Seminars in Ophthalmology
ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: http://www.tandfonline.com/loi/isio20
Evaluation of Retinal Nerve Fiber Layer Thickness in Acromegalic Patients Using Spectral-Domain Optical Coherence Tomography Necati Duru, Reyhan Ersoy, Hasan Altinkaynak, Zeynep Duru, Nurullah Çağil & Bekir Çakir To cite this article: Necati Duru, Reyhan Ersoy, Hasan Altinkaynak, Zeynep Duru, Nurullah Çağil & Bekir Çakir (2014): Evaluation of Retinal Nerve Fiber Layer Thickness in Acromegalic Patients Using Spectral-Domain Optical Coherence Tomography, Seminars in Ophthalmology, DOI: 10.3109/08820538.2014.962165 To link to this article: http://dx.doi.org/10.3109/08820538.2014.962165
Published online: 07 Nov 2014.
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Date: 08 November 2015, At: 20:40
Seminars in Ophthalmology, Early Online, 1–6, 2014 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2014.962165
ORIGINAL ARTICLE
Evaluation of Retinal Nerve Fiber Layer Thickness in Acromegalic Patients Using Spectral-Domain Optical Coherence Tomography
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Necati Duru1, Reyhan Ersoy2, Hasan Altinkaynak1, Zeynep Duru3, Nurullah C ¸ ag˘il1, and Bekir C ¸ akir2 1
Yildirim Beyazit University, Ankara Atatu¨rk Education and Research Hospital, Department of Ophthalmology, Ankara, Turkey, 2Yildirim Beyazit University, Ankara Atatu¨rk Education and Research Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey, and 3Ankara Numune Education and Research Hospital, Department of Ophthalmology, Ankara, Turkey
ABSTRACT Purpose: To evaluate retinal nerve fiber layer (RNFL) thickness in acromegalic patients. Methods: A study group of 29 patients with acromegaly and a control group of 38 age-matched healthy individuals were enrolled in a cross-sectional study. The study group was further divided by tumor size into two subgroups, a macroadenoma group and a microadenoma group. Serum growth hormone (GH) and insulin-like growth factor-1 (IGF-I) levels were detected at the time of ophthalmological examination in the study group. In both the study and control group, the RNFL thickness in the four quadrants was measured by optical coherence tomography. The relationship between GH and IGF-I levels and RNLF thickness was also evaluated. Results: The difference in mean RNLF thickness in all quadrants between the study and control groups was not statistically significant. In acromegalic patients with macroadenoma, the mean RNLF thickness of the inferior quadrant decreased significantly compared to both patients with microadenoma and healthy individuals (p = 0,032 and p = 0,046). GH and IGF-1 levels were not significantly correlated with the RNLF thickness in the study group. Conclusions: Excessive GH and IGF-1 levels do not affect the optic nerve or RNLF thickness, whereas the RNLF becomes thinner in the inferior quadrant in acromegalic patients with macroadenoma as a result of the chiasmal compression. Keywords: Acromegaly, chiasmal compression, growth hormone, insulin-like growth factor-1, retinal nerve fiber layer
tissues.5,8 In addition, the eye has been examined as another target of excessive GH and IGF-1 levels.9–15 In physiological studies, IGF-1 receptors have been shown in subretinal fluid and vitreous humour. Cultured retinal pigment epithelial cells have also been shown to express mRNAs for type 1 and type 2 IGF receptors.13–15 In other studies, both increased corneal thickness and intraocular pressure (IOP) have been reported in patients with acromegaly.9–11 In contrast, deficiency of GH has also been reported to be associated with optic nerve hypoplasia.16 Additionally, studies show that retinal vascularity
INTRODUCTION Acromegaly is an uncommon disease with an annual incidence of only three to four cases per million and an estimated prevalence of 40 cases per million population.1–5 It is characterized by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) oversecretion from a somatotroph adenoma. The clinical features of acromegaly are attributable to both increased GH and IGF-I.6,7 The excess of these hormones affects many tissues, including skin, connective tissue, cartilage, bone, viscera, and epithelial
Received 14 May 2014; accepted 31 August 2014; published online 7 November 2014 Correspondence: Necati Duru, Ankara Atatu¨rk Education and Research Hospital, Department of Ophthalmology, Ankara, Turkey. E-mail: [email protected]
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was reduced in children with growth hormone receptor insensitivity (Laron syndrome).17 In yet another study, GH therapy has been shown to have a growth-promoting effect on ocular tissue in patients with Laron syndrome.18 These studies confirm that GH and IGF-1 have a potential role in the development of the retina and optic nerve. In acromegalic patients, as stated above, excessive GH and IGF-1 levels may affect the optic nerve; conversely, mechanical compression of somatotroph adenoma to the optic chiasm may cause the retrograde degeneration of axons. As a result, the retinal nerve fiber layer (RNLF) may be affected, but there are no studies as of yet concerning RNLF thicknesses in acromegalic patients. The RNFL is the retinal layer that contains the axons of retinal ganglion cells. Its thickness can be measured non-invasively using optical coherence tomography (OCT). Many studies have attested to the effectiveness and reliability of OCT measurement. A number of studies have also demonstrated that OCT can identify loss of RNFL thickness in patients with chiasmal compression. Today, the RNFL is reliably used in the investigation of optic nerve disease.19–23 Our main purpose in this study is to use RNFL evaluation in order to research whether acromegalic patients exhibit a growth in optic nerve, and to investigate whether RNLF thickness is related to GH and IGF-1 levels and tumor size.
MATERIALS AND METHODS Study Population and Design This comparative study was performed at the Ophthalmology and Endocrinology and Metabolism Departments of Ankara Atatu¨rk Education and Research Hospital in Turkey. Declaration of Helsinki Principles were used and informed consent was obtained from all participants. Approval from the Institutional Review Board Ethics Committee was also obtained. A study group of 29 patients with acromegaly and a control group of 38 age-matched healthy participants were enrolled in the study. The study group was further divided by tumor size into two subgroups, a macroadenoma group and a microadenoma group. Exclusion criteria included history of ocular surgery, any anterior and posterior segment disease or optic nerve disease, including known glaucoma, cup/ disc ratio asymmetry greater than 0.2, and optic nerve hemorrhage. We recorded the patient’s name, sex, tumor size (macroadenoma or microadenoma) at the time of diagnosis, therapies received, years of disease duration, and the serum GH and IGF-I levels at the time of ophthalmological examination.
Study and control groups were compared in terms of mean age, sex distribution, best-corrected visual acuity (BCVA), IOP, axial length (AL), and RNLF thicknesses. In the study group, subgroups were also compared according to RNLF thickness. In addition, we evaluated the affects of GH and IGF-I on ocular parameters.
Endocrinological Examination We made our diagnosis of acromegaly according to clinical characteristics, laboratory findings, and radiological imaging. In each patient, the presence of a somatotroph adenoma was confirmed preoperatively by magnetic resonance imaging (MRI). Somatotroph adenomas were classified into macro (410 mm) or microadenomas (510 mm). Sixteen patients exhibited macroadenoma and 13 exhibited microadenoma. All of the patients underwent surgery after the acromegaly diagnosis. Serum GH was assessed by electrochemiluminescence immunoassay (ECLIA) (hGH kit, Roche, Mannheim, Germany), with a 0.03 ng/ml sensitivity. We measured serum total IGF-1 by immunometric chemiluminescence assay (Immulıte 2000, Sıemens, Gwynedd, UK). The detection limit for IGF-1 was 20 ng/ml and no hook effects were present at levels less than 100,000 ng/ml. In evaluating IGF-I levels, age-adjusted reference ranges were used.
Ocular Examination All participants in both the study and control groups underwent a complete examination, including Snellen BCVA, biomicroscopy, dilated stereoscopic fundus examination, IOP measured by Goldmann applanation tonometry, AL, and OCT measurements. The Lenstar LS 900 biometer (Haag-Streit AG, Koeniz, Switzerland) measured the AL. For the assessment of RNLF, we used the RTVue-100 spectral-domain OCT (Optovue, Inc., Fremont, CA, USA), and the working principle of this device has been detailed elsewhere.24–26 We obtained OCT images without pupil dilation, using the nerve head map 4-mm (NHM4) diameter RTVue protocols. Peripapillary RNFL thickness was measured at a diameter of 3.45 mm around the center of the optic disc with a total of 2225 A-scans. We obtained the average RNFL and RNFL in the inferior, temporal, superior, and nasal quadrants in each RNFL thickness map.
Statistical Analysis All statistical tests were performed using SPSS (Statistical Package for the Social Sciences) version 16. For each continuous variable, normality was checked Seminars in Ophthalmology
Retinal Nerve Fiber Layer Thickness in Acromegaly
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by the Kolmogorov Smirnov test. An independent t-test was used to compare variables between study and control groups. Mann-Whitney u-test was used to compare variables between acromegaly with the macroadenoma study subgroup and acromegaly with the microadenoma study subgroup. One-way analysis of variance test was used to pairwise compare among control and study subgroups. Pearson’s correlation was used to examine the relationships among the measured variables in the acromegaly with the macroadenoma study subgroup. Spearman correlation test was used to examine the relationships among the measured variables in the acromegaly with microadenoma study subgroup. A p value of less than 0.05 was considered statistically significant.
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differed significantly (p = 0,001) between the acromegaly with macroadenoma study subgroup and the acromegaly with microadenoma study subgroup.
OCT Parameters Table 2 reveals the results of the between-group comparison of RNLF thickness. The difference in mean RNLF thickness in all quadrants between the study and control groups was not statistically significant.
TABLE 2. Comprasion of RNLF parameters between study group and control group.
RESULTS
RNFL Thickness
Table 1 shows the baseline characteristics in the study group, the two study subgroups, and the control group. The mean age (p = 0,214), mean AL (p = 0,109), and mean IOP (p = 0,370) did not differ significantly between the study and control groups. The mean AL (p = 0,364), mean IOP (p = 0,838), mean years of disease duration (p = 0,059), mean GH levels (p = 0,900), and mean IGF-1 levels (p = 0,900) did not differ significantly between the acromegaly with macroadenoma study subgroup and the acromegaly with microadenoma study subgroup. The mean age, by contrast,
Study Group
Average Mean ± SD 106,19 ± 18,09 Temporal quadrant Mean ± SD 79,33 ± 17,23 Superior quadrant Mean ± SD 133,86 ± 27,04 Nasal quadrant Mean ± SD 76,14 ± 17,67 Inferior quadrant Mean ± SD 135,48 ± 26,07
Control Group
p valuea
109,88 ± 11,91
0,181
82,32 ± 14,61
0,280
139,72 ± 19,63
0,148
77,49 ± 13,22
0,614
140,01 ± 19,50
0,252
RNLF: Retinal nerve fiber layer; SD: Standard deviation. a independent-samples t-test.
TABLE 1. Patient demographics and characteristics. Study Group Parameter Number of Eyes/Patients Sex Female Male Age (years) Mean ± SD Range IOP Mean ± SD Range AL Mean ± SD Range Disease duration (years) Mean ± SD Range GH Mean ± SD Range IGF-1 Mean ± SD Range
Macroadenoma
Microadenoma
p valueb
–
32/16
26/13
–
18 (47%) 20 (53%)
–
11 (69%) 5 (31%)
7 (54%) 6 (46%)
–
51,34 ± 11,17 27–69
48,45 ± 15,65 22–78
0,214
47,06 ± 9,89 27–63
56,62 ± 10,53 35–69
0,001
16,20 ± 3,04 11–26
15,04 ± 3,27 9–21
0,370
16,25 ± 3,50 11–26
16,15 ± 2,41 12–22
0,838
23,58 ± 1,13 21,85–27,04
23,30 ± 0,71 21,24–24,71
0,109
23,74 ± 1,29 21,87–27,04
23,37 ± 0,89 21,85–24,99
0,364
8,83 ± 4,26 1–20
NA NA
–
9,81 ± 4,82 3–20
7,62 ± 3,14 1–14
0,059
1,89 ± 2,14 0,07–9,02
NA NA
–
2,07 ± 2,54 0,18–9,02
1,66 ± 1,54 0,07–4,79
0,900
372,9 ± 218,7 117,0–927,3
NA NA
–
356,3 ± 218,7 117,0–927,3
393,3 ± 221,3 126,7–845,0
0,900
Study Group
Control Group
p value
58/29
76/38
18 (62%) 11 (38%)
a
IOP: Intraocular pressure; AL: Axial length; GH: Growth hormone; IGF-1: Insulin-like growth factor-1; SD: Standard deviation; a independent-samples t-test; bMann-whitney u-test !
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TABLE 3. Comprasion of RNLF parameters between control group and study subgroups. p valuea
RNFL Thickness
Control Group
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Average Mean ± SD 109,88 ± 11,91 Temporal quadrant Mean ± SD 82,32 ± 14,61 Superior quadrant Mean ± SD 139,72 ± 19,63 Nasal quadrant Mean ± SD 77,49 ± 13,22 Inferior quadrant Mean ± SD 140,01 ± 19,50
Study Group with Macroadenoma
Study Group with Microadenoma
Control versus Macroadenoma
Control versus Microadenoma
Macroadenoma versus Microadenoma
102,62 ± 21,26
110,58 ± 12,23
0,054
0,976
0,105
76,59 ± 20,63
82,69 ± 11,32
0,199
0,994
0,309
131,53 ± 31,98
136,73 ± 19,59
0,217
0,837
0,672
73,75 ± 20,42
79,08 ± 13,44
0,478
0,891
0,386
128,81 ± 28,17
143,69 ± 20,95
0,046
0,745
0,032
RNLF: Retinal nerve fiber layer; SD: Standard deviation. a One-way analysis of variance.
TABLE 4. Correlation analyses between GH, IGF-1, and RNLF parameters in study subgroups. GH RNLF Thickness Average Temporal quadrant Superior quadrant Nasal quadrant Inferior quadrant
Macroadenoma a
r
p
0,187 0,130 0,176 0,213 0,111
0,306 0,477 0,337 0,242 0,544
IGF-1 Microadenoma r 0,305 0,147 0,226 0,368 0,273
p
Macroadenoma b
0,129 0,474 0,268 0,064 0,177
a
r
p
0,184 0,074 0,175 0,133 0,197
0,315 0,686 0,339 0,468 0,280
Microadenoma r 0,273 0,345 0,221 0,342 0,230
pb 0,177 0,085 0,279 0,087 0,259
RNLF: Retinal nerve fiber layer; GH: Growth hormone; IGF-1: Insulin-like growth factor-1. a Pearson correlation test; bSpearman correlation test.
Table 3 compares RNLF thickness in the study subgroups and the control group. We found statistically significant differences of inferior RNLF thickness between the study subgroup with macroadenoma and the control group. (p = 0,046). Similarly, there was a decided difference of inferior RNLF thickness between the macroadenoma study subgroup and the microadenoma group (p = 0,032). We did not find, however, a significant difference in mean RNLF thickness in all quadrants between the study subgroups with microadenoma and the control group. Table 4 shows the correlation analyses between GH, IGF-1, and RNLF parameters in the study subgroups. We did not find the RNLF thickness in all quadrants to be significantly correlated with GH and IGF-1 levels in the study subgroups.
DISCUSSION The RNFL consists of unmyelinated axons of ganglion cells that converge at the optic nerve head. After passing through the optic nerve head, the retinal
axons travel in the optic nerve. At the optic chiasma, the nasal fibers decussate to join the temporal fibers of the contralateral optic nerve to form the optic tract, which projects to the lateral geniculate nucleus.27,28 The compressive lesions affecting the visual pathways may cause atrophy of the RNFL by acute transection of axons, and consequently by retrograde degeneration.29 OCT, a recently developed technique, can quantify RNFL thickness to determine loss of RNLF. OCT provides cross-sectional images of tissue structure on the micron scale by measuring the echo delay time of back-scattered infrared light using an interferometer and a low-coherence light source.30 Pituitary adenomas are frequently encountered intracranial tumors, and are the most common cause of chiasmal compression.31,32 Pituitary macroadenomas can lead to visual symptoms, depending on their duration and size, whereas pituitary microadenomas do not usually lead to visual symptoms, as they are confined to the sella. The pathophysiological mechanism of insult to chiasmal fibers includes ischemic damage of crossing nasal retinal fibers and mechanical damage of nasal fibers.33, 34 Seminars in Ophthalmology
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Retinal Nerve Fiber Layer Thickness in Acromegaly Somatotroph adenomas, which cause acromegaly, are an uncommon group of pituitary adenoma. The clinical features of acromegaly include increased levels of GH and IGF-1, and compression of surrounding structures like the optic chiasm and cranial nerves. As the onset of acromegaly is insidious and indolent, a diagnosis is typically delayed for a variable number of years.3–7 During this period, it is believed that RNLF becomes thinner as a result of the prolonged chiasm compression of the somatotroph adenoma. On the contrary, RNLF might very well thicken due to the affect of excess GH and IGF-1. Previous studies have reported some affects of acromegaly disease on the eye,9–11 but as of yet there have been no studies that evaluate the RNLF thickness of patients with acromegaly. To our knowledge, this is the first study to do so. A few studies have researched the RNLF thickness of patients with pituitary adenomas. Monteiro et al.’s study found a statistically significant decrease in RNLF values in patients with chiasmal compression, as compared to healthy individuals.35 Likewise, Chan Hee Moon et al. reported a marked decrease in RNLF in patients with chiasmal compression.36 In yet another study, using time-domain OCT, DaneshMeyer et al. reported that patients with chiasmal compression had thinner RNLF than control patients.23 In the present study, we found no significant difference in RNLF values between the acromegalic patients with microadenoma and healthy individuals. Furthermore, RNFL thickness in these patients with microadenoma failed to correlate with GH and IGF-1 levels. These findings indicate that RNLF is not affected by excessive GH and IGF-1 levels. By contrast, RNLF thickness in the inferior quadrant decreased significantly in acromegalic patients with macroadenoma, as compared to both the acromegalic patients with microadenoma and healthy individuals. We supposed that RNFL in the inferior quadrant thinned as a result of the prolonged compression of the somatotroph adenoma to the inferior of the optic chiasm. This study has several limitations. First, we admit to a small number of participants because of acromegaly disease’s low prevalence. Second, we could not ascertain the amount of time between the onset of disease and the time of diagnosis; hence, we could not correlate RNLF thickness and the duration of tumor compression. Third, we did not determine the intraocular IGF-1 levels; IGF-1 levels might be correlated with RNLF thickness. In conclusion, there is no relationship between RNLF thickness and GH and IGF-1 levels in acromegalic patients. The RNLF becomes thinner in the inferior quadrant in acromegalic patients with macroadenoma as a result of chiasmal compression. In addition to the perimetric tests, the RNLF analysis by !
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OCT in acromegalic patients with macroadenoma offers important information about ganglion cell injury.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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Seminars in Ophthalmology
ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: http://www.tandfonline.com/loi/isio20
Evaluation of Retinal Nerve Fiber Layer Thickness in Acromegalic Patients Using Spectral-Domain Optical Coherence Tomography Necati Duru, Reyhan Ersoy, Hasan Altinkaynak, Zeynep Duru, Nurullah Çağil & Bekir Çakir To cite this article: Necati Duru, Reyhan Ersoy, Hasan Altinkaynak, Zeynep Duru, Nurullah Çağil & Bekir Çakir (2014): Evaluation of Retinal Nerve Fiber Layer Thickness in Acromegalic Patients Using Spectral-Domain Optical Coherence Tomography, Seminars in Ophthalmology, DOI: 10.3109/08820538.2014.962165 To link to this article: http://dx.doi.org/10.3109/08820538.2014.962165
Published online: 07 Nov 2014.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=isio20 Download by: [Washington University in St Louis]
Date: 08 November 2015, At: 20:40
Seminars in Ophthalmology, Early Online, 1–6, 2014 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2014.962165
ORIGINAL ARTICLE
Evaluation of Retinal Nerve Fiber Layer Thickness in Acromegalic Patients Using Spectral-Domain Optical Coherence Tomography
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Necati Duru1, Reyhan Ersoy2, Hasan Altinkaynak1, Zeynep Duru3, Nurullah C ¸ ag˘il1, and Bekir C ¸ akir2 1
Yildirim Beyazit University, Ankara Atatu¨rk Education and Research Hospital, Department of Ophthalmology, Ankara, Turkey, 2Yildirim Beyazit University, Ankara Atatu¨rk Education and Research Hospital, Department of Endocrinology and Metabolism, Ankara, Turkey, and 3Ankara Numune Education and Research Hospital, Department of Ophthalmology, Ankara, Turkey
ABSTRACT Purpose: To evaluate retinal nerve fiber layer (RNFL) thickness in acromegalic patients. Methods: A study group of 29 patients with acromegaly and a control group of 38 age-matched healthy individuals were enrolled in a cross-sectional study. The study group was further divided by tumor size into two subgroups, a macroadenoma group and a microadenoma group. Serum growth hormone (GH) and insulin-like growth factor-1 (IGF-I) levels were detected at the time of ophthalmological examination in the study group. In both the study and control group, the RNFL thickness in the four quadrants was measured by optical coherence tomography. The relationship between GH and IGF-I levels and RNLF thickness was also evaluated. Results: The difference in mean RNLF thickness in all quadrants between the study and control groups was not statistically significant. In acromegalic patients with macroadenoma, the mean RNLF thickness of the inferior quadrant decreased significantly compared to both patients with microadenoma and healthy individuals (p = 0,032 and p = 0,046). GH and IGF-1 levels were not significantly correlated with the RNLF thickness in the study group. Conclusions: Excessive GH and IGF-1 levels do not affect the optic nerve or RNLF thickness, whereas the RNLF becomes thinner in the inferior quadrant in acromegalic patients with macroadenoma as a result of the chiasmal compression. Keywords: Acromegaly, chiasmal compression, growth hormone, insulin-like growth factor-1, retinal nerve fiber layer
tissues.5,8 In addition, the eye has been examined as another target of excessive GH and IGF-1 levels.9–15 In physiological studies, IGF-1 receptors have been shown in subretinal fluid and vitreous humour. Cultured retinal pigment epithelial cells have also been shown to express mRNAs for type 1 and type 2 IGF receptors.13–15 In other studies, both increased corneal thickness and intraocular pressure (IOP) have been reported in patients with acromegaly.9–11 In contrast, deficiency of GH has also been reported to be associated with optic nerve hypoplasia.16 Additionally, studies show that retinal vascularity
INTRODUCTION Acromegaly is an uncommon disease with an annual incidence of only three to four cases per million and an estimated prevalence of 40 cases per million population.1–5 It is characterized by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) oversecretion from a somatotroph adenoma. The clinical features of acromegaly are attributable to both increased GH and IGF-I.6,7 The excess of these hormones affects many tissues, including skin, connective tissue, cartilage, bone, viscera, and epithelial
Received 14 May 2014; accepted 31 August 2014; published online 7 November 2014 Correspondence: Necati Duru, Ankara Atatu¨rk Education and Research Hospital, Department of Ophthalmology, Ankara, Turkey. E-mail: [email protected]
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was reduced in children with growth hormone receptor insensitivity (Laron syndrome).17 In yet another study, GH therapy has been shown to have a growth-promoting effect on ocular tissue in patients with Laron syndrome.18 These studies confirm that GH and IGF-1 have a potential role in the development of the retina and optic nerve. In acromegalic patients, as stated above, excessive GH and IGF-1 levels may affect the optic nerve; conversely, mechanical compression of somatotroph adenoma to the optic chiasm may cause the retrograde degeneration of axons. As a result, the retinal nerve fiber layer (RNLF) may be affected, but there are no studies as of yet concerning RNLF thicknesses in acromegalic patients. The RNFL is the retinal layer that contains the axons of retinal ganglion cells. Its thickness can be measured non-invasively using optical coherence tomography (OCT). Many studies have attested to the effectiveness and reliability of OCT measurement. A number of studies have also demonstrated that OCT can identify loss of RNFL thickness in patients with chiasmal compression. Today, the RNFL is reliably used in the investigation of optic nerve disease.19–23 Our main purpose in this study is to use RNFL evaluation in order to research whether acromegalic patients exhibit a growth in optic nerve, and to investigate whether RNLF thickness is related to GH and IGF-1 levels and tumor size.
MATERIALS AND METHODS Study Population and Design This comparative study was performed at the Ophthalmology and Endocrinology and Metabolism Departments of Ankara Atatu¨rk Education and Research Hospital in Turkey. Declaration of Helsinki Principles were used and informed consent was obtained from all participants. Approval from the Institutional Review Board Ethics Committee was also obtained. A study group of 29 patients with acromegaly and a control group of 38 age-matched healthy participants were enrolled in the study. The study group was further divided by tumor size into two subgroups, a macroadenoma group and a microadenoma group. Exclusion criteria included history of ocular surgery, any anterior and posterior segment disease or optic nerve disease, including known glaucoma, cup/ disc ratio asymmetry greater than 0.2, and optic nerve hemorrhage. We recorded the patient’s name, sex, tumor size (macroadenoma or microadenoma) at the time of diagnosis, therapies received, years of disease duration, and the serum GH and IGF-I levels at the time of ophthalmological examination.
Study and control groups were compared in terms of mean age, sex distribution, best-corrected visual acuity (BCVA), IOP, axial length (AL), and RNLF thicknesses. In the study group, subgroups were also compared according to RNLF thickness. In addition, we evaluated the affects of GH and IGF-I on ocular parameters.
Endocrinological Examination We made our diagnosis of acromegaly according to clinical characteristics, laboratory findings, and radiological imaging. In each patient, the presence of a somatotroph adenoma was confirmed preoperatively by magnetic resonance imaging (MRI). Somatotroph adenomas were classified into macro (410 mm) or microadenomas (510 mm). Sixteen patients exhibited macroadenoma and 13 exhibited microadenoma. All of the patients underwent surgery after the acromegaly diagnosis. Serum GH was assessed by electrochemiluminescence immunoassay (ECLIA) (hGH kit, Roche, Mannheim, Germany), with a 0.03 ng/ml sensitivity. We measured serum total IGF-1 by immunometric chemiluminescence assay (Immulıte 2000, Sıemens, Gwynedd, UK). The detection limit for IGF-1 was 20 ng/ml and no hook effects were present at levels less than 100,000 ng/ml. In evaluating IGF-I levels, age-adjusted reference ranges were used.
Ocular Examination All participants in both the study and control groups underwent a complete examination, including Snellen BCVA, biomicroscopy, dilated stereoscopic fundus examination, IOP measured by Goldmann applanation tonometry, AL, and OCT measurements. The Lenstar LS 900 biometer (Haag-Streit AG, Koeniz, Switzerland) measured the AL. For the assessment of RNLF, we used the RTVue-100 spectral-domain OCT (Optovue, Inc., Fremont, CA, USA), and the working principle of this device has been detailed elsewhere.24–26 We obtained OCT images without pupil dilation, using the nerve head map 4-mm (NHM4) diameter RTVue protocols. Peripapillary RNFL thickness was measured at a diameter of 3.45 mm around the center of the optic disc with a total of 2225 A-scans. We obtained the average RNFL and RNFL in the inferior, temporal, superior, and nasal quadrants in each RNFL thickness map.
Statistical Analysis All statistical tests were performed using SPSS (Statistical Package for the Social Sciences) version 16. For each continuous variable, normality was checked Seminars in Ophthalmology
Retinal Nerve Fiber Layer Thickness in Acromegaly
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by the Kolmogorov Smirnov test. An independent t-test was used to compare variables between study and control groups. Mann-Whitney u-test was used to compare variables between acromegaly with the macroadenoma study subgroup and acromegaly with the microadenoma study subgroup. One-way analysis of variance test was used to pairwise compare among control and study subgroups. Pearson’s correlation was used to examine the relationships among the measured variables in the acromegaly with the macroadenoma study subgroup. Spearman correlation test was used to examine the relationships among the measured variables in the acromegaly with microadenoma study subgroup. A p value of less than 0.05 was considered statistically significant.
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differed significantly (p = 0,001) between the acromegaly with macroadenoma study subgroup and the acromegaly with microadenoma study subgroup.
OCT Parameters Table 2 reveals the results of the between-group comparison of RNLF thickness. The difference in mean RNLF thickness in all quadrants between the study and control groups was not statistically significant.
TABLE 2. Comprasion of RNLF parameters between study group and control group.
RESULTS
RNFL Thickness
Table 1 shows the baseline characteristics in the study group, the two study subgroups, and the control group. The mean age (p = 0,214), mean AL (p = 0,109), and mean IOP (p = 0,370) did not differ significantly between the study and control groups. The mean AL (p = 0,364), mean IOP (p = 0,838), mean years of disease duration (p = 0,059), mean GH levels (p = 0,900), and mean IGF-1 levels (p = 0,900) did not differ significantly between the acromegaly with macroadenoma study subgroup and the acromegaly with microadenoma study subgroup. The mean age, by contrast,
Study Group
Average Mean ± SD 106,19 ± 18,09 Temporal quadrant Mean ± SD 79,33 ± 17,23 Superior quadrant Mean ± SD 133,86 ± 27,04 Nasal quadrant Mean ± SD 76,14 ± 17,67 Inferior quadrant Mean ± SD 135,48 ± 26,07
Control Group
p valuea
109,88 ± 11,91
0,181
82,32 ± 14,61
0,280
139,72 ± 19,63
0,148
77,49 ± 13,22
0,614
140,01 ± 19,50
0,252
RNLF: Retinal nerve fiber layer; SD: Standard deviation. a independent-samples t-test.
TABLE 1. Patient demographics and characteristics. Study Group Parameter Number of Eyes/Patients Sex Female Male Age (years) Mean ± SD Range IOP Mean ± SD Range AL Mean ± SD Range Disease duration (years) Mean ± SD Range GH Mean ± SD Range IGF-1 Mean ± SD Range
Macroadenoma
Microadenoma
p valueb
–
32/16
26/13
–
18 (47%) 20 (53%)
–
11 (69%) 5 (31%)
7 (54%) 6 (46%)
–
51,34 ± 11,17 27–69
48,45 ± 15,65 22–78
0,214
47,06 ± 9,89 27–63
56,62 ± 10,53 35–69
0,001
16,20 ± 3,04 11–26
15,04 ± 3,27 9–21
0,370
16,25 ± 3,50 11–26
16,15 ± 2,41 12–22
0,838
23,58 ± 1,13 21,85–27,04
23,30 ± 0,71 21,24–24,71
0,109
23,74 ± 1,29 21,87–27,04
23,37 ± 0,89 21,85–24,99
0,364
8,83 ± 4,26 1–20
NA NA
–
9,81 ± 4,82 3–20
7,62 ± 3,14 1–14
0,059
1,89 ± 2,14 0,07–9,02
NA NA
–
2,07 ± 2,54 0,18–9,02
1,66 ± 1,54 0,07–4,79
0,900
372,9 ± 218,7 117,0–927,3
NA NA
–
356,3 ± 218,7 117,0–927,3
393,3 ± 221,3 126,7–845,0
0,900
Study Group
Control Group
p value
58/29
76/38
18 (62%) 11 (38%)
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IOP: Intraocular pressure; AL: Axial length; GH: Growth hormone; IGF-1: Insulin-like growth factor-1; SD: Standard deviation; a independent-samples t-test; bMann-whitney u-test !
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TABLE 3. Comprasion of RNLF parameters between control group and study subgroups. p valuea
RNFL Thickness
Control Group
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Average Mean ± SD 109,88 ± 11,91 Temporal quadrant Mean ± SD 82,32 ± 14,61 Superior quadrant Mean ± SD 139,72 ± 19,63 Nasal quadrant Mean ± SD 77,49 ± 13,22 Inferior quadrant Mean ± SD 140,01 ± 19,50
Study Group with Macroadenoma
Study Group with Microadenoma
Control versus Macroadenoma
Control versus Microadenoma
Macroadenoma versus Microadenoma
102,62 ± 21,26
110,58 ± 12,23
0,054
0,976
0,105
76,59 ± 20,63
82,69 ± 11,32
0,199
0,994
0,309
131,53 ± 31,98
136,73 ± 19,59
0,217
0,837
0,672
73,75 ± 20,42
79,08 ± 13,44
0,478
0,891
0,386
128,81 ± 28,17
143,69 ± 20,95
0,046
0,745
0,032
RNLF: Retinal nerve fiber layer; SD: Standard deviation. a One-way analysis of variance.
TABLE 4. Correlation analyses between GH, IGF-1, and RNLF parameters in study subgroups. GH RNLF Thickness Average Temporal quadrant Superior quadrant Nasal quadrant Inferior quadrant
Macroadenoma a
r
p
0,187 0,130 0,176 0,213 0,111
0,306 0,477 0,337 0,242 0,544
IGF-1 Microadenoma r 0,305 0,147 0,226 0,368 0,273
p
Macroadenoma b
0,129 0,474 0,268 0,064 0,177
a
r
p
0,184 0,074 0,175 0,133 0,197
0,315 0,686 0,339 0,468 0,280
Microadenoma r 0,273 0,345 0,221 0,342 0,230
pb 0,177 0,085 0,279 0,087 0,259
RNLF: Retinal nerve fiber layer; GH: Growth hormone; IGF-1: Insulin-like growth factor-1. a Pearson correlation test; bSpearman correlation test.
Table 3 compares RNLF thickness in the study subgroups and the control group. We found statistically significant differences of inferior RNLF thickness between the study subgroup with macroadenoma and the control group. (p = 0,046). Similarly, there was a decided difference of inferior RNLF thickness between the macroadenoma study subgroup and the microadenoma group (p = 0,032). We did not find, however, a significant difference in mean RNLF thickness in all quadrants between the study subgroups with microadenoma and the control group. Table 4 shows the correlation analyses between GH, IGF-1, and RNLF parameters in the study subgroups. We did not find the RNLF thickness in all quadrants to be significantly correlated with GH and IGF-1 levels in the study subgroups.
DISCUSSION The RNFL consists of unmyelinated axons of ganglion cells that converge at the optic nerve head. After passing through the optic nerve head, the retinal
axons travel in the optic nerve. At the optic chiasma, the nasal fibers decussate to join the temporal fibers of the contralateral optic nerve to form the optic tract, which projects to the lateral geniculate nucleus.27,28 The compressive lesions affecting the visual pathways may cause atrophy of the RNFL by acute transection of axons, and consequently by retrograde degeneration.29 OCT, a recently developed technique, can quantify RNFL thickness to determine loss of RNLF. OCT provides cross-sectional images of tissue structure on the micron scale by measuring the echo delay time of back-scattered infrared light using an interferometer and a low-coherence light source.30 Pituitary adenomas are frequently encountered intracranial tumors, and are the most common cause of chiasmal compression.31,32 Pituitary macroadenomas can lead to visual symptoms, depending on their duration and size, whereas pituitary microadenomas do not usually lead to visual symptoms, as they are confined to the sella. The pathophysiological mechanism of insult to chiasmal fibers includes ischemic damage of crossing nasal retinal fibers and mechanical damage of nasal fibers.33, 34 Seminars in Ophthalmology
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Retinal Nerve Fiber Layer Thickness in Acromegaly Somatotroph adenomas, which cause acromegaly, are an uncommon group of pituitary adenoma. The clinical features of acromegaly include increased levels of GH and IGF-1, and compression of surrounding structures like the optic chiasm and cranial nerves. As the onset of acromegaly is insidious and indolent, a diagnosis is typically delayed for a variable number of years.3–7 During this period, it is believed that RNLF becomes thinner as a result of the prolonged chiasm compression of the somatotroph adenoma. On the contrary, RNLF might very well thicken due to the affect of excess GH and IGF-1. Previous studies have reported some affects of acromegaly disease on the eye,9–11 but as of yet there have been no studies that evaluate the RNLF thickness of patients with acromegaly. To our knowledge, this is the first study to do so. A few studies have researched the RNLF thickness of patients with pituitary adenomas. Monteiro et al.’s study found a statistically significant decrease in RNLF values in patients with chiasmal compression, as compared to healthy individuals.35 Likewise, Chan Hee Moon et al. reported a marked decrease in RNLF in patients with chiasmal compression.36 In yet another study, using time-domain OCT, DaneshMeyer et al. reported that patients with chiasmal compression had thinner RNLF than control patients.23 In the present study, we found no significant difference in RNLF values between the acromegalic patients with microadenoma and healthy individuals. Furthermore, RNFL thickness in these patients with microadenoma failed to correlate with GH and IGF-1 levels. These findings indicate that RNLF is not affected by excessive GH and IGF-1 levels. By contrast, RNLF thickness in the inferior quadrant decreased significantly in acromegalic patients with macroadenoma, as compared to both the acromegalic patients with microadenoma and healthy individuals. We supposed that RNFL in the inferior quadrant thinned as a result of the prolonged compression of the somatotroph adenoma to the inferior of the optic chiasm. This study has several limitations. First, we admit to a small number of participants because of acromegaly disease’s low prevalence. Second, we could not ascertain the amount of time between the onset of disease and the time of diagnosis; hence, we could not correlate RNLF thickness and the duration of tumor compression. Third, we did not determine the intraocular IGF-1 levels; IGF-1 levels might be correlated with RNLF thickness. In conclusion, there is no relationship between RNLF thickness and GH and IGF-1 levels in acromegalic patients. The RNLF becomes thinner in the inferior quadrant in acromegalic patients with macroadenoma as a result of chiasmal compression. In addition to the perimetric tests, the RNLF analysis by !
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OCT in acromegalic patients with macroadenoma offers important information about ganglion cell injury.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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