Key words
schizophrenia - optical coherence tomography - outer retinal layer thickness
Schlüsselwörter
Schizophrenie - optische Kohärenztomografie - Dicke der äußeren Netzhautschicht
Introduction
Schizophrenia is a severe chronic debilitating mental disorder of early adulthood
causing a lifelong healthcare burden that has a prevalence of about 1%. The pathophysiology
of the disease
remains obscure. Based on clinical assessment, the diagnosis of schizophrenia
consists of positive, negative, and cognitive symptoms [1].
Neuroectoderm gives rise to the retina as well as the brain, which is the sole component
of the central nervous system that can be observed with the naked eye in its natural
state in living
organisms [2]. Several studies revealed that in patients with schizophrenia, magnetic resonance
imaging demonstrates enlarged ventricles and a decrease in total
brain volume, especially in multiple gray matter regions [3]. However, it is interesting to note that spectral-domain optical coherence tomography
(SD-OCT)
parameters have been shown to be in correlation with intracranial volume, even
in healthy subjects [4]. Furthermore, electrophysiological studies reported numerous
electroretinogram (ERG) abnormalities. Moghimi et al. reported decreased b wave
amplitudes in the photopic negative response (PhNR) of the light-adapted flash-electroretinogram
(PhNR-fERG)
compared to healthy controls [5]. The abnormal biopathological retinal findings including decreased ERG wave amplitudes
and reduced macular volume in schizophrenia
patients are appraised as potential biomarkers that may assist in the early identification
of at-risk individuals and facilitate early treatment options [6].
SD-OCT is a noninvasive high depth and resolution imaging technique used to gather
cross-sectional images of the retina and the optic disc. Recent evolution and advancement
of SD-OCT scan
resolution favored measurements of individual retinal layers such as the outer
retinal layer (ORL) thickness. The ORL thickness consists of the myoid, ellipsoid
zone, outer segment of
photoreceptors, and interdigitating zone. The photoreceptor layer, a portion of
the outer retina, contributes spatial information in the course of visual processing
[7]. Deterioration in visual function following the disruption of photoreceptors and
the ellipsoid zone has been demonstrated [8]. It is noteworthy that the
literature encloses some controversial studies regarding the correlation between
macular thickness and visual acuity. Several studies reported moderate to strong correlations
between macular
thickness and visual acuity, however, some reported weak or no correlation [9], [10], [11], [12], given the fact that the alterations or disruption of particular retinal sublayers,
including ORL, may be associated with visual acuity.
SD-OCT has also been used to evaluate the retinal nerve fiber layer (RNFL) in a variety
of diseases, including neurodegenerative disorders like multiple sclerosis, Parkinsonʼs,
and
Alzheimerʼs disease [4], [13], [14]. A meta-analysis concerning schizophrenia and bipolar disease
demonstrated a significant thinning in RNFL compared to healthy controls [15]. However, in some studies, SD-OCT findings in schizophrenia patients remain
controversial and demonstrate either confined alterations or no changes at all
[16], [17], [18]. To the best
of our knowledge, this is the first study evaluating ORL thickness in patients
with schizophrenia alongside other retinal structural changes in OCT.
The aim of this study was to investigate the association between the occurrence and
nonoccurrence of schizophrenia on the retinal structures, especially on ORL and RNFL
thickness alongside
other SD-OCT parameters such as macular thickness, and to identify retinal potential
biomarkers that could be correlated with schizophrenia.
Materials and Methods
A total of 114 eyes of 57 patients diagnosed with schizophrenia and 114 eyes of 57
age- and gender-matched healthy control subjects was included in this retrospective
study. Patients were
diagnosed with schizophrenia according to the Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition (DSM-5), criteria by an experienced and certified
psychiatrist [19]. This study adheres to the tenets of the Declaration of Helsinki and approval of
the local Ethics Committee of Sivas Cumhuriyet University Faculty of Medicine was
obtained. Demographic data of the subjects and a comprehensive ophthalmic examination
including best-corrected visual acuity, intraocular pressure measurement, slit lamp
biomicroscopy findings
of anterior or posterior segments, and SD-OCT images were obtained from the medical
records of the participants. All OCT image acquisition was done in the same hospital
by a single experienced
technician on the same day following the aforementioned examinations after the
dilation of the pupils with tropicamide 0.5% eye drops. Based on the quality scoring
of the images obtained by
the SD-OCT, only the scans meeting the signal strength of 6 and above were included
in the study. The central foveal thickness (CFT), central macular thickness (CMT),
and ORL thickness were
measured in both groups via the images obtained using an SD-OCT device (Nidek
RS-3000 Advance, Gamagori, Japan) with software version 1.5.1. Peripapillary RNFL
scans were obtained using the
Disc Map method with eye tracking, which performs a centered scan on the optic
nerve head in a 6 × 6 mm2 field. For the macular measurements, the macula radial method with eye
tracking, which utilizes 12 radial cross-sectional images of the macula centered
on the foveal pit, was used. Ellipsoid zone (EZ) integrity was also assessed via evaluating
any EZ disruptions
in all 12 radial scans. All measurements were performed by an experienced ophthalmologist
(E. B.) who was masked to the diagnosis of the patients. CMT measurements were presented
as the
average thickness of the macula in the central 1 mm area on the Early Treatment
Diabetic Retinopathy Study (ETDRS) grid. The ORL thickness was defined as the distance
between the external
limiting membrane and retinal pigment epithelium at the center of the foveal pit.
Representative segmentations of external limiting membrane (ELM) and retinal pigment
epithelium (RPE) on
SD-OCT images and the manual measurement method are shown in [Fig. 1]. RNFL thickness was also assessed in four quadrants (inferior, superior, nasal,
temporal). The
inclusion criteria were as follows: participants with a refractive error of ± 3.0
diopters or less, intraocular pressure less than 21 mmHg, and no present optic disc
or macular pathology.
Participants with ocular pathologies including macular degeneration, any retinopathies,
optic neuropathies, glaucoma, or history of ocular trauma, or any ocular surgery that
might interfere
with the OCT measurements were excluded from the study. Participants with known
systemic or inflammatory diseases such as diabetes mellitus, media opacities intercepting
ophthalmic
examination, or OCT scans and who had more than ± 3.0 diopters of refractive error
were also excluded from the study.
Fig. 1 Representative SD-OCT image of retinal structures and measurement method.
Statistical Analysis
Analyses were performed with Statistical Package for the Social Science (SPSS version
20.0. IBM Corp., Armonk, NY) software for Windows. The data distribution was determined
using the
Kolmogorov-Smirnov test. The homogeneity of variables was determined using the
one-way ANOVA homogeneity of variance test. Continuous variables are reported as means ± standard
deviation.
Categorical variables are reported by percentages. No statistically significant
difference was determined between the two eyes of the participants in terms of ORL
thickness, CFT, CMT, and RNFL
thickness. Therefore, the mean values of both eyes were used in the analysis.
Since the parametric assumptions were fulfilled (Kolmogorov-Smirnov), the independent
samples t-test was used to
compare the measurements obtained from two independent groups. We also provided
the t value with the 95% confidence interval of the difference. Cohenʼs d calculation
was performed to determine
the effect size of significant differences. Dots in the box and whisker graphs
were depicted to convey the distribution of SD-OCT findings. The Mann-Whitney U Test
was applied since the data
of CMT, ORL, CFT, and RNFL in the temporal quadrant was not normally distributed.
Independent samples t-test was applied since the RNFL inferior, superior, and nasal
data was normally
disturbed. A value of p < 0.05 was considered statistically significant.
Results
In the schizophrenia group, the mean age of 57 patients was 37 ± 10 of whom 34 (60%)
were male and 23 (40%) were female. No statistically significant difference was found
between groups in
terms of age and gender (p = 0.8 for age, p = 0.9 for gender). The best-corrected
visual acuity was 20/20 in both groups. Demographics and patient characteristics are
summarized in [Table 1].
Table 1 Demographics of the study population.
|
Schizophrenia group (n = 57)
|
Control group (n = 57)
|
t value (95% confidence interval of the difference)
|
p value
|
|
F: female, M: male, NA: not applicable.
|
|
Age, y (mean ± SD)
|
37.2 ± 9.9
|
36.8 ± 9.6
|
0.220 (− 3.228 and 4.035)
|
0.8
|
|
Gender (F/M)
|
23/34
|
24/33
|
NA
|
0.9
|
|
Medical treatment (%/n)
|
|
|
31.6% (n = 18)
|
NA
|
NA
|
NA
|
|
|
19.2% (n = 11)
|
NA
|
NA
|
NA
|
|
|
17.5% (n = 10)
|
NA
|
NA
|
NA
|
|
|
15.7% (n = 9)
|
NA
|
NA
|
NA
|
|
|
12.3% (n = 7)
|
NA
|
NA
|
NA
|
|
|
10.5% (n = 6)
|
NA
|
NA
|
NA
|
|
|
7% (n = 4)
|
NA
|
NA
|
NA
|
|
|
7% (n = 4)
|
NA
|
NA
|
NA
|
|
|
5.2% (n = 3)
|
NA
|
NA
|
NA
|
[Table 2] presents the SD-OCT findings of the participants. The mean CMT was 255.5 ± 25.8 µm
in the schizophrenia group and 262.2 ± 17.6 µm in the control group
(p = 0.1). The mean ORL thickness was 99.8 ± 8.3 µm and significantly lower in
the schizophrenia group compared to 103.7 ± 6.2 µm in the control group with a medium
effect size (p = 0.005;
Cohenʼs d = 0.490368). The mean RNFL thickness in the inferior quadrant was 126.5 ± 16.9 µm
in the schizophrenia group and 138.1 ± 15.1 µm in the control group and the difference
was
significant with a medium effect size (p < 0.001; Cohenʼs d = 0.723856). The mean
RNFL thickness in the superior quadrant was 127.1 ± 17.7 µm in the schizophrenia group
and that of the
controls was 134.6 ± 14.9 µm and the difference was significant with a medium
effect size (p = 0.017; Cohenʼs d = 0.458435). Although the RNFL analysis demonstrated
a significant thinning in
the inferior and superior quadrants in patients with schizophrenia, there was
no significant difference in the temporal and nasal quadrants between groups. No impairment
was observed regarding
the EZ integrity in the patient group. The data distribution of the schizophrenia
and control groups is demonstrated in [Fig. 2] and [3].
Table 2 Comparison of SD-OCT features of patients with schizophrenia and healthy controls.
|
Schizophrenia group (n = 114 eyes) mean ± SD
|
Control group (n = 114 eyes) mean ± SD
|
t value (95% confidence interval of the difference)
|
p value
|
|
ORL: outer retinal layer, CFT: central foveal thickness, CMT: central macular thickness,
RNFL: retinal nerve fiber layer
|
|
ORL thickness, µm
|
99.8 ± 8.3
|
103.7 ± 6.2
|
− 2.851 (− 6.708 and − 1.206)
|
0.005
|
|
CFT, µm
|
210 ± 18.2
|
213.4 ± 20.4
|
− 0.928 (− 10.777 and 3.903)
|
0.35
|
|
CMT, µm
|
255.5 ± 25.8
|
262.2 ± 17.6
|
− 1.632 (− 15.095 and 1.462)
|
0.1
|
|
Inferior RNFL, µm
|
126.5 ± 16.9
|
138.1 ± 15.1
|
− 3.789 (− 17.657 and − 5.528)
|
< 0.001
|
|
Superior RNFL, µm
|
127.1 ± 17.7
|
134.6 ± 14.9
|
− 2.415 (− 13.718 and − 1.349)
|
0.017
|
|
Nasal RNFL, µm
|
74.9 ± 13.4
|
76.6 ± 11.8
|
− 0.661 (− 6.383 and 3.189)
|
0.5
|
|
Temporal RNFL, µm
|
74.3 ± 19.6
|
73.1 ± 9.0
|
0.438 (− 4.451 and 6.978)
|
0.6
|
Fig. 2 Distribution of data including (a) outer retinal layer thickness, (b) central foveal thickness, and (c) central macular thickness. Data are shown as the
mean ± SD.
Fig. 3 Distribution of data including retinal nerve fiber layer thickness in four quadrants
(a inferior, b superior, c nasal, d temporal). Data are
shown as the mean ± SD.
Discussion
Schizophrenia is a debilitating neurodegenerative disorder. Deficits in visual processing
is a substantial measure that needs to be taken seriously in patients with schizophrenia
[20], [21]. Evaluation of the retinal structures with SD-OCT may be useful to demonstrate the
structural changes that may be associated with
the deficits in visual perception and processing. In the current study, the ORL
and peripapillary RNFL thickness were significantly thinner in patients with schizophrenia
compared to healthy
controls.
In the literature, there are studies evaluating RNFL and macular thickness in schizophrenia.
Yilmaz et al. observed decreased overall and nasal RNFL thicknesses in schizophrenia
patients
[17]. Chu et al. investigated RNFL thickness and macular volume in patients with schizophrenia
and observed no significant change regarding RNFL thickness and
macular volume [18]. However, the authors stated that the findings of the study might be compromised
since they used low-resolution OCT [18]. Ascaso et al. examined OCT findings of schizophrenia patients having a recent illness
episode and compared them with healthy controls [16]. They
observed only non-recent illness episode patients had significantly decreased
macular volume and RNFL measurements. However, Cabezon et al. reported thinning only
in peripapillary RNFL, not in
the macular region [22]. Samani et al. brought up a relatively diverse viewpoint on the subject where they
segmented retinal layers and found that total retinal and
photoreceptor complex thickness was reduced in schizophrenia patients [23]. In a recent study, Alizadeh et al. reported that patients with acute schizophrenia
spectrum disorder showed the lowest macular thickness and largest atrophy in RNFL
thickness [24]. Our findings correlate with the results of the aforementioned
studies. We observed a significant reduction in RNFL thickness, especially in
the inferior and superior quadrants, in schizophrenia patients compared to healthy
controls. Nonetheless,
differences in CFT and CMT were not statistically significant between the two
groups. We also assessed ORL thickness, which has been found to be significantly lower
in schizophrenia patients.
Recent studies revealed that the inflammatory pathways play a significant role
in the pathogenesis of schizophrenia [25]. Considering the progressive inflammation
in schizophrenia over the years, this may result in a damage to the photoreceptors
and even thinning in the ORL.
In schizophrenia patients, magnetic resonance imaging studies have revealed advancing
reduction in the grey matter volume, especially as the disease progresses [26]. Braus et al. also observed widespread deficits in the cortical and subcortical
brain regions [27]. This study is also in harmony with the current
evidence in the literature that schizophrenia is a neurodegenerative disease [3]. Since the retina consists of neurons, such changes are likely to affect retinal
structural integrity. On the other hand, the reduction of visual functions was
found to be correlated with the disruption of the hyperreflective lines, mostly the
EZ [28]. However, we did not observe any impairment in EZ integrity in the patient group.
This result may be related to the relatively young age of our study population.
There are controversial outcomes in terms of the correlation between macular thickness
and visual acuity. A previous study revealed a moderate correlation between visual
acuity and foveal
thickening [29]. On the other hand, correlation coefficients regarding the central retinal thickness
and visual acuity have been shown to be low [30]. In a study by Wong et al., they observed ORL thickness correlated more with visual
acuity than the total retinal thickness [31]. Eliwa
et al. observed reduced ORL thickness in patients with diabetic macular edema
and determined a greater correlation with ORL thickness compared to central foveal
point thickness regarding
visual acuity [32]. In the current study, all participants had a best-corrected visual acuity of 20/20
since they were young or middle-aged adults. Hence, it is not
amenable to point out a correlation between visual acuity and ORL thickness in
our study population. However, it might be a potential indicator for possible imminent
visual deficits during the
progression of schizophrenia. There are several studies revealing the effects
of oxidative stress and inflammation on the pathogenesis of schizophrenia [33], [34]. A previous study conducted on experimental mice under induced oxidative stress
revealed the death of photoreceptor cells and gradual decline in the ERG response
and thinning of the outer nuclear layer with the help of SD-OCT [35]. Therefore, it is plausible that we observed a significant reduction in ORL thickness
in
schizophrenia patients. Taken together, our findings demonstrate the reduced ORL
coheres with the aforementioned studies, considering ORL comprises both rod and cone
photoreceptors and is in
close relation with the outer nuclear layer.
There are limitations to this study. Since the study population consisted of mostly
young and middle-aged adults, we were not able to correlate visual acuity with the
reduction in ORL
thickness since all patients had 20/20 visual acuity. The duration subsequent
to the initial diagnosis of schizophrenia and the classification of the disease duration
as acute or chronic was
not considered. The chronicity of the disease may result in alterations of the
findings. Besides, most of the patients were receiving psychotropic treatment at the
time of participation in the
study. Some of the patients were receiving multiple antipsychotic medications,
therefore, evaluating the possible effect of each drug separately was not applicable.
These medications might
have interfered with the results.
Conclusion
The RNFL and ORL thicknesses were significantly lower in schizophrenia patients. The
ORL thickness may be associated with visual deterioration during the course of the
disease. Although we
could not demonstrate an association between visual acuity and ORL thickness,
long-term randomized studies with larger sample sizes are needed. Consequently, OCT
may help facilitate the
clinical diagnosis of schizophrenia and substantially may be considered as a potential
early biomarker for monitoring the progressive neurodegeneration in schizophrenia.
However, future
studies evaluating OCT findings and their correlation with alterations of brain
neuroimaging would be of benefit to determine retinal changes.
