Current Eye Research, 2014; 39(12): 1216–1220 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.906624
ORIGINAL ARTICLE
Peripapillary Retinal Nerve Fiber Layer Changes in Asymptomatic Essential Thrombocythemia Patients Emre Ayintap1, Gu¨ven Cetin2, Fariz Sadigov1, Ozgur Artunay1, Julide C. U. Akkan1, _ Ibrahim Arif Koytak1 and Kemal Tuncer1 1
Department of Ophthalmology and 2Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey
ABSTRACT Purpose: To investigate peripapillary retinal nerve fiber layer (RNFL) changes using optical coherence tomography (OCT) in patients with asymptomatic essential thrombocythemia (ET). Materials and methods: A consecutive case-control series of 30 patients with asymptomatic ET and age-similar, gender, refractive error, race-matched controls underwent a comprehensive eye examination and OCT of the peripapillary RNFL. Subjects with glaucoma, diabetes mellitus, hemoglobinopaties or other ocular diseases and those who underwent any retinal treatment were excluded. Inferior, superior, nasal and temporal peripapillary RNFL thicknesses were analyzed. One randomly selected eye per subject was compared with those of healthy ones. Results: In the ET patients, the peripapillary RNFL thickness was particularly thin at the temporal quadrant (61.38 ± 9.82 mm, mean ± SD), and the difference was statistically significant (p = 0.036) when compared with the control group (71.24 ± 10.28 mm). The average RNFL thickness was 88.73 ± 12.26 mm in the ET patients and 96.91 ± 13.66 mm in the control group. Although the difference was not statistically significant (p = 0.226), the average RNFL was 8.44% thinner in ET patients than in healthy subjects. Conclusions: Asymptomatic ET patients may have peripapillary RNFL thinning as a result of their systemic illness. This study is the first to demonstrate peripapillary RFNL changes in asymptomatic ET patients. Keywords: Essential thrombocythemia, glaucoma, intraocular pressure, optical coherence tomography, peripapillary retinal nerve fiber layer
INTRODUCTION
occlusive events can also occur in the micro-vessels where they cause a wide range of clinical symptoms. Although conclusive evidence is lacking, this disease is thought to be caused by platelet-mediated transient occlusive thrombosis in the end-arterial circulation.2 As in glaucoma, in diseases that affect the microcirculation, such as diabetes mellitus, branch or central retinal artery occlusion and sickle-cell anaemia, the retinal nerve fiber layer (RNFL) thickness is thinner when compared with healthy subjects.3–6 ET is a chronic transient occlusive disease that also affects microvessels and end-arterial circulation. Therefore, it is assumed that it can cause changes in RNFL, even in the absence of any ocular symptoms. The current
Essential thrombocythemia (ET) is a rare clonal stem cell disease characterized by increased platelet counts, increased risk of hemorrhage and both arterial and venous thrombosis. The prevalence in the general population is approximately 30/100,000, and the female to male ratio is 2:1. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age.1 The clinical picture is dominated by a predisposition to vascular occlusive events, including major thrombotic events involving the coronary, cerebrovascular and peripheral arterial circulation. Vascular
Received 24 November 2013; revised 21 February 2014; accepted 12 March 2014; published online 18 April 2014 Correspondence: Emre Ayintap, Department of Ophthalmology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey. Tel: 905335442111. Fax: 902125332326. E-mail: [email protected]
1216
Retinal Nerve Fiber Layer in Thrombocythemia study investigated peripapillary RNFL changes using optical coherence tomography (OCT) in patients with asymptomatic ET. To the best of our knowledge, this study is the first to demonstrate peripapillary RFNL changes in asymptomatic ET patients.
1217
assessed for normality by use of the Kolmogorov– Smirnov test. The data which follow Gaussians’ distribution was compared by using the independent-samples T test. Nominal data were analyzed using chi-square test. A p value less than 0.05 was considered statistically significant.
_ MATERIALS AND METHODS RESULTS Subjects This consecutive case-control study was undertaken in the ophthalmology department of Bezmialem Vakif University on patients with ET who were followed-up in the hematology and oncology department of the same university. Age, gender, refractive error, racematched healthy controls were selected from patients admitted to the ophthalmology department for a general eye check-up. This study was approved by the ethical committee of Bezmialem Vakif University. All the patients signed informed consent to participate in the research before enrolment. The study adheres to the tenets of the Declaration of Helsinki.
Instrumentation All patients with ET and age/gender/refractive error/race-matched controls underwent a comprehensive eye examination and OCT of the peripapillary RNFL using Stratus OCT (Carl Zeiss Meditec, Dublin, CA). For this study, the fast RNFL thickness protocol (Stratus OCT software version 5.0.0; Carl Zeiss Meditec) was used, and well-focused and centred scans with a signal strength of 7 or greater were included. None of the patients had a history of high intraocular pressure (over 24 mmHg) or an optic nerve vertical cup-to-disc ratio greater than 0.4. Participants with glaucoma, prior retinal treatments, prior eye surgeries, diabetes mellitus or other ocular diseases were excluded from the study. After a detailed ophthalmological examination, the subjects eyes were dilated using cyclopentolate eye drops, and they underwent peripapillary RNFL thickness measurements performed by the same physician (E.A.) using the same OCT device. The data were recorded for each group. Inferior, superior, temporal, nasal and average peripapillary RNFL thicknesses were analyzed.
Statistical Analyses Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL) for Windows 17.0 program. A single eye from each study and control subjects was randomly selected. The distribution of the data was !
2014 Informa Healthcare USA, Inc.
Thirty eyes of 30 ET patients and 30 eyes of 30 age/ gender/race-matched controls were included. The patients diagnosed with ET in the hematology department had an average follow-up period of 4.2 ± 1.4 (Mean ± Standard deviation (SD)) years. The male/ female ratio of the ET patients was 11/19. The mean best-corrected visual acuity of the patients and the controls was logMAR 0.03 and logMAR 0.01, respectively. Eleven of 30 ET patients were myopic, eight were hyperopic, four had myopic astigmatism, and two had hyperopic astigmatism. The mean age of the ET patients was 55.2 ± 13.6 years and that of the healthy controls was 54.4 ± 14.2 years (Table 1). The average RNFL thickness was 88.73 ± 12.26 mm (Mean ± SD) in the ET patients and 96.91 ± 13.66 mm in the control subjects. Although the difference was not statistically significant (p = 0.226), the average RNFL was 8.44% thinner in the ET patients than in the healthy subjects. In the ET patients, the peripapillary RNFL thickness was particularly thin at the temporal quadrant (61.38 ± 9.82mm), and the difference was statistically significant (p = 0.036) when compared with the control group (71.24 ± 10.28mm). Inferior, superior and nasal RNFL thickness measurements were 124.06 ± 14.86 mm, 116.24 ± 13.12 mm and 76.12 ± 10.4 mm in the control group, respectively, and 116.18 ± 12.42 mm, 108.64 ± 12.36 mm, 68.72 ± 9.16 mm in ET patients, respectively. There was no statistically significant difference between these quadrants (p = 0.419, p = 0.482, p = 0.084; respectively). Nevertheless, the RNFL thickness measurements in these quadrants tended to be thinner in the ET patients than in the healthy subjects (Table 2).
DISCUSSION In this study, we found significant thinning in the temporal quadrant of the peripapillary RNFL in ET patients on OCT compared with age/gender/refractive error/race-matched healthy controls. Although no statistically significant difference was found between the two groups, all the peripapillary RNFL thicknesses tended to be thinner in the ET patients than in the healthy controls. There was a decrease of 8.44% in the average peripapillary RNFL thickness in the ET patients in a comparison with the control subjects.
1218 E. Ayintap et al. TABLE 1 Peripapillary retinal nerve fiber layer thickness in asymptomatic essential thrombocythemia: baseline characteristics of study patients. Essential thrombocythemia patients (n = 30)
Controls (n = 30)
p Value
11:19 55.2 ± 13.6 logMAR 0.03 0.34 ± 0.4 16.8 ± 6.2 0.84 ± 0.38
11:19 54.4 ± 14.2 logMAR 0.01 0.36 ± 0.4 16.4 ± 5.8 0.88 ± 0.42
NSa 0.92b 0,84b 0.86b 0.82b 0.74b
Male:female ratio Mean age ± SD (years) Mean best-corrected visual acuity Mean vertical cup-to-disc ratio ± SD Mean intraocular pressure ± SD (mmHg) Mean spherical eqivalent, diopters ± SD
Chi square test; bIndependent-samples t test; NS, non-significant.
a
TABLE 2 Peripapillary retinal nerve fiber layer thickness in asymptomatic essential thrombocythemia mean peripapillary retinal nerve fiber layer thicknesses by sector (mm). RNFL thickness TSNI Mean average ± SD Temporal quadrant ± SD Inferior quadrant ± SD Superior quadrant ± SD Nasal quadrant ± SD
Essential thrombocythemia patients eyes (n = 30)
Healthy controls eyes (n = 30)
p Value
88.73 ± 12.26 mm 61.38 ± 9.82 mm 116.18 ± 12.42 mm 108.64 ± 12.36 mm 68.72 ± 9.16 mm
96.91 ± 13.66 mm 71.24 ± 10.28 mm 124.06 ± 14.86 mm 116.24 ± 13.12 mm 76.12 ± 10.40 mm
p = 0.226b p = 0.036b p = 0.419b p = 0.482b p = 0.084b
b_ Independent-samples t test; TSNI, temporal-superior-nasal-inferior; SD, standard deviation; RNFL, retinal nerve fiber layer.
Peripapillary RNFL thinning occurs especially in ischemic retinopathies. OCT findings in diseases that affect microvessels and/or the microcirculation, such as type1/type2 diabetes mellitus, branch or central retinal artery occlusion and sickle-cell hemoglobinopathy, show peripapillary RNFL changes, even without pre-existing glaucoma.3–6 Chow et al. reported that patients with sickle-cell hemoglobinopathy without pre-existing glaucoma may have peripapillary RNFL thinning. In addition, they reported sickle-cell patient eyes with macular thinning had thinner mean peripapillary RNFL thicknesses in the nasal sector compared with nonsickle-cell control eyes.3 Van Dijk et al. demonstrated ganglion cell layer thinning in the pericentral area and corresponding loss of RNFL thickness in the peripheral macula in patients with type 1 diabetes.4 Other factors that influence RNFL thickness findings are age, race and refractive error. Alasil et al. reported that thinner RNFL measurements were associated with older age, being Caucasian versus being either Hispanic or Asian and being more myopic.7 They also demonstrated an approximately 1.5-mm decrease in the mean RNFL thickness for every decade of increased age. They found no relationship between RNFL thickness and sex.7 Arterial ischemic complications occur in about 35% of patients with ET. Venous thrombosis is more common in polycytemia vera than in ET. It is reported that thromboembolic events occur in about 25–30% of these patients and account for one-third of deaths.1,2,8 Mignon et al. reported that the level of circulating
procoagulant phospholipids was high in patients with ET.9 Labauge et al. reported six cases with neurological complications. In one case, the patient presented with papillitis and peripheral neuropathy.10 They suggested that thrombocythemia may directly induce arterial or venous thrombosis or increase the severity of ischemic strokes of atheromatous origin. In patients with ET, the majority of neurological manifestations are transient and subjective and therefore are easily missed. Studies reported that these manifestations can be diagnosed in 20–55% patients after detailed anamnesis.11,12 Other studies also reported that the etiology of these neurological symptoms and risks factors for their development are unknown.1,2,11 Michiels et al. investigated transient neurologic and ocular manifestations in 17 patients with primary thrombocythemia and analyzed the presenting neurologic and visual symptoms. They found poorly localized symptoms in 14 patients, scintillating scotomata in four patients and transient monocular blindness in two patients with a dull or pulsatile headache. They also found a causal plateletmediated arterial thrombosis in 15 patients. Additionally, they reported no recurrences of thrombotic or ischemic events during long-term treatment of 12 patients with aspirin.13 We believe that the peripapillary RNFL thinning in the current study in patients with ET may be a sign of etiologically unknown neurological symptoms. ET is a rare systemic disease, which is mostly accompanied by asymptomatic eye disorders. Current Eye Research
Retinal Nerve Fiber Layer in Thrombocythemia There are few valuable articles in the ophthalmological literature concerning this issue. The vast majority of the scientific works in the literature focus on cases with occlusive vascular retinal complications.14–18 Imasawa et al. reported ophthalmoscopic and angiographic images of both temporally and spatially independent multiple occlusions of the retinal veins in a patient with ET.14 Bilateral multiple occlusions of retinal veins in the reported case suggested a prothrombotic tendency in retinal circulation in ET. Nobacht et al. reported a 24-year-old man who had an avascular peripheral retina with marked capillary non-perfusion, arteriovenous anastomosis and sea fan neovascularization who presented with acute vitreous hemorrhage.15 Yoshizumi et al. described the case of a 59-year-old man with unilateral central retinal vein occlusion resulting from ET.16 They noted that early thrombocythemia is associated with systemic and ocular thrombotic and embolic complications and that early diagnosis, recognition of ocular complications and appropriate treatment were therefore crucial in controlling central retinal vein occlusion and ocular neovascularization associated with ET. Liu et al. also reported bilateral occlusive retinal disease in patients with ET.17 Sorensen et al. reported sequential severe loss of vision with iritis and ptosis in a patient with essential thrombocytosis.18 The aforementioned studies of ET patients are unique in ophthalmology while our study represents the largest cohort studied to date. In our study, the ET patients were age, gender, refractive error, race-matched with the control subjects. Therefore, we ruled out any other factors that could influence the results. The average RNFL thickness in our study was 88.73 ± 12.26 mm in the ET patients and 96.91 ± 13.66 mm in the control subjects. There was an 8.44% decrease in the total average peripapiller RNFL thickness in the ET patients when compared with the control subjects. We think that the statistically insignificant results in terms of the average RNFL thicknesses between the two groups is due to the relatively small number of patients enrolled in the study. In addition, this slight difference in RNFL measurement may be associated with the arterial ischemic nature of the disease which could be present 35% of ET patients.1,8 However, the tendency in the decrease in the RNFL thickness is noteworthy. Additionally, the temporal peripapillary RNFL thinning was statistically significant. The temporal graph represents a watershed in the risk for terminal arteriolar occlusion and we believe platelet-mediated transient arterial occlusion in the temporal quadrant can be the main reason for the predominantly temporal quadrant thinning in the patients with ET. Therefore, in the differential diagnosis of peripapillary RNFL thinning in ET patients, the influence of systemic disease should be considered, as well as glaucoma. !
2014 Informa Healthcare USA, Inc.
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In this study, the patients diagnosed with ET in the hematology department had an average follow-up period of 4.2 ± 1.4 years. Moreover, we included only patients with well-controlled thrombocythemia who were receiving appropriate treatment. Therefore, our results may differ from studies including ET patients with longer follow-up periods and poorly controlled diseases. Future studies may investigate the associations between RNFL thickness and disease severity or duration of the disease. In current study we used a time-domain OCT. It was reported that RNFL measurements taken with Spectralis, RTVue, and Cirrus all have excellent correlation to Stratus, with good reproducibility in normal eyes.19 Studies by using any spectral-domain OCT can be able to detect smaller differences between groups and can give more precise results. The results of the present study indicate that even in the absence of eye complaints, the temporal peripapillary RNFL thickness is likely to be thinner in ET patients when compared with healthy individuals. We think that the peripapillary RNFL alterations may be the result of platelet-mediated transient occlusive thrombosis in the end-arterial circulation. Patients with asymptomatic ET should be monitored for regular RNFL changes. The cause of RNFL alterations will become clearer in future by prospective studies with a larger number of patients.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
REFERENCES 1. Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2000;65:132–139. 2. Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006;81:159–166. 3. Chow CC, Shah RJ, Lim JI, Chau FY, Hallak JA, Vajaranant TS. Peripapillary retinal nerve fiber layer thickness in sickle-cell hemoglobinopathies using spectral-domain optical coherence tomography. Am J Ophthalmol 2013;155: 456–464. 4. van Dijk HW, Verbraak FD, Kok PH, Garvin MK, Sonka M, Lee K, et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Invest Ophthalmol Vis Sci 2010;51:3660–3665. 5. Takahashi H, Chihara E. Impact of diabetic retinopathy on quantitative retinal nerve fiber layer measurement and glaucoma screening. Invest Ophthalmol Vis Sci 2008;49: 687–692.
1220 E. Ayintap et al. 6. Leung CK, Tham CC, Mohammed S, Li EY, Chan WM, Lam DS. In vivo measurements of macular and nerve fibre layer thickness in retinal arterial occlusion. Eye (Lond) 2007;21:1464–1468. 7. Alasil T, Wang K, Keane PA, Lee H, Baniasadi N, de Boer JF, et al. Analysis of normal retinal nerve fiber layer thickness by age, sex, and race using spectral domain optical coherence tomography. J Glaucoma 2013;22: 532–541. 8. Richard S, Perrin J, Baillot PA, Laccour JC, Ducrocg X. Ischaemic stroke and essential thrombocythemia: a series of 14 cases. Eur J Neurol 2011;18:995–998. 9. Mignon I, Grand F, Boyer F, Hunault-Berger M, Hamel JF, Macchi L. Thrombin generation and procoagulant phospholipids in patients with essential thrombocythemia and reactive thrombocytosis. Am J Hematol. 2013;88: 1007–1011. doi: 10.1002/ajh.23553. 10. Labauge R, Page`s M, Labauge P. Neurologic complications of essential thrombocythemia.6 cases. Rev Neurol (Paris) 1991;147:52–56. 11. Fenaux P, Simon M, Caulier MT, Lai JL, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases. Cancer 1990;66:549–556. 12. Regev A, Stark P, Blickstein D, Lahav M. Thrombotic complications in essential thrombocythemia
13.
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with relatively low platelet counts. Am J Hematol 1997;56: 168–172. Michiels JJ, Koudstaal PJ, Mulder AH, van Vliet HH. Transient neurologic and ocular manifestations in primary thrombocythemia. Neurology 1993;43:1107–1110. Imasawa M, Iijima H. Multiple retinal vein occlusions in essential thrombocythemia. Am J Ophthalmol 2002;133: 152–155. Nobacht S, Cruysberg JR, Deutman AF. Peripheral retinal nonperfusion associated with essential thrombocytosis. Am J Ophthalmol 1999;127:101–102. Yoshizumi MO, Townsend-Pico W. Essential thrombocythemia and central retinal vein occlusion with neovascular glaucoma. Am J Ophthalmol 1996;121:728–730. Liu M, Lee AG, Rice L, Lambert HM. Bilateral retinal vascular occlusive disease in essential thrombocythemia. Retina 1999;19:563–564. Sørensen TL, Mortzos P. Iritis, ptosis, and sequential severe loss of vision in a patient with essential thrombocytosis. Eye (Lond) 2010;24:928. Seibold LK, Mandava N, Kahook MY. Comparison of retinal nerve fiber layer thickness in normal eyes using time-domain and spectral-domain optical coherence tomography. Am J Ophthalmol 2010;150: 807–814.
Current Eye Research
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ORIGINAL ARTICLE
Peripapillary Retinal Nerve Fiber Layer Changes in Asymptomatic Essential Thrombocythemia Patients Emre Ayintap1, Gu¨ven Cetin2, Fariz Sadigov1, Ozgur Artunay1, Julide C. U. Akkan1, _ Ibrahim Arif Koytak1 and Kemal Tuncer1 1
Department of Ophthalmology and 2Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey
ABSTRACT Purpose: To investigate peripapillary retinal nerve fiber layer (RNFL) changes using optical coherence tomography (OCT) in patients with asymptomatic essential thrombocythemia (ET). Materials and methods: A consecutive case-control series of 30 patients with asymptomatic ET and age-similar, gender, refractive error, race-matched controls underwent a comprehensive eye examination and OCT of the peripapillary RNFL. Subjects with glaucoma, diabetes mellitus, hemoglobinopaties or other ocular diseases and those who underwent any retinal treatment were excluded. Inferior, superior, nasal and temporal peripapillary RNFL thicknesses were analyzed. One randomly selected eye per subject was compared with those of healthy ones. Results: In the ET patients, the peripapillary RNFL thickness was particularly thin at the temporal quadrant (61.38 ± 9.82 mm, mean ± SD), and the difference was statistically significant (p = 0.036) when compared with the control group (71.24 ± 10.28 mm). The average RNFL thickness was 88.73 ± 12.26 mm in the ET patients and 96.91 ± 13.66 mm in the control group. Although the difference was not statistically significant (p = 0.226), the average RNFL was 8.44% thinner in ET patients than in healthy subjects. Conclusions: Asymptomatic ET patients may have peripapillary RNFL thinning as a result of their systemic illness. This study is the first to demonstrate peripapillary RFNL changes in asymptomatic ET patients. Keywords: Essential thrombocythemia, glaucoma, intraocular pressure, optical coherence tomography, peripapillary retinal nerve fiber layer
INTRODUCTION
occlusive events can also occur in the micro-vessels where they cause a wide range of clinical symptoms. Although conclusive evidence is lacking, this disease is thought to be caused by platelet-mediated transient occlusive thrombosis in the end-arterial circulation.2 As in glaucoma, in diseases that affect the microcirculation, such as diabetes mellitus, branch or central retinal artery occlusion and sickle-cell anaemia, the retinal nerve fiber layer (RNFL) thickness is thinner when compared with healthy subjects.3–6 ET is a chronic transient occlusive disease that also affects microvessels and end-arterial circulation. Therefore, it is assumed that it can cause changes in RNFL, even in the absence of any ocular symptoms. The current
Essential thrombocythemia (ET) is a rare clonal stem cell disease characterized by increased platelet counts, increased risk of hemorrhage and both arterial and venous thrombosis. The prevalence in the general population is approximately 30/100,000, and the female to male ratio is 2:1. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age.1 The clinical picture is dominated by a predisposition to vascular occlusive events, including major thrombotic events involving the coronary, cerebrovascular and peripheral arterial circulation. Vascular
Received 24 November 2013; revised 21 February 2014; accepted 12 March 2014; published online 18 April 2014 Correspondence: Emre Ayintap, Department of Ophthalmology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey. Tel: 905335442111. Fax: 902125332326. E-mail: [email protected]
1216
Retinal Nerve Fiber Layer in Thrombocythemia study investigated peripapillary RNFL changes using optical coherence tomography (OCT) in patients with asymptomatic ET. To the best of our knowledge, this study is the first to demonstrate peripapillary RFNL changes in asymptomatic ET patients.
1217
assessed for normality by use of the Kolmogorov– Smirnov test. The data which follow Gaussians’ distribution was compared by using the independent-samples T test. Nominal data were analyzed using chi-square test. A p value less than 0.05 was considered statistically significant.
_ MATERIALS AND METHODS RESULTS Subjects This consecutive case-control study was undertaken in the ophthalmology department of Bezmialem Vakif University on patients with ET who were followed-up in the hematology and oncology department of the same university. Age, gender, refractive error, racematched healthy controls were selected from patients admitted to the ophthalmology department for a general eye check-up. This study was approved by the ethical committee of Bezmialem Vakif University. All the patients signed informed consent to participate in the research before enrolment. The study adheres to the tenets of the Declaration of Helsinki.
Instrumentation All patients with ET and age/gender/refractive error/race-matched controls underwent a comprehensive eye examination and OCT of the peripapillary RNFL using Stratus OCT (Carl Zeiss Meditec, Dublin, CA). For this study, the fast RNFL thickness protocol (Stratus OCT software version 5.0.0; Carl Zeiss Meditec) was used, and well-focused and centred scans with a signal strength of 7 or greater were included. None of the patients had a history of high intraocular pressure (over 24 mmHg) or an optic nerve vertical cup-to-disc ratio greater than 0.4. Participants with glaucoma, prior retinal treatments, prior eye surgeries, diabetes mellitus or other ocular diseases were excluded from the study. After a detailed ophthalmological examination, the subjects eyes were dilated using cyclopentolate eye drops, and they underwent peripapillary RNFL thickness measurements performed by the same physician (E.A.) using the same OCT device. The data were recorded for each group. Inferior, superior, temporal, nasal and average peripapillary RNFL thicknesses were analyzed.
Statistical Analyses Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS Inc., Chicago, IL) for Windows 17.0 program. A single eye from each study and control subjects was randomly selected. The distribution of the data was !
2014 Informa Healthcare USA, Inc.
Thirty eyes of 30 ET patients and 30 eyes of 30 age/ gender/race-matched controls were included. The patients diagnosed with ET in the hematology department had an average follow-up period of 4.2 ± 1.4 (Mean ± Standard deviation (SD)) years. The male/ female ratio of the ET patients was 11/19. The mean best-corrected visual acuity of the patients and the controls was logMAR 0.03 and logMAR 0.01, respectively. Eleven of 30 ET patients were myopic, eight were hyperopic, four had myopic astigmatism, and two had hyperopic astigmatism. The mean age of the ET patients was 55.2 ± 13.6 years and that of the healthy controls was 54.4 ± 14.2 years (Table 1). The average RNFL thickness was 88.73 ± 12.26 mm (Mean ± SD) in the ET patients and 96.91 ± 13.66 mm in the control subjects. Although the difference was not statistically significant (p = 0.226), the average RNFL was 8.44% thinner in the ET patients than in the healthy subjects. In the ET patients, the peripapillary RNFL thickness was particularly thin at the temporal quadrant (61.38 ± 9.82mm), and the difference was statistically significant (p = 0.036) when compared with the control group (71.24 ± 10.28mm). Inferior, superior and nasal RNFL thickness measurements were 124.06 ± 14.86 mm, 116.24 ± 13.12 mm and 76.12 ± 10.4 mm in the control group, respectively, and 116.18 ± 12.42 mm, 108.64 ± 12.36 mm, 68.72 ± 9.16 mm in ET patients, respectively. There was no statistically significant difference between these quadrants (p = 0.419, p = 0.482, p = 0.084; respectively). Nevertheless, the RNFL thickness measurements in these quadrants tended to be thinner in the ET patients than in the healthy subjects (Table 2).
DISCUSSION In this study, we found significant thinning in the temporal quadrant of the peripapillary RNFL in ET patients on OCT compared with age/gender/refractive error/race-matched healthy controls. Although no statistically significant difference was found between the two groups, all the peripapillary RNFL thicknesses tended to be thinner in the ET patients than in the healthy controls. There was a decrease of 8.44% in the average peripapillary RNFL thickness in the ET patients in a comparison with the control subjects.
1218 E. Ayintap et al. TABLE 1 Peripapillary retinal nerve fiber layer thickness in asymptomatic essential thrombocythemia: baseline characteristics of study patients. Essential thrombocythemia patients (n = 30)
Controls (n = 30)
p Value
11:19 55.2 ± 13.6 logMAR 0.03 0.34 ± 0.4 16.8 ± 6.2 0.84 ± 0.38
11:19 54.4 ± 14.2 logMAR 0.01 0.36 ± 0.4 16.4 ± 5.8 0.88 ± 0.42
NSa 0.92b 0,84b 0.86b 0.82b 0.74b
Male:female ratio Mean age ± SD (years) Mean best-corrected visual acuity Mean vertical cup-to-disc ratio ± SD Mean intraocular pressure ± SD (mmHg) Mean spherical eqivalent, diopters ± SD
Chi square test; bIndependent-samples t test; NS, non-significant.
a
TABLE 2 Peripapillary retinal nerve fiber layer thickness in asymptomatic essential thrombocythemia mean peripapillary retinal nerve fiber layer thicknesses by sector (mm). RNFL thickness TSNI Mean average ± SD Temporal quadrant ± SD Inferior quadrant ± SD Superior quadrant ± SD Nasal quadrant ± SD
Essential thrombocythemia patients eyes (n = 30)
Healthy controls eyes (n = 30)
p Value
88.73 ± 12.26 mm 61.38 ± 9.82 mm 116.18 ± 12.42 mm 108.64 ± 12.36 mm 68.72 ± 9.16 mm
96.91 ± 13.66 mm 71.24 ± 10.28 mm 124.06 ± 14.86 mm 116.24 ± 13.12 mm 76.12 ± 10.40 mm
p = 0.226b p = 0.036b p = 0.419b p = 0.482b p = 0.084b
b_ Independent-samples t test; TSNI, temporal-superior-nasal-inferior; SD, standard deviation; RNFL, retinal nerve fiber layer.
Peripapillary RNFL thinning occurs especially in ischemic retinopathies. OCT findings in diseases that affect microvessels and/or the microcirculation, such as type1/type2 diabetes mellitus, branch or central retinal artery occlusion and sickle-cell hemoglobinopathy, show peripapillary RNFL changes, even without pre-existing glaucoma.3–6 Chow et al. reported that patients with sickle-cell hemoglobinopathy without pre-existing glaucoma may have peripapillary RNFL thinning. In addition, they reported sickle-cell patient eyes with macular thinning had thinner mean peripapillary RNFL thicknesses in the nasal sector compared with nonsickle-cell control eyes.3 Van Dijk et al. demonstrated ganglion cell layer thinning in the pericentral area and corresponding loss of RNFL thickness in the peripheral macula in patients with type 1 diabetes.4 Other factors that influence RNFL thickness findings are age, race and refractive error. Alasil et al. reported that thinner RNFL measurements were associated with older age, being Caucasian versus being either Hispanic or Asian and being more myopic.7 They also demonstrated an approximately 1.5-mm decrease in the mean RNFL thickness for every decade of increased age. They found no relationship between RNFL thickness and sex.7 Arterial ischemic complications occur in about 35% of patients with ET. Venous thrombosis is more common in polycytemia vera than in ET. It is reported that thromboembolic events occur in about 25–30% of these patients and account for one-third of deaths.1,2,8 Mignon et al. reported that the level of circulating
procoagulant phospholipids was high in patients with ET.9 Labauge et al. reported six cases with neurological complications. In one case, the patient presented with papillitis and peripheral neuropathy.10 They suggested that thrombocythemia may directly induce arterial or venous thrombosis or increase the severity of ischemic strokes of atheromatous origin. In patients with ET, the majority of neurological manifestations are transient and subjective and therefore are easily missed. Studies reported that these manifestations can be diagnosed in 20–55% patients after detailed anamnesis.11,12 Other studies also reported that the etiology of these neurological symptoms and risks factors for their development are unknown.1,2,11 Michiels et al. investigated transient neurologic and ocular manifestations in 17 patients with primary thrombocythemia and analyzed the presenting neurologic and visual symptoms. They found poorly localized symptoms in 14 patients, scintillating scotomata in four patients and transient monocular blindness in two patients with a dull or pulsatile headache. They also found a causal plateletmediated arterial thrombosis in 15 patients. Additionally, they reported no recurrences of thrombotic or ischemic events during long-term treatment of 12 patients with aspirin.13 We believe that the peripapillary RNFL thinning in the current study in patients with ET may be a sign of etiologically unknown neurological symptoms. ET is a rare systemic disease, which is mostly accompanied by asymptomatic eye disorders. Current Eye Research
Retinal Nerve Fiber Layer in Thrombocythemia There are few valuable articles in the ophthalmological literature concerning this issue. The vast majority of the scientific works in the literature focus on cases with occlusive vascular retinal complications.14–18 Imasawa et al. reported ophthalmoscopic and angiographic images of both temporally and spatially independent multiple occlusions of the retinal veins in a patient with ET.14 Bilateral multiple occlusions of retinal veins in the reported case suggested a prothrombotic tendency in retinal circulation in ET. Nobacht et al. reported a 24-year-old man who had an avascular peripheral retina with marked capillary non-perfusion, arteriovenous anastomosis and sea fan neovascularization who presented with acute vitreous hemorrhage.15 Yoshizumi et al. described the case of a 59-year-old man with unilateral central retinal vein occlusion resulting from ET.16 They noted that early thrombocythemia is associated with systemic and ocular thrombotic and embolic complications and that early diagnosis, recognition of ocular complications and appropriate treatment were therefore crucial in controlling central retinal vein occlusion and ocular neovascularization associated with ET. Liu et al. also reported bilateral occlusive retinal disease in patients with ET.17 Sorensen et al. reported sequential severe loss of vision with iritis and ptosis in a patient with essential thrombocytosis.18 The aforementioned studies of ET patients are unique in ophthalmology while our study represents the largest cohort studied to date. In our study, the ET patients were age, gender, refractive error, race-matched with the control subjects. Therefore, we ruled out any other factors that could influence the results. The average RNFL thickness in our study was 88.73 ± 12.26 mm in the ET patients and 96.91 ± 13.66 mm in the control subjects. There was an 8.44% decrease in the total average peripapiller RNFL thickness in the ET patients when compared with the control subjects. We think that the statistically insignificant results in terms of the average RNFL thicknesses between the two groups is due to the relatively small number of patients enrolled in the study. In addition, this slight difference in RNFL measurement may be associated with the arterial ischemic nature of the disease which could be present 35% of ET patients.1,8 However, the tendency in the decrease in the RNFL thickness is noteworthy. Additionally, the temporal peripapillary RNFL thinning was statistically significant. The temporal graph represents a watershed in the risk for terminal arteriolar occlusion and we believe platelet-mediated transient arterial occlusion in the temporal quadrant can be the main reason for the predominantly temporal quadrant thinning in the patients with ET. Therefore, in the differential diagnosis of peripapillary RNFL thinning in ET patients, the influence of systemic disease should be considered, as well as glaucoma. !
2014 Informa Healthcare USA, Inc.
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In this study, the patients diagnosed with ET in the hematology department had an average follow-up period of 4.2 ± 1.4 years. Moreover, we included only patients with well-controlled thrombocythemia who were receiving appropriate treatment. Therefore, our results may differ from studies including ET patients with longer follow-up periods and poorly controlled diseases. Future studies may investigate the associations between RNFL thickness and disease severity or duration of the disease. In current study we used a time-domain OCT. It was reported that RNFL measurements taken with Spectralis, RTVue, and Cirrus all have excellent correlation to Stratus, with good reproducibility in normal eyes.19 Studies by using any spectral-domain OCT can be able to detect smaller differences between groups and can give more precise results. The results of the present study indicate that even in the absence of eye complaints, the temporal peripapillary RNFL thickness is likely to be thinner in ET patients when compared with healthy individuals. We think that the peripapillary RNFL alterations may be the result of platelet-mediated transient occlusive thrombosis in the end-arterial circulation. Patients with asymptomatic ET should be monitored for regular RNFL changes. The cause of RNFL alterations will become clearer in future by prospective studies with a larger number of patients.
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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