COMPARISON OF RETINAL NERVE FIBER LAYER
THICKNESS, MACULA THICKNESS AND OPTIC NERVE HEAD PARAMETERS IN OPIOID DEPENDENT AND NORMAL ADULT
BY
DR WONG CHEE KUEN MBBS (UM)
Dissertation Submitted in Partial Fulfillment Of The Requirement For The Degree of Master of Medicine (Ophthalmology)
SCHOOL OF MEDICAL SCIENCES UNIVERSITI SAINS MALAYSIA
2016
Disclaimer
I hereby certify that the work in this dissertation is my own except for quotations, questionnaires and summaries which have been duly acknowledged.
Dated: 30 November 2016 ………
(Dr Wong Chee Kuen) (PUM0278/11)
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Acknowledgements
I would like to express my deepest appreciation and thanks to my supervisor, Associate Professor Dr Adil Hussein, senior lecturer in the Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, who has been of great help and support throughout the Master program and in the completion of this dissertation.
My gratitude and thanks to my co-supervisor Dr Mohd Azhar Mohd Yasin, Senior Lecturer in the Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, for his assistance in the completion of this dissertation.
I am also grateful to all lecturers in the Department of Ophthalmology Universiti Sains Malaysia and Dr Zamri b. Noordin (Head of Department of Ophthalmology at Hospital Raja Perempuan Zainab II), consultant and specialists, fellow colleagues and staffs in Hospital Raja Perempuan Zainab II for their kind assistance. A special mention to Assoc Prof Nor Azwany and her group of public health student statistician (Dr Siti Aisyah and group) for their assistance and guidance with data analysis.
Above all, I am deeply grateful to my beloved wife Dr Ng Vi Vien and my beloved son Isaac Wong Jian Rui for their love, understanding and sacrifices throughout the Master program. Lastly, a special thanks to my parents and parents-in-law for their help in taking care of my family during the crucial times.
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TABLE OF CONTENTS
Title i
Disclaimer ii
Acknowledgements iii
Table of Contents iv
List of Tables vii
Abstrak viii
Abstract x
CHAPTER 1: INTRODUCTION
1.1 Opioids 2
1.2 Epidemiology of Drug Abuse in Malaysia 2
1.3 Effects of Opioids 3
CHAPTER 2 : OBJECTIVES
2.1 General Objective 6
2.2 Specific Objectives 6
CHAPTER 3: MANUSCRIPT
3.1 Title 8
3.2 Abstract 8
iv
3.3 Introduction 10
3.4 Methodology 11
3.5 Results 14
3.6 Discussion 19
3.7 Conclusion 22
3.8 References 23
3.9 Guidelines / Instruction to Authors for Selected Journal 31
CHAPTER 4: STUDY PROTOCOL
4.1 Introduction 38
4.2 Objectives 40
4.2.1 General Objective 41
4.2.2 Specific Objective 41
4.3 Research Question 41
4.4 Research Hypothesis 41
4.5 Methodology 41
4.6 Flow Chart 47
4.7 Gantt Chart 48
4.8 References 49
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4.9 Appendix
Appendix A – Ethical Approval Form 51
Appendix B – Patient Information Sheet (English) 52
Appendix C – Patient Information Sheet (Bahasa Malaysia) 56
Appendix D – Informed Consent Form (English) 61
Appendix E – Informed Consent Form (Bahasa Malaysia) 63
Appendix F – Data Collection Form 65
Appendix G - Control Group Recruitment Advertisement 67
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List of Tables Page
Table 1 Demographic Data for Both Groups 16
Table 2 Retinal Nerve Fiber Layer Thickness between Opioid 17 Dependent and Control in Right Eye
Table 3 Retinal Nerve Fiber Layer Thickness between Opioid 18 Dependent and Control in Left Eye
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Abstrak
Pengenalan
Penyalahgunaan dadah merupakan masalah sosioekonomi yang mengancam warga awam negara kita. Jenis dadah dalam kumpulan opioid yang sering disalahgunakan di Malaysia adalah heroin dan morfin. Penyalahgunaan opioid dikaitkan dengan ketagihan dan kebergantungan sebagai kesan sampingan. Kesan sampingan yang berkaitan dengan mata adalah miosis anak mata, kemerahan konjunktiva, gangguan pergerakkan mata dan risiko komplikasi seperti endoftalmitis. Degenerasi saraf otak adalah dikaitkan dengan komplikasi penggunaan kronik dadah opioid.
Objektif
Perbandingan antara ketebalan lapisan saraf retina mata, ketebalan makula dan parameter kepala saraf optik di dalam kalangan pengguna opioid dan bukan pengguna.
Metodologi
Kajian kes kawalan antara pengguna opioid dan bukan pengguna opioid telah dilaksanakan di Klinik Methadone, Jabatan Psikiatri dan Klinik Am, Jabatan Oftalmologi Hospital Universiti Sains Malaysia. 35 pengguna opioid dan 35 bukan pengguna dikenalpastikan dan dipelawa untuk menyertai kajian ini. Pemeriksaan oftalmologi dan penyiasatan “optical coherent tomography” dengan menggunakan peralatan Heidelberg Spectralis ® OCT telah dilaksanakan.
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Keputusan
Berbanding dengan bukan pengguna opioid, mata kanan kumpulan pengguna opioid didapati mempunyai purata lapisan saraf retina mata yang lebih nipis (p<0.05).
Ketebalan lapisan saraf retina pada sukuan atasan untuk kedua-dua belah mata didapati lebih nipis dalam kumpulan pengguna opioid berbanding bukan opioid.
Kesimpulan
Penipisan awal dalam lapisan saraf retina mata mungkin merupakan tanda-tanda awal komplikasi dan kesan sampingan daripada penggunaan opioid yang kronik. Penyiasatan lanjutan adalah diperlukan untuk mengenalpasti samaada penipisan ini akan berjanjutan dalam jangka masa lama dan implikasinya kepada penglihatan pengguna opioid.
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Abstract
Introduction
Drug abuse is a socioeconomic problem that affects the public of the country. Heroin and morphine, which falls under the opioid group continues to be the commonest drug of abuse in Malaysia. Opioid usage is associated with addiction and dependence, and reported ocular side effects are pupillary miosis, conjunctiva hyperemia, ocular motility disorder and risk of complication such as endophtalmitis. It was also reported that chronic opioid usage leads to neurological degeneration.
Objective
To compare the retinal nerve fiber layer thickness, macula thickness and optic nerve head parameters in opioid dependent and normal adult.
Method
The study design was a case control with opioid dependent individuals and healthy individuals recruited from the Methadone Clinic, Department of Psychiatry and Ophthalmology Clinic, Department of Ophthalmology, Hospital Universiti Sains Malaysia. Thirty five opioid dependent subjects and thirty five healthy subjects with no history of opioid use were recruited. Ophthalmological examination and optical coherence tomography (Heidelberg Spectralis ® OCT) were performed.
x
Results
Compared to normal healthy subjects, opioid dependent group has thinner average retinal nerve fiber layer in the right eye (p<0.05) and in both superior quadrant of the optic nerve (p<0.05). Analysis of other segments did not show any statistical significance
Conclusion
Early thinning of the retinal nerve fiber layer could be one of the early signs of complication from long term opioid usage. Further studies may be needed to determine if further thinning occurs with time and the implication to the patients’ vision.
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Chapter 1 ___________________
Introduction
1.0 INTRODUCTION
1.1 Opioids
Opioid is a generic term used to describe opiates and their synthetic analogues (United Nations International Drug Control and Laboratory, 2003). Opioid substance binds to opioid receptors to create agonist, partial agonist and antagonist effects (Pathan and Williams, 2012). They are infamously reputed for their use in abuse and addiction.
However, some of it has their usage in medical therapy.
Opioid can be classified according to their origins which are either natural derived, semi-synthetic or synthetic compound. Natural derived from opium poppy includes morphine and codeine while semi-synthetic types are heroin, oxycodone and buprenorphine. Synthetic opioids are methadone, pethidine and fentanyl. Opioid acts on different types of opioid receptors found in our body. Based on International Union of Pharmacology, the four subtypes of opioid receptors are MOP (mu), KOP (kappa), DOP (delta) and NOP.
1.2 Epidemiology of Drug Abuse in Malaysia
Based on 2014statistics provided by the Malaysian National Anti-Drug Agency (AADK), there were a total of 21777 illicit drug users whereby 13605 of them were newly detected users. Of the types of drugs usage reported, heroin and morphine comprises 64.9%, followed by methamphetamine at 18.4% and cannabis 8.6%. The primary route of administration for both heroin and morphine was “chasing the dragon”
(72.2%) compared to by injecting (8.5%)(Maklumat Dadah 2014, 2014). Users are common to mix other drugs besides usage of opioids to maximize the euphoric effects,
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possibility due to increase in tolerance and also reportedly reduced in purity of heroin obtained (Vicknasingam and Navaratnam, 2008).
1.3 Effects of Opioids
Opioid causes effects of sedation, analgesia and especially heroin usage leads to euphoria, which was the primary aim for drug abusers. There are also undesirable side effects such as nausea, vomiting, respiratory depressant, urinary retention, constipation, physical dependence, tolerance and withdrawal symptoms when opioids are stopped abruptly (American Psychiatric et al., 2013; Benyamin et al., 2008; Stahl, 2000). There are many interests in the study of opioids at a molecular level. Animal studies has demonstrated neuronal cells toxicity on exposure to exogenous opioids (Atici et al., 2004; Cunha‐Oliveira et al., 2006; Hu et al., 2002; Tramullas et al., 2008) with the mechanism of apoptotic cell death and oxidative stress described (Guzmán et al., 2006).
A few reported ocular side effects from systemic administration of heroin are pupillary miosis and unreactive pin-point appearance in toxic state, conjunctiva hyperemia, internuclear ophthalmoplegia and nystagmus. Following heroin withdrawal, there were reports of patients having excessive tearing, anisocoria, strabismus and ocular motility disorders (Firth, 2004; McLane and Carroll, 1986). Other known complications as an effect from intravenous injection includes bacterial and fungal endophthalmitis.
Chronic heroin abusers have been shown to develop structural brain changes which could have been from primary cause of heroin or from additional substance used as adulterant. The changes reported includes cerebral atrophy, area of demyelination in white matter and decreased neuronal density (Buttner et al., 2000; Geibprasert et al., 3
2010; Wang et al., 2011). With the retina and optic nerve as the extension of the brain (London et al., 2013), our current study is to determine if there are any changes seen in the retina nerve fiber layer due to chronic opioid usage. Presence of changes in the retinal nerve fiber may further provide data for further study on the harmful effects of opioid.
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Chapter 2 ___________________
Objectives
2.0 OBJECTIVES
2.1 General Objectives
To compare the means of retinal nerve fiber layer (RNFL) thickness, macula thickness and optic nerve head parameters between opioid dependent and healthy non- opioid user adults.
2.2 Specific Objectives
2.2.1 To compare the mean retinal nerve fiber layer thickness between opioid dependent and healthy non-opioid user adults.
2.2.2 To compare the mean macula thickness between opioid dependent and healthy non-opioid user adults.
2.2.3 To compare the mean optic nerve head parameters between opioid dependent and healthy non-opioid user adults.
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Chapter 3 ___________________
Manuscript
3.0 MANUSCRIPT
3.1 Title
Comparison Of Retinal Nerve Fiber Layer Thickness, Macula Thickness and Optic Nerve Head Parameters In Opioid Dependent And Normal Adult
CK Wong1,3, A Hussein1,3, MAM Yasin2,3
1Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
2Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
3Hospital Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
3.2 Abstract
Introduction
Drug abuse is a socioeconomic problem that affects the public of the country. Heroin and morphine, which falls under the opioid group continues to be the commonest drug of abuse in Malaysia. Opioid usage is associated with addiction and dependence, and reported ocular side effects are pupillary miosis, conjunctiva hyperemia, ocular motility disorder and risk of complication such as endophtalmitis. It was also reported that chronic opioid usage leads to neurological degeneration.
Objective
To compare the retinal nerve fiber layer thickness, macula thickness and optic nerve head parameters in opioid dependent and normal adult.
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Method
The study design was a case control with opioid dependent individuals and healthy individuals recruited from the Methadone Clinic, Department of Psychiatry and Ophthalmology Clinic, Department of Ophthalmology, Hospital Universiti Sains Malaysia. Thirty five opioid dependent subjects and thirty five healthy subjects with no history of opioid use were recruited. Ophthalmological examination and optical coherence tomography (Heidelberg Spectralis ® OCT) were performed.
Results
Compared to normal healthy subjects, opioid dependent group has thinner average retinal nerve fiber layer in the right eye (p<0.05) and in both superior quadrant of the optic nerve (p<0.05). Analysis of other segments did not show any statistical significance
Conclusion
Early thinning of the retinal nerve fiber layer could be one of the early signs of complication from long term opioid usage. Further studies may be needed to determine if further thinning occurs in time and the implication to the patients’ vision.
Keyword
Retinal nerve fiber layer, RNFL, Opioid, Heroin
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3.3 Introduction
Opioid is a term used to describe opiates and their synthetic analogues, which includes drugs such as heroin, morphine and methadone. Based on the Malaysian National Anti- Drug Agency 2014 statistics, 64.9% of detected drug users used heroine and morphine.
In experimental laboratory studies, it was reported that street heroin induces apoptosis in rat cortical neurons (Cunha‐Oliveira et al., 2006) while another in vitro experiment on human fetal microglia and has demonstrated morphine-induced apoptosis (Hu et al., 2002).
It is well known that heroin and morphine are associated with addiction and physical dependence. The chronic usage of these substances is known to cause neurodegeneration, cerebral atrophy and white matter impairment which has been demonstrated by neuroimaging modalities such as Computed Tomography (CT) scan and Magnetic Resonance Imaging (MRI) (Geibprasert et al., 2010).
The retinal nerve fiber layer (RNFL) is an important structure in the eye as it is an extension of the ganglion cell axons, which courses along the inner portion of the retina and aggregates to form the optic nerve which continues to form the optic chiasm and optic tract (Gregory L. Skuta et al., 2010). The point where the retinal axons exit the eye is described as the optic nerve head. The RNFL axons are unmyelinated within the retina and they are ideal for the visualizing and analysis of any potential neurodegeneration process (Galetta et al., 2011).
Quantitative examination of the RNFL can be performed using Confocal Scanning Laser Ophthalmoscopy, Scanning Laser Polarimetry or Optical Coherent Tomography. The commonest and widely used method is by using spectral domain Optical Coherent Tomography (OCT). OCT is a non-invasive technique to obtain a 10
cross-sectional image of the retinal. Current spectral domain OCT has an advantage of better quality and resolution, improved reproducibility of images and measurement as compared to the previous generation of time domain OCT (Kiernan et al., 2010). To our knowledge, there are no previous studies that investigate the RNFL thickness in opioid dependent users using OCT.
The aim of this study is to investigate if there are structural changes in the retinal nerve fiber layers and macular in opioid dependent and normal adults. We hypothesize that with chronic usage of opioids, there will be early thinning of the retinal nerve fiber layer as compared to those who are not users.
3.4 Methodology
3.4.1 Subjects
The study was approved by the Research and Ethical Committee, School of Medical Sciences, Universiti Sains Malaysia on 10th February 2014. This study was carried out in accordance to The Code of Ethics of the World Medical Association (Declaration of Helsinki).
All participants provided written informed consent before inclusion in the study. The study design was a case control with opioid dependent individuals and healthy individuals recruited from the Methadone Clinic, Department of Psychiatry and Ophthalmology Clinic, Department of Ophthalmology, Hospital Universiti Sains Malaysia.
Opioid dependent individuals who attended the Methadone Clinic were invited to participate in the study. Inclusion criteria for the opioid dependent group (n=35) were
11
individuals with history of heroin or morphine and methadone use for at least 12 months, clear ocular media at time of examination and age of above 18 years. The exclusion criteria were known clinical history of stroke, neurological or demyelinating disease, previous ocular history of trauma or surgery, optic neuropathies such as glaucoma and optic neuritis, hereditary or acquired retinopathy and maculopathy and refractive error of spherical equivalent of more than 4 dioptres.
As for the healthy control groups (n=35), they were recruited from individuals who had responded to the “Control Group Recruitment Advertisement” and fulfilled the selection criteria. Inclusion criteria were healthy individuals with no history of any substance usage especially opioids group, clear ocular media and age of above 18 years. The exclusion criteria were history of substance abuse, known clinical history of stroke, neurological or demyelinating disease, previous ocular history of trauma or surgery, optic neuropathies such as glaucoma and optic neuritis, hereditary or acquired retinopathy and maculopathy and refractive error of spherical equivalent of more than 4 dioptres.
3.4.2 Ophthalmological Assessment
Ophthalmological assessment included measurement of uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) using Snellen Visual Acuity Chart.
BCVA was determined by using pinhole. Intraocular pressure was measured using Reichert Tono-Pen® tonometer. Slit lamp examination was performed to examine the anterior and posterior segment to document any detected pathology.
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3.4.3 Optical Coherent Tomography (OCT)
RNFL average at the optic disc and RNFL thickness of the quadrants of optic nerve head were measured using Heidelberg Spectralis ® OCT (Heidelberg Engineering, Heidelberg, Germany). The scan centered at the optic disc was automatically acquired.
The Spectralis OCT software version 6.0.14 was used for automatic generation of the quadrants of the optic nerve head, which were superior, inferior, nasal and temporal quadrant.
Macular thickness was measured using Heidelberg Spectralis ® OCT, with the “6mm fast macular mapping” scanning pattern protocol. A good quality macular mapping of the posterior pole with the fovea as the central locus was taken. Quality of at least 25 in the quality bar was accepted for analysis. Both procedures of handling the OCT for measurement was taken by trained medical personnel. Data showing the central macular thickness was used for data analysis.
3.4.4 Statistical Analysis
All statistical analysis and data entry was done using Statistical Package for Social Sciences software version 22.0 (SPSS Inc, IBM, New York, USA). Mean values and standard deviation were used for descriptive analysis.
Values for the RNFL, optic nerve head quadrants and macular thickness were tested for normality and model assumption. Analysis of covariance (ANCOVA) was used to compare the retinal thickness, quadrant RNFL and macular thickness between the opioid dependent group and control group, while controlling for age. Statistical significance was reported at p<0.05.
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3.4.5 Sample Size and Sampling
Sample size calculation was derived using PS Software – Power and Sample Size calculation version 3.0.43 using t-test formula.
Calculation done to detect a mean difference between the two groups difference in RNFL thickness of 5 μm with a standard deviation ±10.14μm (Leung et al., 2010) and a
standardised difference of 0.50, results in a sample size of 35 opioid dependence subjects and 35 controls. This would achieve an 80% probability of detecting differences between two group with p<0.05
3.5 Results
The opioid dependent group consists of 35 subjects with similar number in the normal healthy control. This was the results of convenient sampling recruitment of normal subjects who had responded to the “Recruitment Advertisement”. The demographic data for both groups are shown in Table 1.
Data from both eyes were collected. Analysis by paired t-test was performed to compare differences between right and left eye in each group.
For the opioid dependent group, RNFL parameters shows no differences between eye except in the Temporal group, OD 75.6 ±12.7 vs OS 70.2 ± 11.1, mean of difference 5.4 (p=0.001, 95% CI 2.4,8.4).
For the healthy control group, there was inter eye variability seen in Superior quadrant, OD 133.1 ± 13.9 vs OS 139.5 ± 14.2, mean of difference -6.3 (p<0.001, 95% CI -9.5,-
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3.1) and Nasal quadrant, OD 76.9 ± 14.5 vs OS 71.3 ± 11.5, mean of difference 5.6 (p=0.015, 95% CI 1.1,10.0).
For both opioid dependent and healthy control, there was no inter eye variability in intraocular pressure and vertical cup-to-disc ratio.
The mean age group for opioid dependent were 38.6 ± 6.4 compared to healthy control 29.7 ± 6.9. There was statistical difference (p<0.001) in the mean age group. Analysis of covariance (ANCOVA) was used to control the age confounding factor for subsequent analysis of the retinal thickness, quadrant RNFL and macular thickness between the opioid dependent group and control.
The mean retinal nerve fiber layer thickness between opioid dependent and healthy control were analysed using ANCOVA, adjustment with age. The results are shown in Table 2.
The mean difference in the RNFL between control and opioid dependent group were found to be statistically significant after controlling for age in OD retina average (adjusted mean 97.37 vs 104.63, p=0.015), OD superior quadrant (adjusted mean 118.42 vs 132.78, p=0.001) and OS superior quadrant (adjusted mean 123.02 vs 138.38, p<0.001). Analysis of other segments did not show any statistical significance.
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Table 1: Demographic data for both groups
Opioid dependent n=35
Control
n=35 p
Age (years)
38.6 ± 6.9 29.7 ± 6.9 <0.001a Gender
Male 35 35
Ethnic Malay
35 35
OD Uncorrected Visual Acuity (UCVA), (n,%)
6/6 18 (51.4) 27 (77.1)
6/7.5 - 6/12 12 (34.3) 5 (14.3)
>6/18
5 (14.3) 3 (8.6) OS Uncorrected Visual Acuity
(UCVA), (n,%)
6/6 20 (57.1) 26 (74.3)
6/7.5 - 6/12 10 (28.6) 7 (20.0)
>6/18
5 (14.3) 2 (5.7) OD Best Corrected Visual Acuity
(BCVA)M (n,%)
6/6 29 (82.9) 31 (88.6)
6/7.5 - 6/12 6 (17.1) 4 (11.4)
OS Best Corrected Visual Acuity (BCVA)M (n,%)
6/6 30 (85.7) 32 (91.4)
6/7.5 - 6/12 5 (14.3) 3 (8.6)
OD IOP (mmHg) 13.7 ± 2.4 14.74 ± 2.3 0.022a
OS IOP (mmHg) 13.1 ± 2.2 14.8 ± 2.2 0.002a
OD Cup-disc-ratio 0.41 ± 0.1 0.38 ± 0.1 >0.05a OS Cup-disc-ratio 0.42 ± 0.1 0.39 ± 0.1 >0.05a Coexist disease (n,% )
HIV 6 (17.1) 0
Hepatitis B 3 (8.6) 0
Hepatitis C 26 (74.3) 0
Hypertension 3 (8.6) 1 (2.9)
Diabetes Mellitus 1 (2.9) 2 (5.7)
aStatistical test : t Test
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Table 2: Retinal Nerve Fiber Layer Thickness Between Opioid Dependent and Control in Right Eye
RNFL thickness
(microns) n Adj. Mean (95% CI)a Adj. Mean diff.
(95% CI)b F-stat (df) P value OD Whole Retina
Opioid 35 97.37 (93.59, 101.16) 7.26 (1.40, 13.09) 6.19 (1,70) 0.015 Control 35 104.63 (100.85, 108.42)
OD Macula Thickness
Opioid 35 263.21 (256.05, 270.38) 9.2 (-1.83, 20.23) 2.77 (1,70) 0.101 Control 35 272.42 (265.25, 279.58)
OD Superior
Opioid 35 118.42 (112.97, 123.87) 14.36 (5.97, 22.75) 11.68 (1,70) 0.001 Control 35 132.78 (127.33, 138.23)
OD Inferior
Opioid 35 126.27 (119.78, 132.76) 8.89 (-1.10, 18.87) 3.15 (1,70) 0.080 Control 35 135.16 (128.67, 141.65)
OD Temporal
Opioid 35 75.27 (71.01, 79.52) -1.99 (-8.54, 4.57) 0.37 (1,70) 0.550 Control 35 73.28 (69.02, 77.54)
OD Nasal
Opioid 35 69.61 (63.76, 75.47) 7.8 (-1.21, 16.81) 2.99 (1,70) 0.089 Control 35 77.42 (71.56, 83.27)
aAdjusted mean using ANCOVA after controlling for age
bLeast square difference for 95% CI for difference
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Table 3: Retinal Nerve Fiber Layer Thickness Between Opioid Dependent and Control in Left Eye
RNFL thickness
(microns) n Adj. Mean (95% CI)a Adj. Mean diff.
(95% CI)b F-stat (df) P value OS Whole Retina
Opioid 35 99.96 (96.09, 103.83) 3.5 (-2.45, 9.46) 1.38 (1,70) 0.244 Control 35 103.47 (99.60, 107.34)
OS Macula Thickness
Opioid 35 263.31 (256.42, 270.20) 9.77 (-0.83, 20.38) 3.38 (1,70) 0.070 Control 35 273.09 (266.20, 279.98)
OS Superior
Opioid 35 123.02 (117.96, 128.07) 15.37 (7.59, 23.15) 15.53 (1,70) <0.001 Control 35 138.38 (133.33, 143.44)
OS Inferior
Opioid 35 129.40 (122.61, 136.18) 3.24 (-7.20, 13.68) 0.38 (1,70) 0.538 Control 35 132.63 (125.85, 139.42)
OS Temporal
Opioid 35 70.33 (66.40, 74.25) 1.95 (-4.10, 7.99) 0.41 (1,70) 0.522 Control 35 72.27 (68.35, 76.20)
OS Nasal
Opioid 35 76.67 (70.59, 82.75) -6.25 (-15.61, 3.10) 1.78 (1,70) 0.187 Control 35 70.42 (64.34, 76.49)
aAdjusted mean using ANCOVA after controlling for age
bLeast square difference for 95% CI for difference
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3.6 Discussion
In the demographic table, all patients recruited from both groups are males and of Malay ethnicity. All subjects that were on methadone maintenance therapy at the Methadone Clinic were males. Based on Malaysian National Anti-Drug Agency 2014 statistics, males comprises of 96.8% of all recorded drug addicts (Maklumat Dadah 2014, 2014). Our sample collection of 100% Malay ethnicity does not represent any significance but is due to coincidence of sample collection. The study was conducted in the state of Kelantan where Malay ethnicity comprises of the majority of races. In our study, intereye asymmetry was only found in temporal quadrant of opioid dependent and superior and nasal in control group. Intereye RNFL asymmetry in normal subjects has been found in other studies which mentioned that mean RNFL thickness should not differ more than 9-12µm (Budenz, 2008).
Many researches have been done in regards to RNFL thickness and its relation to diseases such as Alzheimer’s disease, multiple sclerosis and schizophrenia, which showed early abnormal changes (Chu et al., 2012; Frohman et al., 2008; London et al., 2013; Paquet et al., 2007). In our literature search, we could not find any studies that investigated RNFL thickness in subjects taking illicit drugs from opioids group.
Our study found that differences in RNFL thickness between opioid dependent group and control were seen in the OD whole retina (p<0.05) but not in OS (P>0.05). This was unexpected as we predicted changes to occur bilaterally in systemic cause. However, asymmetrical changes can actually occur as demonstrated in open angle glaucoma as OCT studies has been performed in order to detect early primary open-angle glaucoma (Field et al., 2016; Sullivan-Mee et al., 2013). In regards to the comparison of macular
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thickness in both groups, there were no statistical differences seen. As the retina layer is thicker at the macula, the damage from opioid effects may be subtle.
RNFL of the optic nerve head shows statistical difference in the superior quadrant of both eyes but not in other quadrants. Thinning of the superior quadrant shown in both eyes may signify early damages to the retinal nerve fiber layer due to chronic exposure to drug abuse. Anatomical study shows that the retinal nerve fiber layers are thickest inferiorly followed by superior rim. The inferior and superior rim are prone to early damage in glaucomatous changes due to the lamina cribrosa structure which has larger pores and thinner connective tissue and glial support for passing retinal ganglion cell axons (Gupta et al., 2016; Jonas et al., 1991). We hypothesize that the reason thinning occurs in the RNFL is due to accumulated toxicity effect from substance abuse instead of the common risk factors of glaucomatous changes. In our demographic data, there was statistically difference between IOP for control and opioid user. IOP for the opioid dependent group was found to be lower as compared to the healthy control group (13.7
± 2.4 vs 14.74 ± 2.3). This finding was similar to findings by previous study (Drago et al., 1985). Similarly, few experimental animal studies have shown opioid derivatives induced reduction in IOP (Dortch-carnes and Russell, 2006; Russell et al., 2000). There was no statistical difference in cup-disc-ratio between the two groups and there were no intereye asymmetry of cup-disc-ration and IOP to suggest glaucomatous changes.
There are many in vitro studies relating to cellular toxicity caused by drugs from the opioid groups. The exact mechanism of cell death was not known but the studies have shown neuronal cells death caused by cell apoptosis and necrosis (Berrios et al., 2008;
Cunha‐Oliveira et al., 2006; Hu et al., 2002; Mao et al., 2002; Tramullas et al., 2007;
Tramullas et al., 2008). In the brain, white matter and gray matter was shown to be
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impaired in opioid dependent (Buttner et al., 2000; Lin et al., 2012; Lyoo et al., 2006;
Wang et al., 2011).
However, there are also contrasting experimental studies showing neuroprotective effect of opioids in the retina. In an experimental study of induced ischemic retinopathy and subsequent reperfusion, morphine administration post reperfusion has shown a protective effect against ischemia-reperfusion injury (Riazi-Esfahani et al., 2009).
Activation of opioid receptors in the eye has been linked to be neuroprotective against glaucomatous injury by mechanism of suppression of TNF-α production (Husain, 2015;
Husain et al., 2012a; Husain et al., 2012b; Husain et al., 2009)
In our study, we noticed some limitations. The term opioid was used as it comprises of all types of opiates from substance from opium, morphine, heroin, fentanyl and methadone. We are unable to demonstrate the exact drug that causes the thinning of the retinal nerve fiber layer.
Another limitation was due to patient factor. As we know, drug abuse is a social problem and is against the law. Heroin or morphine obtained by users was by illegal means and it is unknown of the quality and purity of the drug. It is also common for unknown substance added to the drug leading to unavoidable confounding factors.
Subjects are also prone for recall bias when providing history. The saving factor for our study was patients were from Methadone clinic which has good record keeping of the duration and amount of methadone taken by patient.
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3.7 Conclusion
There was significant difference in the whole RNFL thickness between opioid dependent and control as examined for right eye but there was no significant difference in the left eye.
There was no significant difference in the mean central macula thickness in both opioid dependent and control group.
Superior quadrant of the optic nerve head was shown to be statistically thinner in opioid dependent group as compared to control.
This shows that there is a possible long term negative side effect of opioid usage in addition to the known negative side effects of opioids. It is recommended that further studies be conducted to monitor if the changes will lead to detectable clinical signs.
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3.8 References
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Diagnostic and statistical manual of mental disorders : DSM-5. Arlington, VA:
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experimental rat model. International journal of neuroscience, 114(8), 1001-1011.
Benyamin, R., Trescot, A. M., Datta, S., Buenaventura, R., Adlaka, R., Sehgal, N., Glaser, S. E. & Vallejo, R. (2008). Opioid complications and side effects. Pain Physician, 11(2 Suppl), S105-120.
Berrios, I., Castro, C. & Kuffler, D. P. (2008). Morphine: axon regeneration, neuroprotection, neurotoxicity, tolerance, and neuropathic pain. Puerto Rico health sciences journal, 27(2).
Budenz, D. L. (2008). Symmetry Between the Right and Left Eyes of the Normal Retinal Nerve Fiber Layer Measured with Optical Coherence Tomography (An AOS Thesis). Transactions of the American Ophthalmological Society, 106, 252-275.
Buttner, A., Mall, G., Penning, R. & Weis, S. (2000). The neuropathology of heroin abuse. Forensic Sci Int, 113(1-3), 435-442.
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Chu, E. M.-Y., Kolappan, M., Barnes, T. R., Joyce, E. M. & Ron, M. A. (2012). A window into the brain: an in vivo study of the retina in schizophrenia using optical coherence tomography. Psychiatry Research: Neuroimaging, 203(1), 89-94.
Cunha‐Oliveira, T., Rego, A. C., Garrido, J., Borges, F., Macedo, T. & Oliveira, C. R.
(2006). Street heroin induces mitochondrial dysfunction and apoptosis in rat cortical neurons. Journal of neurochemistry, 101(2), 543-554.
Dortch-carnes, J. & Russell, K. R. M. (2006). Morphine-Induced Reduction of Intraocular Pressure and Pupil Diameter: Role of Nitric Oxide. Pharmacology, 77(1), 17-24. doi: http://dx.doi.org/10.1159/000091993
Drago, F., Panissidi, G., Bellomio, F., Dal Bello, A., Aguglia, E. & Gorgone, G. (1985).
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Field, M. G., Alasil, T., Baniasadi, N., Que, C., Simavli, H., Sobeih, D., Sola-Del Valle, D., Best, M. J. & Chen, T. C. (2016). Facilitating glaucoma diagnosis with intereye retinal nerve fiber layer asymmetry using spectral-domain optical coherence
tomography. Journal of glaucoma, 25(2), 167-176.
Firth, A. (2004). Ocular sequelae from the illicit use of class A drugs. British and Irish Orthoptic Journal, 1, 10-18.
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Frohman, E. M., Fujimoto, J. G., Frohman, T. C., Calabresi, P. A., Cutter, G. & Balcer, L. J. (2008). Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nature Clinical Practice Neurology, 4(12), 664-675.
Galetta, K. M., Calabresi, P. A., Frohman, E. M. & Balcer, L. J. (2011). Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. Neurotherapeutics, 8(1), 117-132.
Geibprasert, S., Gallucci, M. & Krings, T. (2010). Addictive Illegal Drugs: Structural Neuroimaging. American Journal of Neuroradiology, 31(5), 803-808. doi:
10.3174/ajnr.A1811
Gregory L. Skuta, M. D., Louis B. Cantor, M. D. & Jayne S. Weiss, M. D. (2010).
Retina and Vitreous 2010-2011: Amer Academy of Ophthalmology.
Gupta, P., Cheung, C. Y., Baskaran, M., Tian, J., Marziliano, P., Lamoureux, E. L., Cheung, C. M., Aung, T., Wong, T. Y. & Cheng, C. Y. (2016). Relationship Between Peripapillary Choroid and Retinal Nerve Fiber Layer Thickness in a Population-Based Sample of Nonglaucomatous Eyes. Am J Ophthalmol, 161, 4-11.e11-12. doi:
10.1016/j.ajo.2015.09.018
Guzmán, D. C., Vázquez, I. E., Brizuela, N. O., Alvarez, R. G., Mejía, G. B., García, E.
H., Santamaría, D., de Apreza, M. l. R. & Olguín, H. J. (2006). Assessment of oxidative
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damage induced by acute doses of morphine sulfate in postnatal and adult rat brain.
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Hu, S., Sheng, W. S., Lokensgard, J. R. & Peterson, P. K. (2002). Morphine induces apoptosis of human microglia and neurons. Neuropharmacology, 42(6), 829-836.
Husain, S. (2015). Opioid Receptors: Methods for Detection and Their Modes of Actions in the Eye. In: Spampinato, M. S. (ed.), Opioid Receptors: Methods and Protocols. New York, NY: Springer New York, pp 243-251.
Husain, S., Abdul, Y. & Crosson, C. E. (2012a). Preservation of Retina Ganglion Cell Function by Morphine in a Chronic Ocular-Hypertensive Rat ModelRetina
Neuroprotection by Morphine against Glaucoma. Investigative ophthalmology & visual science, 53(7), 4289-4298.
Husain, S., Abdul, Y. & E Potter, D. (2012b). Non-analgesic effects of opioids:
neuroprotection in the retina. Current pharmaceutical design, 18(37), 6101-6108.
Husain, S., Potter, D. E. & Crosson, C. E. (2009). Opioid receptor-activation: retina protected from ischemic injury. Investigative ophthalmology & visual science, 50(8), 3853-3859.
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Morphometry of the human lamina cribrosa surface. Invest Ophthalmol Vis Sci, 32(2), 401-405.
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Leung, C. K., Ye, C., Weinreb, R. N., Cheung, C., Qiu, Q., Liu, S., Xu, G. & Lam, D.
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Correlating with Memory and Depression in Heroin Users under Methadone Maintenance Treatment. PLoS One, 7(4).
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10.1038/nrneurol.2012.227
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J., Yurgelun-Todd, D. A., Kaufman, M. J. & Renshaw, P. F. (2006). Prefrontal and 27
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10.1097/IAE.0b013e31818a211d
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Hydrodynamics and Iris Function by Bremazocine, a Kappa Opioid Receptor Agonist.
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Tramullas, M., Martínez-Cué, C. & Hurlé, M. A. (2007). Chronic methadone treatment and repeated withdrawal impair cognition and increase the expression of apoptosis- related proteins in mouse brain. Psychopharmacology, 193(1), 107-120.
Tramullas, M., Martínez-Cué, C. & Hurlé, M. A. (2008). Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory. Neuropharmacology, 54(4), 640-652.
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3.9 Guidelines / Instruction To Authors For Selected Journal
Journal Selected : International Journal of Ophthalmology (IJO)
Website : http://www.ijo.cn/gjyken/ch/index.aspx
Instruction for Authors website:
http://www.ijo.cn/gjyken/ch/first_menu.aspx?parent_id=20120104164955001
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Instructions for Authors
Instructions for Authors
GENERAL INFORMATION
International journal of Ophthalmology-1)0 , published continuously since 2008, a global ophthalmological scientific publication and a peer-reviewed, open access periodical published in print and online monthly (ISSN: 2222-3959 print, ISSN: 2227-4898 online). IJO is sponsored by the Chinese Medical Association Xi' an Branch, China and obtains guidance.
and support from World Health Organization (WHO) and International Council of Ophthalmology (ICO).
It is indexed in SCI Expanded, PubMed, PubMed Central, Chemical Abstract, Scopus, EM BASE etc. The latest JCR IF is 0.939.
Aim & Scope
IJO is a comprehensive journal on ophthalmology accepting contributions in English from all over the world. These contributions mainly
include original and review articles, both basic and clinical scientific manuscript. With more than 1000 manuscripts received annually, IJO accepts about 24% submitted manuscripts. IJO applies itself to establish a leading ophthalmology journal in the world, to provide a platform for ophthalmologists and impulse the advanced development of
ophthalmology.
Manuscript Types: Original Articles (Basic Research and Clinical Research), Review.
Meta-Analysis, Commentary, Investigation, Perspective, Opinion, Research Highlight, and Letter to the Editor. etc.
EDITORIAL POLICIES
Peer Review
All manuscripts are subjected to double blind peer-review and
editorial approval before accepting for publication. All contributions will be sent to at least three or more independent reviewers, selected by the editors. Authors are welcome to suggest suitable independent reviewers and may also request that the journal excludes one or two individuals or laboratories, but the editor's decision on the choice of referees is
final.Editors, authors and reviewers are required to keep confidential all details of the editorial and peer review process on submitted
manuscripts, the peer review process is confidential and conducted anonymously; Outcomes of the review process include acceptance, acceptance with revisions but without re-review, revise and resubmit, or rejection. Results of the review process are normally available in about 2-4 months of submission.
Ethical Approval of Studies and Informed Consent: For all manuscripts reporting data from studies involving human participants or animals, a formal review and approval, or formal review and waiver by an appropriate institutional review board or ethics committee is required, and should be described in the Subjects and Methods section. For investigators who do not have a formal ethics review committee (institutional or regional), the principles outlined in the Declaration of Helsinki (2008) must be followed. For investigations done in humans. the Methods section must state the manner in which informed consent was
33
obtained from the subjects {i.e. oral, or written), and whether participants received a
stipend. If experimental animals were used in the research, ljO requires that authors confirm adherence to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research in the Methods section of their manuscript.
Conflicts of Interest: A conflict of interest may exist when an author (or the author's institution or employer) has financial, or personal relationships that could inappropriately influence (or bias) the author's decisions, work, or manuscript. All authors are required to disclose potential conflicts of interest in the Acknowledgments section of the manuscript by following the Recommendations of the International Committee of Medical journal Editors (ICMjE) http://www.icmje.org/urm_main.html
Authors without conflicts of interest, including relevant financial interests, activities, relationships, and affiliations, should indicate that no conflicts of interest exist in the Acknowledgments section of their manuscript.
e.g. Conflicts of Interest: Wang H, None; Barteselli G, None; Freeman WR, None;
Lee SN, None; Chhablani J, None; EI-Emam S, None; Cheng L, None.
Foundations: All financial support for the research and the work should be clearly and completely identified in an Acknowledgment section of the manuscript.
Clinical Trials: When publishing clinical studies, ljO aims to comply with the
Recommendations of International Committee of Medical journal Editors (ICMjE) on trials
registration. Therefore, authors are requested to register the clinical trial presented in the
manuscript in a public trials registry, and include the trial registration number at the end of the abstract.
The following sites are recognized primary registries by the World Health Organization and the ICMjE.
http://www.anzctr.org.au/ (Australia) http://www.chictr.org/ (China) http://www.clinicaltrials.gov (US) https://www.clinicaltrialsregister.eu (EU)
http://ctri.nic.in (India)
http://www.germanctr.de (Germany) http://www.ensaiosclinicos.gov.br (Brazil) http://www.irct.ir (Iran)
http://isrctn.org (UK)
http://ncrc.cdc.go.kr (Republic of Korea)
http://registrocli nico.sld .cu (Cuba)
http://www.umin.ac.jp/ctr/index/htm (Japan)
http://www. trial register. nl/trialreg/index.asp (the Netherlands)
Plagiarism
IJO uses Crossref Similarity Check (powered by iThenticate) to screen submitted contents, and we will do some investigation if the software raises any concerns. If plagiarism is detected after manuscript is
submitted, the manuscript will be rejected; If plagiarism is detected after publication, we may issue a correction or retraction notice for the related paper. We reserve the right to inform authors' institutions about
plagiarism detected either before or after publication. Articles containing plagiarism will be removed from publication and will be reported to the proper authorities.
MANUSCRIPT PREPARATION REQUIREMENTS
Manuscripts are received with the explicit understanding that they are not under
simultaneous consideration by any other publication, except in abstract form. Submission of an article for publication implies the transfer of the copyright from the author to the
publisher upon acceptance.
Language Polishing: If an author's manuscript requires a language polishing service (excludinq translation & rewrite). thev can use the services from the Charlesworth
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All other persons who have made substantial contributions to the work reported in this manuscript (e.g. data collection, analysis, and writing or editing assistance). but who do not fulfill the authorship criteria should be named with their specific contributions in an
Acknowledgements in the manuscript.
Authors must obtain written permission to include the names of all individuals included in the Acknowledgements section, and the corresponding author must confirm that such
permission.
References: Authors should cite the literatures published in recent 5 years as many as possible, while over past 10 years as few as possible. The Price Index (number of literatures
published in recent 5 years/total number of referencesx100) should be over 30%. List
references numerically by order of citation in the text, not alphabetically. All references must be cited in the text or tables. shown as superscript numbers. Authors are responsible for the accuracy of references. References should follow the standards summarized in the recommendations of ICMJE http://www.icmje.org/urm_main.html.
journals
Authors' surnames and initials. Article title. Abbreviated name of journal Year;vol(issue No.):inclusive pages.
e.g. Yuan A, Ahmad BU, Xu D, Singh RP, Kaiser PK, Martin DF, Sears JE, Schachat AP, Ehlers JP. Comparison of intravitreal ranibizumab and bevacizumab for the treatment of macular edema secondary to retinal vein occlusion. lnt) Ophthalmol 2014;7(1):86-91.
Books
1 An entire book: Authors' surnames and initials. Book Title. Edition number (if it is the second edition or above). State (or Country) of publisher: Publisher's name; copyright year.
e.g. Naumann GOH, Hoi bach L, Kruse FE. Applied Pathology for Ophthalmic Microsurgeons.
Germany:Springer; 2008.
2 Chapter in a book: Authors' surnames and initials. Chapter Title. Surname and initials of book authors or editors (or translator, if any). Book Title. Edition number (if it is the second edition or above). State (or Country) of publisher: Publisher's name; copyright year. Page number.
e.g. Bye L, Modi N, Stanford M. Anatomy. Basic Sciences for Ophthalmology. UK: Oxford University Press; 2013:1-10.
Figure Legends and Figures: Figures should be embedded in the main text where the figures are applicable and also should be uploaded as separate files to the online
submission system. Figures should be numbered as 1, 2, 3 and so on, and mentioned clearly in the main text. For photomicrographs, include the type of specimen, original magnification or a scale bar, and stain. For gross pathology specimens, label any rulers with unit of measure. Digitally enhanced images (CT/MRI, blots, photographs, photomicrographs, ultrasound images, x-ray films, etc.) must be clearly identified in the figure legends as
digitally processed images.
Individual figure files-must be TIFF (.tif). or JPG (.jpg) files.
- -Minimum resolution is 300 dpi for photographs and 1200 dpi for line art --Color files are RGB or CMYK
- -Multiple panels of figures are combined in a single figure file, i.e. there is only one Figure 1 file, not Figure 1A file, Figure 1B file etc.
- -Figures are the approximate size they will appear in the final published PDF, i.e. they are not thumbnails, which will lose resolution when enlarged
Tables: Tables should be in Word format and placed in the main text where the table is first cited, which should not use picture tools to create tables or upload tables in image format or in Excel files. Tables must be cited in the main text in numerical order. A table need to be simplified when it cannot fit onto one page. Tables should be self-explanatory and the data they contain must not be duplicated in the text or figures. Each table should have a brief title and all abbreviations within the table should be included in a footnote to the table. Each piece of data needs to be contained in its own cell and the boxhead should not be empty.
MANUSCRIPT SUBMISSION REQUIREMENTS
All manuscripts must be submitted via our online manuscript submission and review system
36 (https://mc03 .ma nuscriptcentral.com/ijo ).
Manuscript Components: Include in the manuscript file a title page, abstract, text, acknowledgments, references, and figure legends. Beginning with the title page, start each of these sections on a new page, and number them consecutively.
Recommended File Sizes: We recommend individual file sizes of no more than SOOKB, and not exceeding 1MB, with the total size for all files not exceeding l OMB (not including any video files).
Manuscript File Formats: For submission and review, the acceptable manuscript file format is Microsoft Word. Do not submit your manuscript in PDF format.
COPYRIGHT
Once the manuscript is adopted by IJO, a Copyright Transfer Agreement signed by all the authors should be submitted immediately.
Publication Policy
Article processing charges
According to the IJOPRESS publication Policy, only the Publication Fees are billed per article upon acceptance in order to offset processing charges of articles (more than 500$ per article); the paper reaching the world advanced level will acquire the priority with free publication on IJO.
Open Access statement
All of the articles are free to access immediately on IJO website and PMC from the date of publication.
Content License
1]0 Press applies the Creative Commons Attribution (CC BY NC ND) license to the works we publish including 1]0 and IES. This license was developed to facilitate open access.
Citation Example:
Sanctis Ud,Alovisi C,Bauchiero L,Caramello G,Girotto G,Panico C,Vinai L,Genzano F,Amoroso A,Grignolo F.Changing trends in corneal graft surgery: a ten-year review.Intj Ophthalmol 2016;9(1):48-
52,doi:l 0.18240/ijo.2016.01.08
Contact us
Press of International journal of Ophthalmology (IJO Press)
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WebsiteOwww.ijo.cn
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