present address, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. 2 present address, Department of Psychology, Yale University, New Haven, CT, USA.
neuropsychiatric disorders (e.g., Parkinson’s disease and multiple sclerosis) where it often parallels aspects of brain volume loss, disease progression, and cognitive impairment (Tian et al., 2011; Saidha et al., 2013; Frohman et al., 2008; Ko et al., 2018). Studies have consistently demonstrated differences between people with schizophrenia and controls on optical coherence tomography (OCT) of the retina; these findings included thinning of the retinal nerve fiber layer (RNFL), macular layer and ganglion cell-inner plexiform layer (GCL-IPL) (Silverstein et al., 2019; Kazakos and Karageorgiou, 2019). However, many questions remain including the agreement between scanners. The current study seeks to determine, for the first time, inter-device agreement of OCT data in schizophrenia
https://doi.org/10.1016/j.schres.2019.10.046 0920-9964/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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compared to controls and to also explore the relations between OCT and visual function measures. 2. Materials and methods 2.1. Participants Participants consisted of 12 individuals meeting Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria for schizophrenia-spectrum disorders and 12 healthy volunteers. Diagnoses were obtained using the Structured Clinical Interview for DSM-IV (SCID)(First et al., 2010) and all available clinical information. Patients were a subset of those who previously had participated in a study of D-cycloserine Augmentation of Cognitive Behavioral Therapy for Delusions at New York University Langone Medical Center (NYULMC) (Dr. Donald Goff, PI). No participants were still enrolled in that trial or taking D-cyloserine or placebo. Controls were a subset of those who had participated in an OCT research study at NYULMC (Dr. Laura Balcer, PI) and were age- and sex-matched to patients. All participants had vision that could be corrected to 20/30 on an Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Precision Vision, La Salle, IL). Participants were excluded if they had a history of neurological disorder or diseases of the eye (e.g., cataracts, glaucoma). This study was approved by the NYULMC Institutional Review Board and all participants provided informed consent according to the Declaration of Helsinki. Table 1 provides demographic and clinical data.
resolution, was used, as is done for other published papers from our group (e.g., Nolan et al., 2019; Sabadia et al., 2016). Fig. 1 illustrates retinal areas where the scans were performed. There was some missing data for the RNFL and macular volume scans. One patient is missing Cirrus RNFL measurement in both eyes due to difficulty scanning because of behavioral/attention issues. Another patient was missing Cirrus RNLF measurement in the right eye due to difficulty scanning because of behavior/attention issues. Three controls did not receive macular volume scans on either the Cirrus or Spectralis machines because they were collected under a different protocol. In addition, one patient had a Spectralis macular volume measurement that was performed with a different scan protocol and so it was not used in the current analysis. 2.2.2. The King-Devick test This test of oculomotor function requires saccadic eye movements (Galetta et al., 2016; Hasanaj et al., 2018). It includes one practice card and three test cards, which become progressively more difficult by staggering spacing between letters and crowding
2.2. Measures 2.2.1. Optical coherence tomography (OCT) OCT measures were obtained using two different spectral domain-OCT machines: Cirrus 4000, version 6.5.0.772 software (Carl Zeiss Meditec, Jena, Germany), and Spectralis, version 6.0.7 software (Heidelberg Engineering, Carlsbad, CA, USA). Peripapillary RNFL thickness was measured centered on the optic disc and macular volume was measured centered on the fovea using both machines. Measurements of macular GCL þ IPL thickness were obtained only on the Cirrus device. Machine-specific automatic algorithms were applied to compute thickness and volume with inherent differences. Details of OCT scan protocols are given in previous publications from our group (Nolan et al., 2019; Sabadia et al., 2016). The scan with the highest quality according to OSCAR-IB criteria (Tewarie et al., 2012) (i.e., highest signal strength, fewest segmentation errors, and least movement), irrespective of
Table 1 Demographic and clinical information. Patients
Controls
M (SD)
M (SD)
Age (years) Duration of Illness (years) CPZ Equivalent Dose MATRICS Composite Score
48.25 (10.29) 27.25 (14.41) 551.1 (453.7) 33.6 (11.4) % (n)
48.29 (10.64)
Male Female Diagnosis Schizophrenia Schizoaffective Delusional Disorder Antipsychotics First Generation Second Generation Not on Antipsychotic
66.7 (8) 33.3 (4)
66.7 (8) 33.3 (4)
% (n)
66.7 (8) 25.0 (3) 8.3 (1) 25 (3) 50 (6) 25 (3)
Note: n ¼ 12 patients and 12 controls, except duration of illness, n ¼ 11.
Fig. 1. For the RNFL, measurements were obtained in the area around the optic disc and for the macula and GCL þ IPL, measurements were taken in the foveal area. For GCL þ IPL thickness, the arrow points to the layers where the measurements were taken. The vertical white lines for the GCL þ IPL and macula show more specifically where the layers used for these measurements are. The RNFL is made up of unmyelinated ganglion cells that form the optic nerve. The ganglion cell layer of the macula is where the cell bodes of the optic nerve are concentrated. The optic disc is nasal to the fovea. RNFL ¼ retinal nerve fiber layer; GCL þ IPL ¼ ganglion cell layer þ inner plexiform layer.
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
M. Miller et al. / Schizophrenia Research xxx (xxxx) xxx
letters closer to each other. Participants read aloud as quickly as possible a series of single-digit numbers from left to right. Performance on the three test cards in seconds constitutes the summary score. 2.2.3. Acuity testing ETDRS Low-Contrast Sloan Letter Charts (Precision Vision, La Salle, IL; 2.5% and 1.25% contrast), which involve identification of gray letters of progressively smaller size, were used to assess low contrast visual acuity. Performance was scored based on the number of letters identified correctly. 2.3. Statistical analysis Separate linear mixed-effects models (LMM) were used to assess OCT results for RNFL thickness, macular volume, and GCL þ IPL thickness. Repeated measurements were fellow eye data (i.e., right and left eyes) and results on the two OCT machines. GCL þ IPL thickness was only obtained on the CIRRUS. Fixed effects were eye condition, OCT machine type, and group (patient/control). Participant was entered into the model as a random (intercept) effect. Post-hoc testing used Mann-Whitney U to follow up on significant results from the LMM. To look at the agreement between fellow eyes and OCT machines, intraclass correlation coefficients (ICCs) were evaluated with a two-way mixed effects model for both relative and absolute agreement.
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thickness was greater by 2 mm in patients vs. controls, but on Cirrus RNFL thickness was lower by 0.4 mm in patients vs. controls, collapsed over fellow eyes. These differences between groups on RNFL were not significant (Table 4). Given the small sample sizes in these analyses (and those reported below), only large effects (d > 1.0) achieved significance, with the smaller effect sizes obtained (0.05e0.85) yielding post hoc power values of only 0.02 0.57. 3.1.2. Macular volume LMM showed a significant main effect of OCT device (F1,61.1 ¼ 2766.1, p < .001), with Cirrus showing greater macular volume than Spectralis. ICCs showed excellent relative agreement, but poor absolute agreement, between the two machines for both patients and controls separately (Table 2A and 2B) and for both groups together (data not shown), due to greater macular volume on Cirrus than Spectralis (Fig. 2). There was no significant fixed effect for eye. ICCs showed excellent relative and absolute agreement between eyes for macular volume (Table 3A and 3B). Though all ICCs were high, they were greater for macular volume measures on Spectralis as compared to Cirrus. These differences in ICCs were not significant, as seen by overlap in the confidence intervals. LMM showed a significant fixed effect of group given the large effect size obtained (F1,20.9 ¼ 6.01, p ¼ .023), with patients showing decreased macular volume across both machines and eyes (Table 4). 3.1.3. Ganglion cell layer þ inner plexiform layer thickness For GCL þ IPL thickness, results of the LMM did not show any significant fixed effects for group or eye or a significant Group Eye interaction with small effect sizes obtained.
3. Results 3.1. Optical coherence tomography 3.1.1. Retinal nerve fiber layer thickness LMM showed a significant fixed effect of OCT device (F1,69 ¼ 111.5, p < .001), with Spectralis showing greater RNFL thickness than Cirrus. ICCs showed excellent relative, but poor absolute, agreement between the two machines for patients and controls separately (Table 2A and 2B) and for both groups together (data not shown), due to the greater thickness on Spectralis than Cirrus. There was a small but significant main effect of eye condition (F1,68.9 ¼ 5.14, p ¼ .026) with the right eye yielding greater RNFL thickness than the left eye. ICCs showed excellent relative and absolute agreement between eyes for both patients and controls (Table 3A and 3B). Though all ICCs were high, they were greater for RNFL measures on Spectralis as compared to Cirrus. These differences in ICCs were not significant, as seen by overlap in the confidence intervals. In addition, correlations between eyes for both patients and controls on each OCT measurement and device ranged from r ¼ .828-.969 with all p values .001. There was also a small but significant Group x OCT device interaction (F1,69 ¼ 4.46, p ¼ .038), in which on Spectralis, RNFL
3.2. Correlations Within the control group, there were significant correlations between King-Devick test times and RNFL thickness and macular volume, with the expected inverse relations, and a significant positive correlation was found between 2.5% low-contrast acuity and GCL þ IPL thickness. Conversely, within the schizophrenia group, there were no significant correlations between OCT measurements and these measures of perceptual function. 4. Discussion We found excellent relative agreement between Spectralis and Cirrus on RNFL thickness and macular volume measurements. However, the machines differed in absolute measurements. RNFL thickness values obtained from Spectralis were higher than those obtained from Cirrus, which is consistent with previous literature (Faghihi et al., 2014; Warner et al., 2011), whereas macular volume measurements obtained from Spectralis were lower than those
Table 2A Agreement between spectralis and cirrus OCT machines e controls. Retinal Measurements
Spectralis
Cirrus
M (SD)
M (SD)
n
ICC(c)
ICC(a)
Right RNFL (mm)
96.42 (7.35)
91.33 (7.75)
12
95.17 (6.04)
90.67 (5.82)
12
Right Macular Volume (mm3)
8.59 (0.31)
10.10 (0.32)
9
Left Macular Volume (mm3)
8.56 (0.30)
10.08 (0.39)
9
.940 [.807,.982] .903 [.700,.971] .852 [.477,.965] .836 [.434,.961]
.770 [-.067,.951] .706 [-.083,.931] .068 [-.006,.356] .079 [-.008,.396]
Left RNFL (mm)
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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Table 2B Agreement between Spectralis and Cirrus OCT Machines e Patients. Retinal Measurements
n
ICC(c)
ICC(a)
90.90 (10.97)
10
98.91 (15.75)
90.91 (14.52)
11
Right Macular Volume (mm )
8.24 (0.31)
9.65 (0.36)
11
Left Macular Volume (mm3)
8.23 (0.32)
9.72 (0.42)
11
.945 [.796,.986] .990 [.963,.997] .849 [.533,.957] .879 [.615,.966]
.812 [-.057,.963] .869 [-.018,.978] .087 [-.008,.397] .098 [-.007,.429]
Right RNFL (mm) Left RNFL (mm) 3
Spectralis
Cirrus
M (SD)
M (SD)
97.40 (11.32)
Note: RNFL ≡ retinal nerve fiber layer. n ≡ number of paired observations, all p .001. ICC(c) ¼ relative agreement, ICC(a) ¼ absolute agreement.
Table 3A Agreement between right and left eyes e controls. Retinal Measurements
n
ICC(c)
ICC(a)
95.17 (6.04)
12
8.59 (0.31)
8.56 (0.30)
9
.895 [.678,.969] .959 [.831,.991]
.888 [.667,.966] .960 [.844,.991]
91.33 (7.75)
90.67 (5.82)
12
Macular Volume (mm3)
10.10 (0.32)
10.08 (0.39)
9
GCL þ IPL (mm)
78.50 (6.26)
79.0 (6.30)
12
.817 [.483,.944] .903 [.631,.977] .971 [.903,.992]
.826 [.506,.947] .911 [.661,.979] .970 [.905,.991]
n
ICC(c)
ICC(a)
.953 [.846,.986] .963 [.871,.990]
.955 [.856,.987] .966 [.881,.991]
.881 [.594,.969] .826 [.503,.947] .908 [.713,.973]
.879 [.609,.968] .834 [.526,.949] .913 [.730,.974]
Spectralis RNFL (mm) Macular Volume (mm3) Cirrus RNFL (mm)
Right Eye
Left Eye
M (SD)
M (SD)
96.42 (7.35)
Table 3B Agreement between right and left eyes e patients. Retinal Measurements
Right Eye
Left Eye
M (SD)
M (SD)
98.25 (13.34)
97.33 (15.98)
12
8.24 (.31)
8.23 (.32)
11
90.90 (10.97)
88.80 (13.41)
10
Macular Volume (mm3)
9.70 (.38)
9.74 (.41)
12
GCL þ IPL (mm)
77.58 (4.58)
77.25 (5.74)
12
Spectralis RNFL (mm) Macular Volume (mm3) Cirrus RNFL (mm)
Note: RNFL ≡ retinal nerve fiber layer, n ≡ number of paired observations, all p < .001. ICC(c) ≡ relative agreement, ICC(a) ≡ absolute agreement.
from Cirrus in the current study. Spectralis and Cirrus have different algorithms for segmentation of the retinal areas used for measurement. In a study in which the macular region was manually segmented in exactly the same way on both machines using an open-source algorithm rather than the algorithms automatically used by the machines, good absolute agreement was found between controls and patients with multiple sclerosis (Bhargava et al., 2015). Most studies, including the current one, use the automatic algorithms and thus differences in absolute agreement are not surprising. Lack of good absolute agreement also indicates that it will not be possible to compare findings from different machines to a single normative standard. Participants with schizophrenia demonstrated significantly reduced macular volume on both Spectralis and Cirrus. While the
difference between patients and controls was relatively small, the effect size was large. This is consistent with previous studies showing reduced macular thickness and/or volume in schizophrenia in many (Joe et al., 2018; Ascaso et al., 2015; Lee et al., 2013; Samani et al., 2018; Topcu-Yilmaz et al., 2018) but not all (Ascaso et al., 2010; Silverstein et al., 2018; Chu et al., 2012) studies. The finding of decreased macular volume on both machines provides further support that between-group differences are similar between devices. In contrast, there were no significant differences between groups in RNFL and GCL þ IPL thickness in the present study. It should also be noted that while the excellent relative reliability shows that the offset between machines remains constant over the range of measures, there was a small but significant interaction between group and machine for RNFL. Thus, while some
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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Table 4 Group differences in retinal parameters. Measure
SCZ
CON
M (n, SD)
M (n, SD)
U
p
Cohen’s d
Retinal Measurements, Spectralis OC T Right RNFL (mm) Left RNFL (mm) Right Macular Volume (mm3) Left Macular Volume (mm3)
98.25 (12, 13.34) 97.33 (12, 15.98) 8.24 (11, 0.31) 8.23 (11, 0.32)
96.42 (12, 7.35) 95.17 (12, 6.04) 8.59 (9, 0.31) 8.56 (9, 0.30)
65.5 60.0 22.0 21.5
.713 .514 .038* .031*
0.18 0.20 1.13 1.06
Retinal Measurements, Cirrus OCT Right RNFL (mm) Left RNFL (mm) Right Macular Volume (mm3) Left Macular Volume (mm3) Right GCL þ IPL (mm) Left GCL þ IPL (mm)
90.90 (10, 10.97) 90.91 (11, 14.52) 9.70 (12, 0.38) 9.74 (12, 0.41) 77.58 (12, 4.58) 77.25 (12, 5.74)
91.33 (12, 7.75) 90.67 (12, 5.82) 10.10 (9, 0.32) 10.08 (9, 0.39) 78.50 (12, 6.26) 79.0 (12, 6.30)
57.0 52.5 22.5 28.5 63.0 56.5
.872 .413 .023* .079 .630 .378
0.05 0.02 1.13 .85 0.17 0.29
Note: RNFL ≡ retinal nerve fiber layer, GCL þ IPL ≡ ganglion cell layer and inner plexiform layer. *p < .05 in post hoc Mann-Whitney U tests.
Fig. 2. Scatterplots of macular volume for the two machines. There is an offset in data from the black line centered on the origin with slope of 1 (indicating absolute agreement) due to greater macular volume on Cirrus than Spectralis.
caution may be warranted, the use of different machines should not affect comparisons between groups. The expected associations between OCT measures and perceptual function (i.e., the King-Devick test that assesses oculomotor function and low-contrast letter acuity) were found in healthy controls but not in participants with schizophrenia. Our results are consistent with what has been found in multiple sclerosis on these tests in relation to OCT measures (Moster et al., 2014; Saidha et al., 2011; Balcer et al., 2017; Walter et al., 2012). Significant relations between OCT measurements and perceptual function were not seen in schizophrenia, which suggests aberrant retinal structure. Few studies have looked at relationships between retinal structure and perceptual function in schizophrenia. Samani et al. (2018) found that decreased contrast sensitivity was related to retinal ganglion cell complex thinning. Further work is needed to assess
relationships between retinal structure and perceptual function in schizophrenia. Limitations of the study include the small sample. However, large effect sizes were obtained for macular volume and sufficient to achieve statistical significance. In addition, the current study did not exclude participants with medical comorbidities, such as diabetes and hypertension. Most schizophrenia studies show retinal thinning but results are somewhat inconsistent between studies which may be due to differences in study samples in terms of stage of illness, medical comorbidities, smoking, neuroinflammation, and other factors that are often not assessed (Silverstein et al., 2019). The high relative agreement between machines found in this study suggests that factors such as medical comorbidity and stage of illness may be more relevant in understanding OCT differences between studies
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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than machine used. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device. Contributors Drs. Miller, Butler, Balcer, Goff, and Zemon and Ms. NolanKenney designed the study and wrote the protocol. Drs. Miller, Butler, and Zemon and Ms. Nolan-Kenney managed the literature searches. Drs. Miller and Zemon and Ms. Nolan-Kenney undertook the statistical analysis, and Dr. Miller wrote the first draft of the manuscript. Dr. Miller and Ms. Nolan-Kenney, Hasanaj, and Worthington, collected and managed data. All authors contributed to and have approved the final manuscript. Funding This project was supported by NIMH R34MH100296 (Goff, PI). Declaration of competing interest All authors declare that they have no conflicts of interest. Acknowledgements The authors thank all who participated in this study. We also thank Dr. Erica Diminich and Ms. Kamber Hart for their contribution to the clinical aspects of this study. References Ascaso, F.J., Cabezon, L., Quintanilla, M., Lopez-Anton, R., Cristobal, J., Lobo, A., 2010. Retinal nerve fiber layer thickness measured by optical coherence tomography in patients with schizophrenia: a short report. Eur. J. Psychiatry 24. Ascaso, F.J., Rodriguez-Jimenez, R., Cabezon, L., Lopez-Anton, R., Santabarbara, J., De la Camara, C., Modrego, P.J., Quintanilla, M.A., Bagney, A., Gutierrez, L., Cruz, N., Cristobal, J.A., Lobo, A., 2015. Retinal nerve fiber layer and macular thickness in patients with schizophrenia: influence of recent illness episodes. Psychiatry Res. 229, 230e236. Balcer, L.J., Raynowska, J., Nolan, R., Galetta, S.L., Kapoor, R., Benedict, R., Phillips, G., LaRocca, N., Hudson, L., Rudick, R., 2017. Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis. Mult. Scler. 23, 734e747. Bhargava, P., Lang, A., Al-Louzi, O., Carass, A., Prince, J., Calabresi, P.A., Saidha, S., 2015. Applying an open-source segmentation algorithm to different OCT devices in multiple sclerosis patients and healthy controls: implications for clinical trials. Mult. Scler. Int. 2015, 136295. Chu, E.M., Kolappan, M., Barnes, T.R., Joyce, E.M., Ron, M.A., 2012. A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography. Psychiatry Res. 203, 89e94. Faghihi, H., Hajizadeh, F., Hashemi, H., Khabazkhoob, M., 2014. Agreement of two different spectral domain optical coherence tomography instruments for retinal nerve fiber layer measurements. J. Ophthalmic Vis. Res. 9, 31e37. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2010. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. SCID-I/P) Biometrics Research, New York State Psychiatric Institute, New York. Revision 2010. Frohman, E.M., Fujimoto, J.G., Frohman, T.C., Calabresi, P.A., Cutter, G., Balcer, L.J., 2008. Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nat. Clin. Pract. Neurol. 4, 664e675. Galetta, K.M., Liu, M., Leong, D.F., Ventura, R.E., Galetta, S.L., Balcer, L.J., 2016. The
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Nolan, R.C., Liu, M., Akhand, O., Calabresi, P.A., Friedemann, P., Petzold, A., Balk, L., Brandt, A.U., Martinez-Lapiscina, E.H., Saidha, S., Villoslada, P., Al-Hassan, A.A., Behbehani, R., Frohman, E.M., Frohman, T., Havla, J., Hemmer, B., Jiang, H., Knier, B., Korn, T., Leocani, L., Papadopoulou, A., Pisa, M., Zimmerman, H., Galetta, S.L., Balcer, L.J., 2019. Optimal inter-eye difference thresholds by OCT in MS: an international study. Ann. Neurol. 85, 618e629. Sabadia, S.B., Nolan, R.C., Galetta, K.M., Narayana, K.M., Wilson, J.A., Calabresi, P.A., Frohman, E.M., Galetta, S.L., Balcer, L.J., 2016. 20/40 or better visual acuity after optic neuritis: not as good as we once thought? J. Neuro Ophthalmol. 36, 369e376. Saidha, S., Sotirchos, E.S., Oh, J., Syc, S.B., Seigo, M.A., Shiee, N., Eckstein, C., Durbin, M.K., Oakley, J.D., Meyer, S.A., Frohman, T.C., Newsome, S., Ratchford, J.N., Balcer, L.J., Pham, D.L., Crainiceanu, C.M., Frohman, E.M., Reich, D.S., Calabresi, P.A., 2013. Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis. JAMA Neurol. 70, 34e43. Saidha, S., Syc, S.B., Durbin, M.K., Eckstein, C., Oakley, J.D., Meyer, S.A., Conger, A., Frohman, T.C., Newsome, S., Ratchford, J.N., Frohman, E.M., Calabresi, P.A., 2011. Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness. Mult. Scler. 17, 1449e1463. Samani, N.N., Proudlock, F.A., Siram, V., Suraweera, C., Hutchinson, C., Nelson, C.P., Al-Uzri, M., Gottlob, I., 2018. Retinal layer abnormalities as biomarkers of schizophrenia. Schizophr. Bull. 44, 876e885. Silverstein, S.M., Fradkin, S.I., Demmin, D.L., 2019. Schizophrenia and the Retina: towards at 2020 Perspective. Schizophrenia Research (in press). Silverstein, S.M., Paterno, D., Cherneski, L., Green, S., 2018. Optical coherence tomography indices of structural retinal pathology in schizophrenia. Psychol. Med. 48, 2023e2033. Tewarie, P., Balk, L., Costello, F., Green, A., Martin, R., Schippling, S., Petzold, A., 2012. The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS One 7, e34823. Tian, T., Zhu, X.H., Liu, Y.H., 2011. Potential role of retina as a biomarker for progression of Parkinson’s disease. Int. J. Ophthalmol. 4, 433e438. Topcu-Yilmaz, P., Aydin, M., Cetin Ilhan, B., 2018. Evaluation of retinal nerve fiber layer, macular, and choroidal thickness in schizophrenia: spectral optic coherence tomography findings. Psychiatr. Clin. Psychopharmacol. 1e6. Walter, S.D., Ishikawa, H., Galetta, K.M., Sakai, R.E., Feller, D.J., Henderson, S.B., Wilson, J.A., Maguire, M.G., Galetta, S.L., Frohman, E., Calabresi, P.A., Schuman, J.S., Balcer, L.J., 2012. Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology 119, 1250e1257. Warner, C.V., Syc, S.B., Stankiewicz, A.M., Hiremath, G., Farrell, S.K., Crainiceanu, C.M., Conger, A., Frohman, T.C., Bisker, E.R., Balcer, L.J., Frohman, E.M., Calabresi, P.A., Saidha, S., 2011. The impact of utilizing different optical coherence tomography devices for clinical purposes and in multiple sclerosis trials. PLoS One 6, e22947.
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Optical coherence tomography of the retina in schizophrenia: Interdevice agreement and relations with perceptual function Margaret Miller a, b, c, 1, Vance Zemon c, Rachel Nolan-Kenney a, e, Laura J. Balcer a, d, e, Donald C. Goff b, f, Michelle Worthington b, 2, Lisena Hasanaj a, Pamela D. Butler b, f, * a
Department of Neurology, New York University School of Medicine, New York, NY, USA Department of Psychiatry, New York University School of Medicine, New York, NY, USA Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY, USA d Department of Ophthalmology, New York University School of Medicine, New York, NY, USA e Department of Population Health, New York University School of Medicine, New York, NY, USA f Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 April 2019 Received in revised form 18 October 2019 Accepted 21 October 2019 Available online xxx
Background: Optical coherence tomography (OCT) studies have demonstrated differences between people with schizophrenia and controls. Many questions remain including the agreement between scanners. The current study seeks to determine inter-device agreement of OCT data in schizophrenia compared to controls and to explore the relations between OCT and visual function measures. Methods: Participants in this pilot study were 12 individuals with schizophrenia spectrum disorders and 12 age- and sex-matched controls. Spectralis and Cirrus OCT machines were used to obtain retinal nerve fiber layer (RNFL) thickness and macular volume. Cirrus was used to obtain ganglion cell layer þ inner plexiform layer (GCL þ IPL) thickness. Visual function was assessed with low-contrast visual acuity and the King-Devick test of rapid number naming. Results: There was excellent relative agreement in OCT measurements between the two machines, but poor absolute agreement, for both patients and controls. On both machines, people with schizophrenia showed decreased macular volume but no difference in RNFL thickness compared to controls. No between-group difference in GCL þ IPL thickness was found on Cirrus. Controls showed significant associations between King-Devick performance and RNFL thickness and macular volume, and between low-contrast visual acuity and GCL þ IPL thickness. Patients did not show significant associations between OCT measurements and visual function. Conclusions: Good relative agreement suggests that the offset between machines remains constant and should not affect comparisons between groups. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device. © 2019 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia Optical coherence tomography Retina Visual Perception
1. Introduction The retina has been described as a “window to the brain” (Silverstein et al., 2018; Chu et al., 2012) because it is part of the central nervous system and, like the brain, develops from the neuroectoderm. Thinning of retinal tissue has been observed in
* Corresponding author. Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY, 10962, USA. E-mail address: [email protected] (P.D. Butler). 1 present address, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. 2 present address, Department of Psychology, Yale University, New Haven, CT, USA.
neuropsychiatric disorders (e.g., Parkinson’s disease and multiple sclerosis) where it often parallels aspects of brain volume loss, disease progression, and cognitive impairment (Tian et al., 2011; Saidha et al., 2013; Frohman et al., 2008; Ko et al., 2018). Studies have consistently demonstrated differences between people with schizophrenia and controls on optical coherence tomography (OCT) of the retina; these findings included thinning of the retinal nerve fiber layer (RNFL), macular layer and ganglion cell-inner plexiform layer (GCL-IPL) (Silverstein et al., 2019; Kazakos and Karageorgiou, 2019). However, many questions remain including the agreement between scanners. The current study seeks to determine, for the first time, inter-device agreement of OCT data in schizophrenia
https://doi.org/10.1016/j.schres.2019.10.046 0920-9964/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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compared to controls and to also explore the relations between OCT and visual function measures. 2. Materials and methods 2.1. Participants Participants consisted of 12 individuals meeting Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria for schizophrenia-spectrum disorders and 12 healthy volunteers. Diagnoses were obtained using the Structured Clinical Interview for DSM-IV (SCID)(First et al., 2010) and all available clinical information. Patients were a subset of those who previously had participated in a study of D-cycloserine Augmentation of Cognitive Behavioral Therapy for Delusions at New York University Langone Medical Center (NYULMC) (Dr. Donald Goff, PI). No participants were still enrolled in that trial or taking D-cyloserine or placebo. Controls were a subset of those who had participated in an OCT research study at NYULMC (Dr. Laura Balcer, PI) and were age- and sex-matched to patients. All participants had vision that could be corrected to 20/30 on an Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Precision Vision, La Salle, IL). Participants were excluded if they had a history of neurological disorder or diseases of the eye (e.g., cataracts, glaucoma). This study was approved by the NYULMC Institutional Review Board and all participants provided informed consent according to the Declaration of Helsinki. Table 1 provides demographic and clinical data.
resolution, was used, as is done for other published papers from our group (e.g., Nolan et al., 2019; Sabadia et al., 2016). Fig. 1 illustrates retinal areas where the scans were performed. There was some missing data for the RNFL and macular volume scans. One patient is missing Cirrus RNFL measurement in both eyes due to difficulty scanning because of behavioral/attention issues. Another patient was missing Cirrus RNLF measurement in the right eye due to difficulty scanning because of behavior/attention issues. Three controls did not receive macular volume scans on either the Cirrus or Spectralis machines because they were collected under a different protocol. In addition, one patient had a Spectralis macular volume measurement that was performed with a different scan protocol and so it was not used in the current analysis. 2.2.2. The King-Devick test This test of oculomotor function requires saccadic eye movements (Galetta et al., 2016; Hasanaj et al., 2018). It includes one practice card and three test cards, which become progressively more difficult by staggering spacing between letters and crowding
2.2. Measures 2.2.1. Optical coherence tomography (OCT) OCT measures were obtained using two different spectral domain-OCT machines: Cirrus 4000, version 6.5.0.772 software (Carl Zeiss Meditec, Jena, Germany), and Spectralis, version 6.0.7 software (Heidelberg Engineering, Carlsbad, CA, USA). Peripapillary RNFL thickness was measured centered on the optic disc and macular volume was measured centered on the fovea using both machines. Measurements of macular GCL þ IPL thickness were obtained only on the Cirrus device. Machine-specific automatic algorithms were applied to compute thickness and volume with inherent differences. Details of OCT scan protocols are given in previous publications from our group (Nolan et al., 2019; Sabadia et al., 2016). The scan with the highest quality according to OSCAR-IB criteria (Tewarie et al., 2012) (i.e., highest signal strength, fewest segmentation errors, and least movement), irrespective of
Table 1 Demographic and clinical information. Patients
Controls
M (SD)
M (SD)
Age (years) Duration of Illness (years) CPZ Equivalent Dose MATRICS Composite Score
48.25 (10.29) 27.25 (14.41) 551.1 (453.7) 33.6 (11.4) % (n)
48.29 (10.64)
Male Female Diagnosis Schizophrenia Schizoaffective Delusional Disorder Antipsychotics First Generation Second Generation Not on Antipsychotic
66.7 (8) 33.3 (4)
66.7 (8) 33.3 (4)
% (n)
66.7 (8) 25.0 (3) 8.3 (1) 25 (3) 50 (6) 25 (3)
Note: n ¼ 12 patients and 12 controls, except duration of illness, n ¼ 11.
Fig. 1. For the RNFL, measurements were obtained in the area around the optic disc and for the macula and GCL þ IPL, measurements were taken in the foveal area. For GCL þ IPL thickness, the arrow points to the layers where the measurements were taken. The vertical white lines for the GCL þ IPL and macula show more specifically where the layers used for these measurements are. The RNFL is made up of unmyelinated ganglion cells that form the optic nerve. The ganglion cell layer of the macula is where the cell bodes of the optic nerve are concentrated. The optic disc is nasal to the fovea. RNFL ¼ retinal nerve fiber layer; GCL þ IPL ¼ ganglion cell layer þ inner plexiform layer.
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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letters closer to each other. Participants read aloud as quickly as possible a series of single-digit numbers from left to right. Performance on the three test cards in seconds constitutes the summary score. 2.2.3. Acuity testing ETDRS Low-Contrast Sloan Letter Charts (Precision Vision, La Salle, IL; 2.5% and 1.25% contrast), which involve identification of gray letters of progressively smaller size, were used to assess low contrast visual acuity. Performance was scored based on the number of letters identified correctly. 2.3. Statistical analysis Separate linear mixed-effects models (LMM) were used to assess OCT results for RNFL thickness, macular volume, and GCL þ IPL thickness. Repeated measurements were fellow eye data (i.e., right and left eyes) and results on the two OCT machines. GCL þ IPL thickness was only obtained on the CIRRUS. Fixed effects were eye condition, OCT machine type, and group (patient/control). Participant was entered into the model as a random (intercept) effect. Post-hoc testing used Mann-Whitney U to follow up on significant results from the LMM. To look at the agreement between fellow eyes and OCT machines, intraclass correlation coefficients (ICCs) were evaluated with a two-way mixed effects model for both relative and absolute agreement.
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thickness was greater by 2 mm in patients vs. controls, but on Cirrus RNFL thickness was lower by 0.4 mm in patients vs. controls, collapsed over fellow eyes. These differences between groups on RNFL were not significant (Table 4). Given the small sample sizes in these analyses (and those reported below), only large effects (d > 1.0) achieved significance, with the smaller effect sizes obtained (0.05e0.85) yielding post hoc power values of only 0.02 0.57. 3.1.2. Macular volume LMM showed a significant main effect of OCT device (F1,61.1 ¼ 2766.1, p < .001), with Cirrus showing greater macular volume than Spectralis. ICCs showed excellent relative agreement, but poor absolute agreement, between the two machines for both patients and controls separately (Table 2A and 2B) and for both groups together (data not shown), due to greater macular volume on Cirrus than Spectralis (Fig. 2). There was no significant fixed effect for eye. ICCs showed excellent relative and absolute agreement between eyes for macular volume (Table 3A and 3B). Though all ICCs were high, they were greater for macular volume measures on Spectralis as compared to Cirrus. These differences in ICCs were not significant, as seen by overlap in the confidence intervals. LMM showed a significant fixed effect of group given the large effect size obtained (F1,20.9 ¼ 6.01, p ¼ .023), with patients showing decreased macular volume across both machines and eyes (Table 4). 3.1.3. Ganglion cell layer þ inner plexiform layer thickness For GCL þ IPL thickness, results of the LMM did not show any significant fixed effects for group or eye or a significant Group Eye interaction with small effect sizes obtained.
3. Results 3.1. Optical coherence tomography 3.1.1. Retinal nerve fiber layer thickness LMM showed a significant fixed effect of OCT device (F1,69 ¼ 111.5, p < .001), with Spectralis showing greater RNFL thickness than Cirrus. ICCs showed excellent relative, but poor absolute, agreement between the two machines for patients and controls separately (Table 2A and 2B) and for both groups together (data not shown), due to the greater thickness on Spectralis than Cirrus. There was a small but significant main effect of eye condition (F1,68.9 ¼ 5.14, p ¼ .026) with the right eye yielding greater RNFL thickness than the left eye. ICCs showed excellent relative and absolute agreement between eyes for both patients and controls (Table 3A and 3B). Though all ICCs were high, they were greater for RNFL measures on Spectralis as compared to Cirrus. These differences in ICCs were not significant, as seen by overlap in the confidence intervals. In addition, correlations between eyes for both patients and controls on each OCT measurement and device ranged from r ¼ .828-.969 with all p values .001. There was also a small but significant Group x OCT device interaction (F1,69 ¼ 4.46, p ¼ .038), in which on Spectralis, RNFL
3.2. Correlations Within the control group, there were significant correlations between King-Devick test times and RNFL thickness and macular volume, with the expected inverse relations, and a significant positive correlation was found between 2.5% low-contrast acuity and GCL þ IPL thickness. Conversely, within the schizophrenia group, there were no significant correlations between OCT measurements and these measures of perceptual function. 4. Discussion We found excellent relative agreement between Spectralis and Cirrus on RNFL thickness and macular volume measurements. However, the machines differed in absolute measurements. RNFL thickness values obtained from Spectralis were higher than those obtained from Cirrus, which is consistent with previous literature (Faghihi et al., 2014; Warner et al., 2011), whereas macular volume measurements obtained from Spectralis were lower than those
Table 2A Agreement between spectralis and cirrus OCT machines e controls. Retinal Measurements
Spectralis
Cirrus
M (SD)
M (SD)
n
ICC(c)
ICC(a)
Right RNFL (mm)
96.42 (7.35)
91.33 (7.75)
12
95.17 (6.04)
90.67 (5.82)
12
Right Macular Volume (mm3)
8.59 (0.31)
10.10 (0.32)
9
Left Macular Volume (mm3)
8.56 (0.30)
10.08 (0.39)
9
.940 [.807,.982] .903 [.700,.971] .852 [.477,.965] .836 [.434,.961]
.770 [-.067,.951] .706 [-.083,.931] .068 [-.006,.356] .079 [-.008,.396]
Left RNFL (mm)
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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Table 2B Agreement between Spectralis and Cirrus OCT Machines e Patients. Retinal Measurements
n
ICC(c)
ICC(a)
90.90 (10.97)
10
98.91 (15.75)
90.91 (14.52)
11
Right Macular Volume (mm )
8.24 (0.31)
9.65 (0.36)
11
Left Macular Volume (mm3)
8.23 (0.32)
9.72 (0.42)
11
.945 [.796,.986] .990 [.963,.997] .849 [.533,.957] .879 [.615,.966]
.812 [-.057,.963] .869 [-.018,.978] .087 [-.008,.397] .098 [-.007,.429]
Right RNFL (mm) Left RNFL (mm) 3
Spectralis
Cirrus
M (SD)
M (SD)
97.40 (11.32)
Note: RNFL ≡ retinal nerve fiber layer. n ≡ number of paired observations, all p .001. ICC(c) ¼ relative agreement, ICC(a) ¼ absolute agreement.
Table 3A Agreement between right and left eyes e controls. Retinal Measurements
n
ICC(c)
ICC(a)
95.17 (6.04)
12
8.59 (0.31)
8.56 (0.30)
9
.895 [.678,.969] .959 [.831,.991]
.888 [.667,.966] .960 [.844,.991]
91.33 (7.75)
90.67 (5.82)
12
Macular Volume (mm3)
10.10 (0.32)
10.08 (0.39)
9
GCL þ IPL (mm)
78.50 (6.26)
79.0 (6.30)
12
.817 [.483,.944] .903 [.631,.977] .971 [.903,.992]
.826 [.506,.947] .911 [.661,.979] .970 [.905,.991]
n
ICC(c)
ICC(a)
.953 [.846,.986] .963 [.871,.990]
.955 [.856,.987] .966 [.881,.991]
.881 [.594,.969] .826 [.503,.947] .908 [.713,.973]
.879 [.609,.968] .834 [.526,.949] .913 [.730,.974]
Spectralis RNFL (mm) Macular Volume (mm3) Cirrus RNFL (mm)
Right Eye
Left Eye
M (SD)
M (SD)
96.42 (7.35)
Table 3B Agreement between right and left eyes e patients. Retinal Measurements
Right Eye
Left Eye
M (SD)
M (SD)
98.25 (13.34)
97.33 (15.98)
12
8.24 (.31)
8.23 (.32)
11
90.90 (10.97)
88.80 (13.41)
10
Macular Volume (mm3)
9.70 (.38)
9.74 (.41)
12
GCL þ IPL (mm)
77.58 (4.58)
77.25 (5.74)
12
Spectralis RNFL (mm) Macular Volume (mm3) Cirrus RNFL (mm)
Note: RNFL ≡ retinal nerve fiber layer, n ≡ number of paired observations, all p < .001. ICC(c) ≡ relative agreement, ICC(a) ≡ absolute agreement.
from Cirrus in the current study. Spectralis and Cirrus have different algorithms for segmentation of the retinal areas used for measurement. In a study in which the macular region was manually segmented in exactly the same way on both machines using an open-source algorithm rather than the algorithms automatically used by the machines, good absolute agreement was found between controls and patients with multiple sclerosis (Bhargava et al., 2015). Most studies, including the current one, use the automatic algorithms and thus differences in absolute agreement are not surprising. Lack of good absolute agreement also indicates that it will not be possible to compare findings from different machines to a single normative standard. Participants with schizophrenia demonstrated significantly reduced macular volume on both Spectralis and Cirrus. While the
difference between patients and controls was relatively small, the effect size was large. This is consistent with previous studies showing reduced macular thickness and/or volume in schizophrenia in many (Joe et al., 2018; Ascaso et al., 2015; Lee et al., 2013; Samani et al., 2018; Topcu-Yilmaz et al., 2018) but not all (Ascaso et al., 2010; Silverstein et al., 2018; Chu et al., 2012) studies. The finding of decreased macular volume on both machines provides further support that between-group differences are similar between devices. In contrast, there were no significant differences between groups in RNFL and GCL þ IPL thickness in the present study. It should also be noted that while the excellent relative reliability shows that the offset between machines remains constant over the range of measures, there was a small but significant interaction between group and machine for RNFL. Thus, while some
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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Table 4 Group differences in retinal parameters. Measure
SCZ
CON
M (n, SD)
M (n, SD)
U
p
Cohen’s d
Retinal Measurements, Spectralis OC T Right RNFL (mm) Left RNFL (mm) Right Macular Volume (mm3) Left Macular Volume (mm3)
98.25 (12, 13.34) 97.33 (12, 15.98) 8.24 (11, 0.31) 8.23 (11, 0.32)
96.42 (12, 7.35) 95.17 (12, 6.04) 8.59 (9, 0.31) 8.56 (9, 0.30)
65.5 60.0 22.0 21.5
.713 .514 .038* .031*
0.18 0.20 1.13 1.06
Retinal Measurements, Cirrus OCT Right RNFL (mm) Left RNFL (mm) Right Macular Volume (mm3) Left Macular Volume (mm3) Right GCL þ IPL (mm) Left GCL þ IPL (mm)
90.90 (10, 10.97) 90.91 (11, 14.52) 9.70 (12, 0.38) 9.74 (12, 0.41) 77.58 (12, 4.58) 77.25 (12, 5.74)
91.33 (12, 7.75) 90.67 (12, 5.82) 10.10 (9, 0.32) 10.08 (9, 0.39) 78.50 (12, 6.26) 79.0 (12, 6.30)
57.0 52.5 22.5 28.5 63.0 56.5
.872 .413 .023* .079 .630 .378
0.05 0.02 1.13 .85 0.17 0.29
Note: RNFL ≡ retinal nerve fiber layer, GCL þ IPL ≡ ganglion cell layer and inner plexiform layer. *p < .05 in post hoc Mann-Whitney U tests.
Fig. 2. Scatterplots of macular volume for the two machines. There is an offset in data from the black line centered on the origin with slope of 1 (indicating absolute agreement) due to greater macular volume on Cirrus than Spectralis.
caution may be warranted, the use of different machines should not affect comparisons between groups. The expected associations between OCT measures and perceptual function (i.e., the King-Devick test that assesses oculomotor function and low-contrast letter acuity) were found in healthy controls but not in participants with schizophrenia. Our results are consistent with what has been found in multiple sclerosis on these tests in relation to OCT measures (Moster et al., 2014; Saidha et al., 2011; Balcer et al., 2017; Walter et al., 2012). Significant relations between OCT measurements and perceptual function were not seen in schizophrenia, which suggests aberrant retinal structure. Few studies have looked at relationships between retinal structure and perceptual function in schizophrenia. Samani et al. (2018) found that decreased contrast sensitivity was related to retinal ganglion cell complex thinning. Further work is needed to assess
relationships between retinal structure and perceptual function in schizophrenia. Limitations of the study include the small sample. However, large effect sizes were obtained for macular volume and sufficient to achieve statistical significance. In addition, the current study did not exclude participants with medical comorbidities, such as diabetes and hypertension. Most schizophrenia studies show retinal thinning but results are somewhat inconsistent between studies which may be due to differences in study samples in terms of stage of illness, medical comorbidities, smoking, neuroinflammation, and other factors that are often not assessed (Silverstein et al., 2019). The high relative agreement between machines found in this study suggests that factors such as medical comorbidity and stage of illness may be more relevant in understanding OCT differences between studies
Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046
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than machine used. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device. Contributors Drs. Miller, Butler, Balcer, Goff, and Zemon and Ms. NolanKenney designed the study and wrote the protocol. Drs. Miller, Butler, and Zemon and Ms. Nolan-Kenney managed the literature searches. Drs. Miller and Zemon and Ms. Nolan-Kenney undertook the statistical analysis, and Dr. Miller wrote the first draft of the manuscript. Dr. Miller and Ms. Nolan-Kenney, Hasanaj, and Worthington, collected and managed data. All authors contributed to and have approved the final manuscript. Funding This project was supported by NIMH R34MH100296 (Goff, PI). Declaration of competing interest All authors declare that they have no conflicts of interest. Acknowledgements The authors thank all who participated in this study. We also thank Dr. Erica Diminich and Ms. Kamber Hart for their contribution to the clinical aspects of this study. References Ascaso, F.J., Cabezon, L., Quintanilla, M., Lopez-Anton, R., Cristobal, J., Lobo, A., 2010. Retinal nerve fiber layer thickness measured by optical coherence tomography in patients with schizophrenia: a short report. Eur. J. Psychiatry 24. Ascaso, F.J., Rodriguez-Jimenez, R., Cabezon, L., Lopez-Anton, R., Santabarbara, J., De la Camara, C., Modrego, P.J., Quintanilla, M.A., Bagney, A., Gutierrez, L., Cruz, N., Cristobal, J.A., Lobo, A., 2015. Retinal nerve fiber layer and macular thickness in patients with schizophrenia: influence of recent illness episodes. Psychiatry Res. 229, 230e236. Balcer, L.J., Raynowska, J., Nolan, R., Galetta, S.L., Kapoor, R., Benedict, R., Phillips, G., LaRocca, N., Hudson, L., Rudick, R., 2017. Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis. Mult. Scler. 23, 734e747. Bhargava, P., Lang, A., Al-Louzi, O., Carass, A., Prince, J., Calabresi, P.A., Saidha, S., 2015. Applying an open-source segmentation algorithm to different OCT devices in multiple sclerosis patients and healthy controls: implications for clinical trials. Mult. Scler. Int. 2015, 136295. Chu, E.M., Kolappan, M., Barnes, T.R., Joyce, E.M., Ron, M.A., 2012. A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography. Psychiatry Res. 203, 89e94. Faghihi, H., Hajizadeh, F., Hashemi, H., Khabazkhoob, M., 2014. Agreement of two different spectral domain optical coherence tomography instruments for retinal nerve fiber layer measurements. J. Ophthalmic Vis. Res. 9, 31e37. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2010. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. SCID-I/P) Biometrics Research, New York State Psychiatric Institute, New York. Revision 2010. Frohman, E.M., Fujimoto, J.G., Frohman, T.C., Calabresi, P.A., Cutter, G., Balcer, L.J., 2008. Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nat. Clin. Pract. Neurol. 4, 664e675. Galetta, K.M., Liu, M., Leong, D.F., Ventura, R.E., Galetta, S.L., Balcer, L.J., 2016. The
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Please cite this article as: Miller, M et al., Optical coherence tomography of the retina in schizophrenia: Inter-device agreement and relations with perceptual function, Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.10.046