Elsevier Editorial System(tm) for Journal of Vascular and Interventional Radiology Manuscript Draft Manuscript Number: JVIR-D-16-00029R2 Title: Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences. Article Type: Review Article Corresponding Author: Dr. Kieran J. Murphy, M.D. Corresponding Author's Institution: University of Toronto First Author: Danyal
Khan
Order of Authors: Danyal Khan; Marie-Constance Rizwana Khan, MD; Kieran J. Murphy, M.D.
Lacass, MD FRCPC;
Abstract: In the high volume and increasingly complex world of image guided therapy and medical imaging, awareness of the potential risks secondary to occupational radiation exposure in medical professionals needs greater focus. One of these risks are radiation-induced cataracts, a recently recognized entity, which may impact the physician's professional proficiency, quality of life and career span. This review article aims to explain the pathogenesis of radiation-induced cataracts, exploring emerging evidence on its development. It also explores the existing monitoring and protection measures available to protect against such radiation-induced pathologies.
Title Page - Include All Author Information
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Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences.
Danyal Zaman Khan 1 Marie Constance Lacasse MD 2 Rizwana Khan MD 1 Kieran PJ Murphy MD FRCPC FSIR 2
1 The Royal College of Surgeons, Dublin, Ireland 2 Toronto Western Hospital, University Health Network, University of Toronto
Corresponding author Kieran Murphy MB FRCPC FSIR Dept of Medical Imaging Toronto Western Hospital University Health Network
[email protected]
*Response to Reviewers
MS JVIR-D-16-00029 MANUSCRIPT TITLE: Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences. Point by Point Response to Editor/Reviewers Dear Editors and Reviewers, Thank you very much for conditional acceptance of this article. Here are the point-by-point modifications we made to our manuscript (in red font) in order to address your recommendations. Due to further editing of the article in order to shorten it, some of the specific points mentioned by the reviewers might have been taken out of the article. We hope the new version of our manuscript will satisfy you. Regards,
REVIEWER #3 COMMENTS -There is a discrepancy between the title and some of the contents. -Amended to: Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences. -First line of an abstract: "Radiation-induced cataracts secondary to occupational exposure is a disease specific to the interventional radiology field". This pathology needs to be urgently recognized as one of the main occupational risk to the interventional radiologist, leading to early cataract surgery in middle-aged successful professionals. These statement are misleading and unacceptable*. -Amended to: In the rapidly evolving world of medical imaging, awareness about the potential risks secondary to occupational radiation exposure in medical professionals has to be emphasized. One of such risks are radiation-induced cataracts, a recently recognized entity, which may impact the physician’s professional proficiency, quality of life and career span. -All Fluoroscopy guided interventionalists are at risk and not IR's only. -Agreed, although IR's and radiation technologists represent a group of particular concern and hence are the focus of many of major studies in this field which is why our focus was directed towards them in the “Occupational radiation exposure studies: dose accumulation and cataract prevalence” section. -Moreover, it's not specific, there are various degrees of the problem, when the Cataract is the most advanced and irreversible one. -Mentioned at Pathogenesis section: “The principal proposed mechanism of PSCCs is radiation damage to germinative zone dividing cells [4], which induces a short period of mitotic inhibition at the basement membrane, followed by overcompensation with disorganized abnormal mitoses [8, 9]. This results in accumulation of aberrantly organized and shaped lens fiber cells with pyknotic nuclei that are theorized to produce the cloudy lentoid body at the PSC region [6]. This manifests histologically as small dots and vacuoles of opacification, which progressively coalesce overtime to form larger conglomerates, eventually causing visual impairment if left untreated [10].” -We talk about posterior subcapsular opacification of various degrees. -The Merriam-Focht system and LOCS III systems were both mentioned.
REVIEWER #4 COMMENTS -Addressing the 85% left sided distribution: The original article does not claim statistical significance of the findings; the known left-right dose distribution is about 65%-35% for cardiologists and essentially no gradient (50-50) for radiologists. -Amended statement to illustrate the suggestive but not statistical signifigant nature of the finding: ‘These specific tumors are known for their potential to be radiation-induced [22], with some case cohorts observing an 85% left-sided dominance, thought to possibly be secondary to the more direct radiation exposure to this area during interventional procedures [21].” -Addressing the technologists: The references do not provide dose related correlations; the possibility of other causes of the findings (beyond radiation) in the IR environment are not discussed. The assumption in the references and much of the other recent literature that all adverse findings are radiogenic is not supported. -Presuming this is refering to the 2008, Chodick et al. study, it states ”we found a significant association between history of three or more diagnostic x-rays to the face or neck and increased risk of cataract” which we used to in conjugation with other studies to simply imply a suggestion of a possible risk of cataractogenesis at low radiation doses and hence as a reason to be concerned. Thus, the paragraph was adjusted according to emphasize the possibility of increased risk suggested by this study as opposed a conclusive correlation.
-Turning to the aims of the paper: Data for cataracts are presented only as embedded text; there are no summary tables or figures. The paper does not critically compare the reported findings, something that one would expect in a review paper. Section 3 a) similarly presents a listing of radiation monitoring and protective devices without any substantial advice on their applicability. Table I is simply a non-critically reviewed listing of radiation management techniques. -Results: Results are presented as text in a disorganized manner. No tables of comparative findings are provided -Discussion: There is no critical discussion of the findings. Advice on radiation reduction methods are not critically reviewed or discussed -Tables: A review paper should synthesize the findings in tabular format. One is trying to understand the consistency of the literature in order to draw conclusions. -The hetrogenous nature of the methods of cataract classification systems, measering lens dosing and availabilities of protective equipment across centres & specialities served to greatly complicate the simplication of the data into tabular format. Hence, the text format was chosen to present the information in a logical order of paragraphs. Where possible and appropiate, we attempted to highlight areas of concern based on current literature: -“ In order to decrease chronic radiation exposure, there has to be strict adherence and appropriate use of the active (patient dose reduction techniques) and passive (room and personal protection devices) components of radiation protection” -“ Finally, to achieve the greatest reduction in dose exposure, room-shielding equipment must be combined with personal protective devices.” -“ Although current technology has the ability to provide major protective benefits to physicians, unnecessarily high dose protocols and poor compliance needs to be addressed in future guidelines.” -Materials and Methods: Cited literature seems to be a random selection rather than a comprehensive review. No description of systematic methods of literature review, comprehensive literature review, table of data that could be abstracted or reviewed by readers (esp compared with other review) -Added a Materials and Methods section with our search stragedy in Table 1
-Summary : My impression is that this manuscript is an uncritically reviewed dive into the literature. A good and critical review of this topic would be very timely. Can the authors increase the rigor of their reporting, by methods used to search for literature (eg PRISMA), provide a literature table, etc? These would be parts of all useful reviews for scholarly journals and would be important. -Added a Materials and Methods section with a search stragedy figure.
*Clean Revised Manuscript - No Author Information Click here to view linked References
COMPLETE MANUSCRIPT TITLE: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences.
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Manuscript Type: Review Article 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Word Count:4527
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Abbreviations: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
BMI: Body mass index CI: Confidence interval DSA: Digital subtraction angiography ERCP: Endoscopic retrograde cholangiopancreatography EVAR: Endovascular aortic repair IAEA: International atomic energy agency ICRP: International commission on radiological protection LOCS: Lens opacities classifications system NCRP: National council on radiation protection and measurements OCCCGS: Oxford clinical cataract classification and grading system O’CLOC: Occupational cataracts and lens opacities in interventional cardiology OR: Odds ratio PSC: Posterior sub-capsular RELID: Retrospective evaluation of lens injuries and dose UNSCEAR: United Nations scientific committee on the effects of atomic radiation UVB: Ultraviolet B WHO: World health organization
Key words: cataractogenesis, radiation-induced cataracts, interventional radiology, radiation protection.
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ABSTRACT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
In the high volume and increasingly complex world of image guided therapy and medical imaging, awareness of the potential risks secondary to occupational radiation exposure in medical professionals needs greater focus. One of these risks are radiation-induced cataracts, a recently recognized entity, which may impact the physician’s professional proficiency, quality of life and career span. This review article aims to explain the pathogenesis of radiation-induced cataracts, exploring emerging evidence on its development. It also explores the existing monitoring and protection measures available to protect against such radiation-induced pathologies..
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INTRODUCTION Radiation-induced cataracts secondary to occupational exposure represent a recently recognized entity. In the rapidly expanding world of medical imaging and image guided therapy, awareness about the potential radiation risks to medical professionals has to be emphasized. Knowledge and constant reinforcement of the basic radiation protection principles needs to be implemented to decrease unnecessary radiation exposure. Thus, this article explores our development of understanding of the pathogenesis of radiation induced cataracts and its close link with radiation-induced oncogenesis. This is followed by discussion of existing monitoring and protection measures available to protect against such radiationinduced pathologies.
MATERIALS AND METHODS We obtained anatomic pathology specimens of human lens with posterior chamber catarcts (Figure 1,2,3,4). A systematic literature search was performed by the authors using the PubMed database (US National Library of Medicine, National Institutes of Health) and the following initial terms: “radiation-induced cataracts” and “lens occupational radiation monitoring and protection”. Any further searches were more specific to source information regarding radiation-induced oncologic pathologies of relevance to the scope of this paper. Inclusion criteria for initial literature searches were broad and as follows: full-text articles, publications in English, between the years 1950-2016 with the subject matter on radiation-induced cataracts pathogenesis, lens dose monitoring or radiation protection strategies. The exclusion criteria were formed from the converse of the inclusion criteria. By reading the titles or abstracts, the same authors excluded studies not fulfilling the parameters set by the inclusion and exclusion criteria. Each remaining article was reviewed and relevant information was extracted if in congruence with the scope of the paper. This information is presented as part of the paper’s results and discussion. This search strategy is presented in (Figure 5).
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RESULTS AND DISCUSSION 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
1.The Pathogenesis of Radiation-Induced Cataracts: Modern cataract surgery uses an emulscification process to minimize incision size no anatomic specimens are obtained. After extensive searching we found anatomic pathology of the human lens in a pathology museum. The unique structure of the lens is fundamental to its refraction capabilities, and is the basis for its high radiosensitivity and unique pathology, cataracts [1] (Figure 1). The development of cataracts results from the opacification of the lens [1]. It is the main cause of blindness worldwide, and second reason for visual impairment after uncorrected refractive errors [2]. Age-related "senile" cataracts are the most common type of cataracts [3].
Cataracts are the classified anatomically into nuclear, cortical and posterior subcapsular (PSC) subtypes [1]. Nuclear and cortical cataracts develop from pathological changes within the lens fiber cells, while PSC cataracts (PSCCs) are associated with abnormalities at the germinative zone of the lens [1, 4] (Figures 2-4). PSCCs are most commonly associated with ionizing radiation exposure(2), followed by cortical cataracts [5]. However, other contributive factors to PSC cataract development include lack of endogenous antioxidants and steroid use [6, 7].
Cataract pathogenesis is not fully understood and is most likely multifactorial, involving numerous genetic and environmental factors. The principal proposed mechanism of PSCCs is radiation damage to germinative zone dividing cells [4], which induces a short period of mitotic inhibition at the basement membrane, followed by overcompensation with disorganized abnormal mitoses [8, 9]. This results in accumulation of aberrantly organized and shaped lens fiber cells with pyknotic nuclei that are theorized to produce the cloudy lentoid body at the PSC region [6]. This manifests histologically as small dots and vacuoles of opacification, which progressively coalesce overtime to form larger conglomerates, eventually causing visual impairment if left untreated [10]. Relatively minor opacities to the posterior pole of the lens’ visual axis lead to significant visual impairment [10]. Interestingly, PSCCs have been viewed as the “cancer-like pathology” of the lens [4] 6
as the ionizing radiation also damages specific genes involved in DNA repair and cell 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
cycle control which are usually attributed to the process of carcinogenesis [4].
2. Emerging evidence and its consequences on the understanding:
a) Major influencing factors for radiation-induced cataractogenesis: Many factors have been shown to influence the development of radiation-induced cataractogenesis. Age is the single most important risk factor, with a 15% increased risk for each year of life [11, 12]. Other risk factors identified include female sex, marital status (single), low socioeconomic status, >15 packs/year smoking history, >25kg/ m2 body mass index (BMI), increased alcohol consumption, diabetes, hypertension, hypercholesterolemia as well as chronic use of systemic steroids [11, 12]. However, most of the previously stated risk factors also affect the incidence of non-radiation-induced cataracts, such as senile cataracts [3], which complicates the analysis of radiation-induced cataractogenesis prevalence.
Lately, there has been increased interest in identifying specific genetic variations influencing individual susceptibility to radiation-induced cataracts following radiation exposure [13]. These potential genetic factors complicate the elaboration of safety guidelines which currently assume relative homogeneity of radio-sensitivity within populations [7]. In animals, earlier appearance of radiation-induced cataractogenesis was found in mice nullizygous or heterozygous for the DNA repair genes ATM, RAD9 and BRCA 1 [14, 15]. Indeed, human ATM polymorphisms were found in atomic bomb survivors, and seemed to modify the risk of undergoing cataract surgery [16]. Interestingly, heterozygosity for the ATM gene has been estimated in 13% of the United States population [17]. BRCA 1 and 2 germ line mutations are found in 2% of the Ashkenazi Jewish population. If some interventionalists are more radiosensitive that others should consideration be given to genetic screening for those with deminished DNA repair ability?
b) Radiation-induced oncogenesis: In the last few years, it was hypothesized that radiation cataractogenesis may possibly function as a stochastic process [6, 18, 19]. Indeed, Hamada et al. 7
proposed that the lack of a dose rate effect may suggest there is only an initial 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
accumulation of damage from radiation needed within the lens tissue in order to trigger the stochastic process [6]. This stochastic relationship with radiation exposure is also evident in radiation-induced oncogenesis, which is emerging as an important group of pathologies to investigate when exploring radiation exposure to the head region,
A particularly concerning group of oncological entities in close proximity to the eye are brain neoplasms, however, current evidence for a direct causal relationship between brain tumors and chronic occupational radiation is suggestive but not conclusive, due to small sample sizes and lack of follow-up [20]. Nonetheless, when anecdotal reports of clustering are considered, the issues become quite concerning [20]. For example, a 2013 case study identified 31 cases of brain cancers in interventionalists including glioblastoma multiforme (17/31), meningioma (5/31) and astrocytoma (2/31) [21]. These specific tumors are known for their potential to be radiation-induced [22], with some case cohorts observing an 85% left-sided dominance, thought to possibly be secondary to the more direct radiation exposure to this area during interventional procedures [21]. Furthermore, a recent observational study performed on technologists working with radiation showed a twofold increased risk of brain cancer mortality, and mild elevations in the incidence of melanoma and breast cancer when compared to technologists never exposed to radiation [23].
Furthermore, although specific genes have not yet been conclusively identified, epidemiological studies, as mentioned earlier, have displayed variations in radiation sensitivity amongst particular sub-populations, which may important implications regarding radiation-induced oncogenesis of the head and reck [24].
c) Dosing of radiation: concepts and mechanisms understood: As mentioned earlier, there is still uncertainty about the exact pathogenesis of cataracts. The knowledge is also scarce on the relationship between cataract development, dose protraction and latency period, as well the stochastic versus deterministic nature of radiation-induced cataracts [4].
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In April 2011, following emerging evidence from numerous studies, the International 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Commission on Radiological Protection (ICRP) reviewed its previous 2007 guidelines concerning lens dose thresholds for radiation cataractogenesis [25, 26]. The eye lens absorbed dose threshold was established at 500mSv for lifetime exposure, and decreased from 150mSv to 20mSv per year for the annual occupational exposure limit [25, 26]. The annual occupational exposure limit now has to be averaged over 5 years, with no single year to exceed 50mSv [25]. The slim evidence for the risk lowering effect of dose protraction has suggested it did not significantly affect the threshold dose [18, 19]. Data on the latency period is also scarce and suggests an inverse relationship between dose and latency [27]. In order to better understand the decision of the ICRP to significantly decrease the radiation thresholds for professionals, knowledge of the studies that led to those changes is essential.
Field studies: investigations of dose thresholds and dose effects: In 2007, Neriishi et al. analyzed the radiation dose exposure and dose response of 3,761 atomic bomb survivors, including 479 postoperative cataract cases [28]. Neriishi et al. found an increased cataract prevalence with a dose of 1Gy at an odds ratio (OR) of 1.39 [28] . Within the 0- 1Gy range, a non-significant dose threshold of 0.1Gy was seen [28]. These results advocated for a far lower threshold than the 2007 ICRP recommendations, and also suggested the concept of a no threshold, dose-response relationship between radiation exposure and cataractogenesis [28]. Previous research also supported Neriishi et al.’s conclusions. At 1Gy exposure, a study by Hall et al. reported a 1.49 OR for PSC in infants treated with radiation therapy for skin hemangiomas [5] and Worghul et al. reported an OR of 1.42 for PSC cataracts [29] when examining 8,607 Chernobyl clean-up workers. These studies reporting an increased risk of cataracts with low doses of radiation supported the idea of a threshold as low as 0.5Gy, or no threshold at all [13, 18, 19].
Occupational radiation exposure studies: dose accumulation and cataract prevalence: Multiple epidemiological and clinical studies investigating occupational radiation exposure to healthcare professionals have confirmed the prevalence of radiation9
induced cataracts in the medical community. In 2008, Chodick et al. published 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
results of a 1983-2004 cohort study of 35,705 US radiology technologists (initially cataract free), aged 24–44 years, followed-up using two detailed questionnaires [11]. They reported 2,382 cataracts and 647 cataract extractions, with 25% of the cataracts occurring before 50 years of age [11]. Results showed a mean radiation dose to the lens of 28.1mGy in the entire cohort and after being adjusted for other known confounding factors, suggested a possible risk of cataractogenesis at low radiation doses [11]. Just three or more diagnostic head or neck x-rays were found to increase the risk of cataractogenesis [11]. The dose to risk of cataract relationship was strongest with subjects younger than 50 years old, with PSC cataracts being the most prevalent type of opacity found in this age group [11]. Furthermore, a study on Finnish physicians reported an OR for any lens opacities of 0.13 (95% CI -0.02-0.28) per 10mSv of whole body cumulative effective dose [12].
Organizations such as the ICRP, the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the International Atomic Energy Agency (IAEA) and the National Council on Radiation Protection and Measurements (NRCP) have also attempted to raise awareness and evaluate the risk of cataracts from a chronic occupational radiation exposure by publishing annual reports and guidelines and initiating collaborative studies [25, 26, 30-32]. In the last few years, the steady increase in the number of medical procedures requiring radiation has led the UNSCEAR group to undertake a task force in order to analyse and record worldwide radiation exposures coming from the medical field [32]. In an epidemiological study by the O’CLOC group in 2013, Jacob et al. investigated the risk of cataract in French interventional cardiologists and electrophysiologists [10, 33]. The retrospective assessment showed a cumulative eye lens exposure ranging from 25 to over 1600mSv, as estimated by taking into account the number of procedures done, the average radiation dose per procedure, and the various radiation protection equipment utilized [33]. A mean exposure of 423mSv was found for a mean working time of 22 years , with an OR of 3.8 (1.3–11.4) for the development of PSC in exposed medical personnel compared to non-exposed controls [33]. This data suggested that approximately 25% of these professionals were over the revised ICRP threshold of 500mSv [33]. Furthermore, the new ICRP annual exposure limit of 20 mSv/year was surpassed a minimum of once by 60% of cardiologists during the 10
study period [33]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Indeed, interventional cardiologists have become the focus of many similar studies attempting to estimate occupational lens dose and cataract prevalence in this group. Ciraj-Bjelac et al.’s study found a lifetime cumulative dose to the lens of 3.7±7.5Gy (0.02-43Gy) over an average of 9 working years [34], while Vano et al. found a cumulative occupational lens dose of 6.0±6.6Sv (0.1-27Sv) over a mean working time of 14 years [35]. These results were, like the O’CLOC study, estimated from the numbers of procedures performed by the interventionalist, the baseline eye lens dose per procedure type, and the radiation protection conditions [33]. The doses were likely overestimated in these studies, since lens opacities were found in only 38% of participants in Vano et al. [35], less than what would be expected with medians of such high values [33]. The wide discrepancies between estimated levels of exposure and the PSCC incidence was hypothesized to be secondary to a lack of systematic monitoring, leading to inaccurate estimates of occupational exposure [33]. However, all these studies ultimately did show an increase in the crude relative risk of radiation cataractogenesis, which was still significant after being adjusted for confounding factors and compared with the control subject [33-35].
Another important source of discrepancies in studies reporting the prevalence of PSC cataracts comes from the use of different classification systems and grading schemes available. For example, the reported prevalence of PSC opacities in the O’CLOC, Vano et al., and Ciraj-Bjelac et al. studies were evaluated at 17%, 38% and 52% respectively [10, 34, 35]. Ciraj-Bjelac et al. and Vano et al. both used a modified Merriam-Focht system specifically designed for posterior lens opacities [36], while the O’CLOC study used the Lens Opacities Classification System III (LOCS III) [37], a system that evaluates and grades any type of cataract. With LOCS III, the ophthalmologist compares the morphology of the lens fiber in all regions of the lens (nuclear, cortical and PSC), and compares it to reference slides in order to determine the severity of the opacities in each region [37]. All these grading systems also differ in the methods used to assess the opacities, including dilated slit-lamp biomicroscopy, retro illumination and Scheimpflug imaging [6]. These factors constitute a major limiting factor when comparing studies, and further complicate pooled analysis [6]. Hence, for future studies, standardization of the cataract grading 11
systems and is critical for an effective analysis of prevalence [6]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
3. Protocol, clinical applications and their issues:
a) Monitoring and protection: Radiation dose monitoring devices are essential to assess the physician’s occupational risk. Because of the lack of a direct quantification method to measure eye lens dose, studies such as the O’CLOC, Vano et al., and Ciraj-Bjelac et al. studies have sought to use various formulae to estimate retrospective assessment of eye lens exposure [33-35]. These methods are not reliable or reproducible for the assessment of radiation dose, due to inherent differences in patients, physicians, procedures and protective equipment used [38, 39]. Furthermore, many physicians unfortunately do not routinely use personal dosimeters even when made available [40].
Hp(3) is the most accurate operational quantity for the eye lens dose [41]. However, the dosimeters provided to clinicians often only include effective dose/whole-body dosimeter Hp(10) and local skin dose/partial body dosimeter Hp(0.07), and calibration for Hp(3) is impossible[40, 41]. In this context, Hp(0.07) is used to provide the closest dose estimate to the lens [38, 40].
Recently, studies have explored the use of electronic active dosimeters that provide physicians with real-time maximum dose rates and total cumulative dose for a single procedure [42, 43]. Such devices could serve as an occupational dose education and awareness tool for physicians, while potentially increasing compliance to protective equipment and other dose reduction techniques [42, 43].
In order to decrease chronic radiation exposure, there has to be strict adherence and appropriate use of the active (patient dose reduction techniques) and passive (room and personal protection devices) components of radiation protection (Table 1).
Radiation to the eye in the fluoroscopy room mainly comes from scatter radiation from the patient [44, 45]. Central to any dose reduction strategy is first and foremost 12
to decide if the exam to be performed is clinically indicated, and if the use of the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
fluoroscopy guidance is essential. If the procedure is deemed appropriate, careful planning of the procedure to optimize the use of radiation is necessary [44]. Strategies to reduce radiation dose to the patient include shorter fluoroscopy time, decreased frame rate, use of collimation, avoidance of magnification, decreased digital subtraction angiography (DSA) sequences acquisitions, increased distance between the source and the patient, and decreased distance between the patient and the image receptor [44].
Passive strategies such as room shielding devices protect against the scatter radiation, and include ceiling-suspended shields and shielded drapes [44]. Ceilingsuspended shields, when used properly, were shown to reduce occupational exposure doses by up to 100-fold and therefore should always be used if interventionalist positioning is not compromised as a result [44]. Similarly, drapes placed around the image intensifier was shown to provide an approximate 90% dose exposure reduction to the endoscopist during endoscopic retrograde cholangiopancreatography (ERCP) [45]. Other measures to reduce scatter radiation include using protective disposable shielded drapes, which showed a 23% reduction in total radiation dose to the operators in a randomized controlled trial [46], and dose reduction to the hands and chest of interventionalists of 49% and 55% respectively during endovascular aortic repair (EVAR) procedures [47].
Finally, to achieve the greatest reduction in dose exposure, room-shielding equipment must be combined with personal protective devices. These include protective aprons, thyroid shields, gloves and eyewear for physicians [44]. The use of lead eyewear that is properly fitted and has lateral eye shielding can reduce eye lens dose by a factor of 2.1 for the tube side eye, and 0.8 for the non-tube side eye [48]. Unfortunately, evidence suggests poor compliance with only 25% of interventionalists and 36% of cardiologists wearing glasses during the procedures [41]. Although current technology has the ability to provide major protective benefits to physicians, ineffective protocols and poor compliance needs to be addressed in future guidelines.
b) Proficiency and treatment procedure: 13
Without comprehensive evidence-based guidelines, effective dose monitoring tools 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
and the use of appropriate protective equipment and dose-reducing strategies, physicians are at risk of pathological manifestations from their occupational radiation exposure. This might impact on the physician’s professional proficiency, quality of life and career span [6]. For example, because of their central position, PSCCs may cause significant visual impairment and decrease contrast sensitivity and present a specific surgical group of patients that is likely to be younger than the majority of "senile" cataract patients [49].
CONCLUSION Throughout this paper, the numerous potential risk factors of cataractogenesis were presented, and the pathogenesis of radiation-induced cataracts was reviewed. A brief parallel was made between radiation-induced cataractogenesis and oncogenesis, two process that share multiple similarities. The recent IRCP guidelines changes were described, and the studies which led to these changes were presented. Future areas of research include the study of specific genetic traits that could potentially affect an individual’s vulnerability to radiation, and more precise and homogeneous ophthalmologic diagnostic tools for the diagnosis of PSC cataracts. In the current interventional radiology field, there is an urgent need to recognize that there is no safe dose of radiation. Will we one day see Posterior Chamber Cataracts as the canary in the cold mine? In order to prevent the detrimental effects of occupational radiation on health workers, there must be a strict worldwide application of the recent lower radiation threshold guidelines, a more effective means of monitoring radiation exposure, and finally, the consistent use of appropriate radiation protection strategies.
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Jacob, S., et al., Interventional cardiologists and risk of radiation-induced cataract: results of a French multicenter observational study. Int J Cardiol, 2013. 167(5): p. 1843-7.
11.
Chodick, G., et al., Risk of cataract after exposure to low doses of ionizing radiation: a 20-year prospective cohort study among US radiologic technologists. Am J Epidemiol, 2008. 168(6): p. 620-31.
12.
Mrena, S., et al., Lens opacities among physicians occupationally exposed to ionizing radiation--a pilot study in Finland. Scand J Work Environ Health, 2011. 37(3): p. 237-43.
13.
Hammer, G.P., et al., Occupational exposure to low doses of ionizing radiation and cataract development: a systematic literature review and perspectives on future studies. Radiat Environ Biophys, 2013. 52(3): p. 303-19.
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Worgul, B.V., et al., Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts. Proc Natl Acad Sci U S A, 2002. 99(15): p. 9836-9.
15.
Kleiman, N.J., et al., Mrad9 and atm haploinsufficiency enhance spontaneous and Xray-induced cataractogenesis in mice. Radiat Res, 2007. 168(5): p. 567-73.
16.
Neriishi, K., Hayashi, T., Nakashima, E., Imai, K., Nakachi, K., ATM haplotypes and radiosensitivity in A-bomb survivors – preliminary trial using existing data at RERF., in Abstract Book of Radiation Cataractogenesis Workshop 2009. 2009: Hiroshima, Japan, RERF.
17.
Swift, M., et al., Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med, 1987. 316(21): p. 1289-94.
18.
Ainsbury, E.A., et al., Radiation cataractogenesis: a review of recent studies. Radiat Res, 2009. 172(1): p. 1-9.
19.
Bouffler, S., et al., Radiation-induced cataracts: the Health Protection Agency's response to the ICRP statement on tissue reactions and recommendation on the dose limit for the eye lens. J Radiol Prot, 2012. 32(4): p. 479-88.
20.
Picano, E., et al., Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure. BMC Cancer, 2012. 12: p. 157.
21.
Roguin, A., et al., Brain and neck tumors among physicians performing interventional procedures. Am J Cardiol, 2013. 111(9): p. 1368-72.
22.
Flint-Richter, P. and S. Sadetzki, Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol, 2007. 8(5): p. 403-10.
23.
Rajaraman, P., et al., JOURNAL CLUB: Cancer Risks in U.S. Radiologic Technologists Working With Fluoroscopically Guided Interventional Procedures, 1994. AJR Am J Roentgenol, 2016: p. 1-9.
24.
Hricak, H., et al., Managing radiation use in medical imaging: a multifaceted challenge. Radiology, 2011. 258(3): p. 889-905.
25.
ICRP, Statement on Tissue Reactions, in ref. 4825-3093-1464, ICRP, Editor. 2011. Available on http://www.icrp.org/docs/icrp statement on tissue reactions.pdf.
26.
ICRP, The 2007 Recommendations of the International Commission on Radiological Protection, in Publication 103, ICRP, Editor. 2007, Elsevier.
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Merriam, G.R., Jr. and B.V. Worgul, Experimental radiation cataract--its clinical relevance. Bull N Y Acad Med, 1983. 59(4): p. 372-92.
28.
Neriishi, K., et al., Postoperative cataract cases among atomic bomb survivors: radiation dose response and threshold. Radiat Res, 2007. 168(4): p. 404-8.
29.
Worgul, B.V., et al., Cataracts among Chernobyl clean-up workers: implications regarding permissible eye exposures. Radiat Res, 2007. 167(2): p. 233-43.
30.
IAEA, IAEA Annual Report 2012- Human Health. 2012. p. 41-44.
31.
NCRP, NCRP Annual Report 2011. 2011. p. 66.
32.
UNSCEAR, Sources and Effects of Ionizing Radiation Vol. 1. 2000. p. 1-203.
33.
Jacob, S., et al., Eye lens radiation exposure to interventional cardiologists: a retrospective assessment of cumulative doses. Radiat Prot Dosimetry, 2013. 153(3): p. 282-93.
34.
Ciraj-Bjelac, O., et al., Risk for radiation-induced cataract for staff in interventional cardiology: is there reason for concern? Catheter Cardiovasc Interv, 2010. 76(6): p. 826-34.
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Vano, E., et al., Radiation cataract risk in interventional cardiology personnel. Radiat Res, 2010. 174(4): p. 490-5.
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Merriam, G.R., Jr. and E.F. Focht, A clinical and experimental study of the effect of single and divided doses of radiation on cataract production. Trans Am Ophthalmol Soc, 1962. 60: p. 35-52.
37.
Chylack, L.T., Jr., et al., The Lens Opacities Classification System III. The Longitudinal Study of Cataract Study Group. Arch Ophthalmol, 1993. 111(6): p. 831-6.
38.
IAEA. Radiation and cataract : Staff protection. 2013 [cited 2015 July 17]; Available from: https://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessional s/6_OtherClinicalSpecialities/radiation-cataract/Radiation-and_cataract.htm CAT_FAQ11.
39.
Ciraj-Bjelac, O. and M.M. Rehani, Eye dosimetry in interventional radiology and cardiology: current challenges and practical considerations. Radiat Prot Dosimetry, 2014. 162(3): p. 329-37.
40.
Duran, A., et al., Recommendations for occupational radiation protection in interventional cardiology. Catheter Cardiovasc Interv, 2013. 82(1): p. 29-42. 17
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Vanhaverea F., C.E., Domienikc J., Donadilled L., Ginjaumee M., Gualdrinif G., Koukoravab C., Krima S., Nikodemovag D., Ruiz-Lopezh N., Sans-Merceh M. and L. Struelensa, Measurements of eye lens doses in interventional radiology and cardiology: Final results of the ORAMED project. Radiation Measurements, November 2011. 46(11): p. p.1243-1247.
42.
Vano, E., et al., Occupational radiation doses in interventional cardiology: a 15year follow-up. Br J Radiol, 2006. 79(941): p. 383-8.
43.
Prlic, I., M. Suric Mihic, and Z. Vucic, Active electronic personal dosemeter in interventional radiology. Radiat Prot Dosimetry, 2008. 132(3): p. 308-12.
44.
Bartal, G., et al., Management of patient and staff radiation dose in interventional radiology: current concepts. Cardiovasc Intervent Radiol, 2014. 37(2): p. 289-98.
45.
Muniraj, T., et al., A double-blind, randomized, sham-controlled trial of the effect of a radiation-attenuating drape on radiation exposure to endoscopy staff during ERCP. Am J Gastroenterol, 2015. 110(5): p. 690-6.
46.
Politi, L., et al., Reduction of scatter radiation during transradial percutaneous coronary angiography: a randomized trial using a lead-free radiation shield. Catheter Cardiovasc Interv, 2012. 79(1): p. 97-102.
47.
Kloeze, C., et al., Editor's choice--Use of disposable radiation-absorbing surgical drapes results in significant dose reduction during EVAR procedures. Eur J Vasc Endovasc Surg, 2014. 47(3): p. 268-72.
48.
van Rooijen, B.D., et al., Efficacy of radiation safety glasses in interventional radiology. Cardiovasc Intervent Radiol, 2014. 37(5): p. 1149-55.
49.
Elliott, D.B. and P. Situ, Visual acuity versus letter contrast sensitivity in early cataract. Vision Res, 1998. 38(13): p. 2047-52.
18
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Figure Legends
Figure 1. Normal lens showing (1) lens capsule, (2) peripheral lens fiber, (3) nucleus with higher concentration of lens fibers, (4) iris, (5) cornea, (6) ciliary body, (7) artifact.
Figure 2. Posterior sub-capsular cataract showing (1) presence of a layer of epithelial cells under the posterior capsule which have migrated from the equatorial cells, (2) the lens fibers still maintain some normal appearance.
Figure 3. Posterior sub-capsular cataract with (1) epithelial cells under the posterior lens capsule that have migrated from the equator or lens bow cells, (2) artifacts.
Figure 4. Nuclear cataract showing (1) lens fibers have lost their concentric lamination giving rise to homogenous eosinophilic appearance, (2) separation of lens fibers during slide processing, (3) artifact.
Figure 5 Search strategy
19
*Revised Manuscript with Tracked Changes - No Author Information
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1
COMPLETE MANUSCRIPT TITLE:
2
Radiation Cataractogenesis: The Progression of our Understanding and its
3
Clinical Consequences.
4 5 6
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Manuscript Type: Review Article
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Word Count:4257.
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10
Abbreviations:
11
BMI: Body mass index
12
CI: Confidence interval
13
DSA: Digital subtraction angiography
14
ERCP: Endoscopic retrograde cholangiopancreatography
15
EVAR: Endovascular aortic repair
16
IAEA: International atomic energy agency
17
ICRP: International commission on radiological protection
18
LOCS: Lens opacities classifications system
19
NCRP: National council on radiation protection and measurements
20
OCCCGS: Oxford clinical cataract classification and grading system
21
O’CLOC: Occupational cataracts and lens opacities in interventional cardiology
22
OR: Odds ratio
23
PSC: Posterior sub-capsular
24
RELID: Retrospective evaluation of lens injuries and dose
25
UNSCEAR: United Nations scientific committee on the effects of atomic radiation
26
UVB: Ultraviolet B
27
WHO: World health organization
28 29
Key words: cataractogenesis, radiation-induced cataracts, interventional radiology,
30
radiation protection.
31
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ABSTRACT
33 34
In the high volume and increasingly complex world of image guided therapy and
35
medical imaging, awareness of the potential risks secondary to occupational
36
radiation exposure in medical professionals needs greater focus. One of these risks
37
are radiation-induced cataracts, which may impact the physician’s professional
38
proficiency, quality of life and career span. This review article aims to explain the
39
pathogenesis of radiation-induced cataracts, exploring emerging evidence on its
40
developmenrt. It also explores the existing monitoring and protection measures
41
available to protect against such radiation-induced pathologies.It is important that
42
interventionalists realise that annual lens dose limits have been lowered to 1/7 of
43
previous levels. They also should be aware that the cataracts that occur in this
44
context are fundamentally different in pathogenesis and anatomic location to
45
common senile cataracts.
4
46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
47
INTRODUCTION
48
Radiation-induced cataracts secondary to occupational exposure represent a
49
recently recognized entity. In the rapidly expanding world of medical imaging and
50
image guided therapy, awareness about the potential radiation risks to medical
51
professionals has to be emphasized. Knowledge and constant reinforcement of the
52
basic radiation protection principles needs to be implemented to decrease
53
unnecessary radiation exposure. Thus, this article explores our development of
54
understanding of the pathogenesis of radiation induced cataracts and its close link
55
with radiation-induced oncogenesis. This is followed by discussion of existing
56
monitoring and protection measures available to protect against such radiation-
57
induced pathologies.
58 59
MATERIALS AND METHODS
60
We obtained anatomic pathology specimens of human lens with posterior chamber
61
catarcts (Figure 1,2,3,4). A systematic literature search was performed by the
62
authors using the PubMed database (US National Library of Medicine, National
63
Institutes of Health) and the following initial terms: “radiation-induced cataracts” and
64
“lens occupational radiation monitoring and protection”. Any further searches were
65
more specific to source information regarding radiation-induced oncologic
66
pathologies of relevance to the scope of this paper. Inclusion criteria for initial
67
literature searches were broad and as follows: full-text articles, publications in
68
English, between the years 1950-2016 with the subject matter on radiation-induced
69
cataracts pathogenesis, lens dose monitoring or radiation protection strategies. The
70
exclusion criteria were formed from the converse of the inclusion criteria. By reading
71
the titles or abstracts, the same authors excluded studies not fulfilling the parameters
72
set by the inclusion and exclusion criteria. Each remaining article was reviewed and
73
relevant information was extracted if in congruence with the scope of the paper. This
74
information is presented as part of the paper’s results and discussion. This search
75
strategy is presented in (Table1Figure 5).
76 77
5
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78
RESULTS AND DISCUSSION
79
1.The Pathogenesis of Radiation-Induced Cataracts:
80
Modern cataract surgery uses an emulscification process to minimize incision size
81
no anatomic specimens are obtained. After extensive searching we found anatomic
82
pathology of the human lens in a pathology museum. The unique structure of the
83
lens is fundamental to its refraction capabilities, and is the basis for its high radio-
84
sensitivity and unique pathology, cataracts [1] (Figure 1). The development of
85
cataracts results from the opacification of the lens [1]. It is the main cause of
86
blindness worldwide, and second reason for visual impairment after uncorrected
87
refractive errors [2]. Age-related "senile" cataracts are the most common type of
88
cataracts [3].
89 90
Cataracts are the classified anatomically into nuclear, cortical and posterior sub-
91
capsular (PSC) subtypes [1]. Nuclear and cortical cataracts develop from
92
pathological changes within the lens fiber cells, while PSC cataracts (PSCCs) are
93
associated with abnormalities at the germinative zone of the lens [1, 4] (Figures 2-4).
94
PSCCs are most commonly associated with ionizing radiation exposure(2), followed
95
by cortical cataracts [5]. However, other contributive factors to PSC cataract
96
development include lack of endogenous antioxidants and steroid use [6, 7].
97 98
Cataract pathogenesis is not fully understood and is most likely multifactorial,
99
involving numerous genetic and environmental factors. The principal proposed
100
mechanism of PSCCs is radiation damage to germinative zone dividing cells [4],
101
which induces a short period of mitotic inhibition at the basement membrane,
102
followed by overcompensation with disorganized abnormal mitoses [8, 9]. This
103
results in accumulation of aberrantly organized and shaped lens fiber cells with
104
pyknotic nuclei that are theorized to produce the cloudy lentoid body at the PSC
105
region [6]. This manifests histologically as small dots and vacuoles of opacification,
106
which progressively coalesce overtime to form larger conglomerates, eventually
107
causing visual impairment if left untreated [10]. Relatively minor opacities to the
108
posterior pole of the lens’ visual axis lead to significant visual impairment [10].
109 110
Interestingly, PSCCs have been viewed as the “cancer-like pathology” of the lens [4] 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
111
as the ionizing radiation also damages specific genes involved in DNA repair and cell
112
cycle control which are usually attributed to the process of carcinogenesis [4].
113 114
2. Emerging evidence and its consequences on the understanding:
115 116
a) Major influencing factors for radiation-induced cataractogenesis:
117
Many factors have been shown to influence the development of radiation-induced
118
cataractogenesis. Age is the single most important risk factor, with a 15% increased
119
risk for each year of life [11, 12]. Other risk factors identified include female sex,
120
marital status (single), low socioeconomic status, >15 packs/year smoking history,
121
>25kg/ m2 body mass index (BMI), increased alcohol consumption, diabetes,
122
hypertension, hypercholesterolemia as well as chronic use of systemic steroids [11,
123
12]. However, most of the previously stated risk factors also affect the incidence of
124
non-radiation-induced cataracts, such as senile cataracts [3], which complicates the
125
analysis of radiation-induced cataractogenesis prevalence.
126 127
Lately, there has been increased interest in identifying specific genetic variations
128
influencing individual susceptibility to radiation-induced cataracts following radiation
129
exposure [13]. These potential genetic factors complicate the elaboration of safety
130
guidelines which currently assume relative homogeneity of radio-sensitivity within
131
populations [7]. In animals, earlier appearance of radiation-induced cataractogenesis
132
was found in mice nullizygous or heterozygous for the DNA repair genes ATM,
133
RAD9 and BRCA 1 [14, 15]. Indeed, human ATM polymorphisms were found in
134
atomic bomb survivors, and seemed to modify the risk of undergoing cataract
135
surgery [16]. Interestingly, heterozygosity for the ATM gene has been estimated in 1-
136
3% of the United States population [17]. BRCA 1 and 2 germ line mutations are
137
found in 2% of the Ashkenazi Jewish population. If some interventionalists are more
138
radiosensitive that others should consideration be given to genetic screening for
139
those with deminished DNA repair ability?
140 141
b) Radiation-induced oncogenesis:
142
In the last few years, it was hypothesized that radiation cataractogenesis may
143
possibly function as a stochastic process [6, 18, 19]. Indeed, Hamada et al. 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
144
proposed that the lack of a dose rate effect may suggest there is only an initial
145
accumulation of damage from radiation needed within the lens tissue in order to
146
trigger the stochastic process [6]. This stochastic relationship with radiation exposure
147
is also evident in radiation-induced oncogenesis, which is emerging as an important
148
group of pathologies to investigate when exploring radiation exposure to the head
149
region,
150 151
A particularly concerning group of oncological entities in close proximity to the eye
152
are brain neoplasms, however, current evidence for a direct causal relationship
153
between brain tumors and chronic occupational radiation is suggestive but not
154
conclusive, due to small sample sizes and lack of follow-up [20]. Nonetheless, when
155
anecdotal reports of clustering are considered, the issues become quite concerning
156
[20]. For example, a 2013 case study identified 31 cases of brain cancers in
157
interventionalists including glioblastoma multiforme (17/31), meningioma (5/31) and
158
astrocytoma (2/31) [21]. These specific tumors are known for their potential to be
159
radiation-induced [22], with some case cohorts observing an 85% left-sided
160
dominance, thought to possibly be secondary to the more direct radiation exposure
161
to this area during interventional procedures [21]. Furthermore, a recent
162
observational study performed on technologists working with radiation showed a
163
twofold increased risk of brain cancer mortality, and mild elevations in the incidence
164
of melanoma and breast cancer when compared to technologists never exposed to
165
radiation [23].
166 167
Furthermore, although specific genes have not yet been conclusively identified,
168
epidemiological studies, as mentioned earlier, have displayed variations in radiation
169
sensitivity amongst particular sub-populations, which may important implications
170
regarding radiation-induced oncogenesis of the head and reck [24].
171 172
c) Dosing of radiation: concepts and mechanisms understood:
173
As mentioned earlier, there is still uncertainty about the exact pathogenesis of
174
cataracts. The knowledge is also scarce on the relationship between cataract
175
development, dose protraction and latency period, as well the stochastic versus
176
deterministic nature of radiation-induced cataracts [4].
177 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
178
In April 2011, following emerging evidence from numerous studies, the International
179
Commission on Radiological Protection (ICRP) reviewed its previous 2007
180
guidelines concerning lens dose thresholds for radiation cataractogenesis [25, 26].
181
The eye lens absorbed dose threshold was established at 500mSv for lifetime
182
exposure, and decreased from 150mSv to 20mSv per year for the annual
183
occupational exposure limit [25, 26]. The annual occupational exposure limit now has
184
to be averaged over 5 years, with no single year to exceed 50mSv [25]. The slim
185
evidence for the risk lowering effect of dose protraction has suggested it did not
186
significantly affect the threshold dose [18, 19]. Data on the latency period is also
187
scarce and suggests an inverse relationship between dose and latency [27]. In order
188
to better understand the decision of the ICRP to significantly decrease the radiation
189
thresholds for professionals, knowledge of the studies that led to those changes is
190
essential.
191 192
Field studies: investigations of dose thresholds and dose effects:
193
In 2007, Neriishi et al. analyzed the radiation dose exposure and dose response of
194
3,761 atomic bomb survivors, including 479 postoperative cataract cases [28].
195
Neriishi et al. found an increased cataract prevalence with a dose of 1Gy at an odds
196
ratio (OR) of 1.39 [28] . Within the 0- 1Gy range, a non-significant dose threshold of
197
0.1Gy was seen [28]. These results advocated for a far lower threshold than the
198
2007 ICRP recommendations, and also suggested the concept of a no threshold,
199
dose-response relationship between radiation exposure and cataractogenesis [28].
200 201
Previous research also supported Neriishi et al.’s conclusions. At 1Gy exposure, a
202
study by Hall et al. reported a 1.49 OR for PSC in infants treated with radiation
203
therapy for skin hemangiomas [5] and Worghul et al. reported an OR of 1.42 for PSC
204
cataracts [29] when examining 8,607 Chernobyl clean-up workers. These studies
205
reporting an increased risk of cataracts with low doses of radiation supported the
206
idea of a threshold as low as 0.5Gy, or no threshold at all [13, 18, 19].
207 208
Occupational radiation exposure studies: dose accumulation and cataract
209
prevalence:
210
Multiple epidemiological and clinical studies investigating occupational radiation
211
exposure to healthcare professionals have confirmed the prevalence of radiation9
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
212
induced cataracts in the medical community. In 2008, Chodick et al. published
213
results of a 1983-2004 cohort study of 35,705 US radiology technologists (initially
214
cataract free), aged 24–44 years, followed-up using two detailed questionnaires [11].
215
They reported 2,382 cataracts and 647 cataract extractions, with 25% of the
216
cataracts occurring before 50 years of age [11]. Results showed a mean radiation
217
dose to the lens of 28.1mGy in the entire cohort and after being adjusted for other
218
known confounding factors, suggested a possible risk of cataractogenesis at low
219
radiation doses [11]. Just three or more diagnostic head or neck x-rays were found to
220
increase the risk of cataractogenesis [11]. The dose to risk of cataract relationship
221
was strongest with subjects younger than 50 years old, with PSC cataracts being the
222
most prevalent type of opacity found in this age group [11]. Furthermore, a study on
223
Finnish physicians reported an OR for any lens opacities of 0.13 (95% CI -0.02-0.28)
224
per 10mSv of whole body cumulative effective dose [12].
225 226
Organizations such as the ICRP, the United Nations Scientific Committee on the
227
Effects of Atomic Radiation (UNSCEAR), the International Atomic Energy Agency
228
(IAEA) and the National Council on Radiation Protection and Measurements (NRCP)
229
have also attempted to raise awareness and evaluate the risk of cataracts from a
230
chronic occupational radiation exposure by publishing annual reports and guidelines
231
and initiating collaborative studies [25, 26, 30-32]. In the last few years, the steady
232
increase in the number of medical procedures requiring radiation has led the
233
UNSCEAR group to undertake a task force in order to analyse and record worldwide
234
radiation exposures coming from the medical field [32]. In an epidemiological study
235
by the O’CLOC group in 2013, Jacob et al. investigated the risk of cataract in French
236
interventional cardiologists and electrophysiologists [10, 33]. The retrospective
237
assessment showed a cumulative eye lens exposure ranging from 25 to over
238
1600mSv, as estimated by taking into account the number of procedures done, the
239
average radiation dose per procedure, and the various radiation protection
240
equipment utilized [33]. A mean exposure of 423mSv was found for a mean working
241
time of 22 years , with an OR of 3.8 (1.3–11.4) for the development of PSC in
242
exposed medical personnel compared to non-exposed controls [33]. This data
243
suggested that approximately 25% of these professionals were over the revised
244
ICRP threshold of 500mSv [33]. Furthermore, the new ICRP annual exposure limit of
245
20 mSv/year was surpassed a minimum of once by 60% of cardiologists during the 10
246 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
study period [33].
247 248
Indeed, interventional cardiologists have become the focus of many similar studies
249
attempting to estimate occupational lens dose and cataract prevalence in this group.
250
Ciraj-Bjelac et al.’s study found a lifetime cumulative dose to the lens of 3.7±7.5Gy
251
(0.02-43Gy) over an average of 9 working years [34], while Vano et al. found a
252
cumulative occupational lens dose of 6.0±6.6Sv (0.1-27Sv) over a mean working
253
time of 14 years [35]. These results were, like the O’CLOC study, estimated from the
254
numbers of procedures performed by the interventionalist, the baseline eye lens
255
dose per procedure type, and the radiation protection conditions [33]. The doses
256
were likely overestimated in these studies, since lens opacities were found in only
257
38% of participants in Vano et al. [35], less than what would be expected with
258
medians of such high values [33]. The wide discrepancies between estimated levels
259
of exposure and the PSCC incidence was hypothesized to be secondary to a lack of
260
systematic monitoring, leading to inaccurate estimates of occupational exposure
261
[33]. However, all these studies ultimately did show an increase in the crude relative
262
risk of radiation cataractogenesis, which was still significant after being adjusted for
263
confounding factors and compared with the control subject [33-35].
264 265
Another important source of discrepancies in studies reporting the prevalence of
266
PSC cataracts comes from the use of different classification systems and grading
267
schemes available. For example, the reported prevalence of PSC opacities in the
268
O’CLOC, Vano et al., and Ciraj-Bjelac et al. studies were evaluated at 17%, 38% and
269
52% respectively [10, 34, 35]. Ciraj-Bjelac et al. and Vano et al. both used a modified
270
Merriam-Focht system specifically designed for posterior lens opacities [36], while
271
the O’CLOC study used the Lens Opacities Classification System III (LOCS III) [37],
272
a system that evaluates and grades any type of cataract. With LOCS III, the
273
ophthalmologist compares the morphology of the lens fiber in all regions of the lens
274
(nuclear, cortical and PSC), and compares it to reference slides in order to determine
275
the severity of the opacities in each region [37]. All these grading systems also differ
276
in the methods used to assess the opacities, including dilated slit-lamp bio-
277
microscopy, retro illumination and Scheimpflug imaging [6]. These factors constitute
278
a major limiting factor when comparing studies, and further complicate pooled
279
analysis [6]. Hence, for future studies, standardization of the cataract grading 11
280 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
systems and is critical for an effective analysis of prevalence [6].
281 282
3. Protocol, clinical applications and their issues:
283 284
a) Monitoring and protection:
285
Radiation dose monitoring devices are essential to assess the physician’s
286
occupational risk. Because of the lack of a direct quantification method to measure
287
eye lens dose, studies such as the O’CLOC, Vano et al., and Ciraj-Bjelac et al.
288
studies have sought to use various formulae to estimate retrospective assessment of
289
eye lens exposure [33-35]. These methods are not reliable or reproducible for the
290
assessment of radiation dose, due to inherent differences in patients, physicians,
291
procedures and protective equipment used [38, 39]. Furthermore, many physicians
292
unfortunately do not routinely use personal dosimeters even when made available
293
[40].
294 295
Hp(3) is the most accurate operational quantity for the eye lens dose [41]. However,
296
the dosimeters provided to clinicians often only include effective dose/whole-body
297
dosimeter Hp(10) and local skin dose/partial body dosimeter Hp(0.07), and
298
calibration for Hp(3) is impossible[40, 41]. In this context, Hp(0.07) is used to provide
299
the closest dose estimate to the lens [38, 40].
300 301
Recently, studies have explored the use of electronic active dosimeters that provide
302
physicians with real-time maximum dose rates and total cumulative dose for a single
303
procedure [42, 43]. Such devices could serve as an occupational dose education
304
and awareness tool for physicians, while potentially increasing compliance to
305
protective equipment and other dose reduction techniques [42, 43].
306 307
In order to decrease chronic radiation exposure, there has to be strict adherence and
308
appropriate use of the active (patient dose reduction techniques) and passive (room
309
and personal protection devices) components of radiation protection (Table 12).
310 311
Radiation to the eye in the fluoroscopy room mainly comes from scatter radiation
312
from the patient [44, 45]. Central to any dose reduction strategy is first and foremost 12
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
313
to decide if the exam to be performed is clinically indicated, and if the use of the
314
fluoroscopy guidance is essential. If the procedure is deemed appropriate, careful
315
planning of the procedure to optimize the use of radiation is necessary [44].
316
Strategies to reduce radiation dose to the patient include shorter fluoroscopy time,
317
decreased frame rate, use of collimation, avoidance of magnification, decreased
318
digital subtraction angiography (DSA) sequences acquisitions, increased distance
319
between the source and the patient, and decreased distance between the patient
320
and the image receptor [44].
321 322
Passive strategies such as room shielding devices protect against the scatter
323
radiation, and include ceiling-suspended shields and shielded drapes [44]. Ceiling-
324
suspended shields, when used properly, were shown to reduce occupational
325
exposure doses by up to 100-fold and therefore should always be used if
326
interventionalist positioning is not compromised as a result [44]. Similarly, drapes
327
placed around the image intensifier was shown to provide an approximate 90% dose
328
exposure reduction to the endoscopist during endoscopic retrograde cholangio-
329
pancreatography (ERCP) [45]. Other measures to reduce scatter radiation include
330
using protective disposable shielded drapes, which showed a 23% reduction in total
331
radiation dose to the operators in a randomized controlled trial [46], and dose
332
reduction to the hands and chest of interventionalists of 49% and 55% respectively
333
during endovascular aortic repair (EVAR) procedures [47].
334 335
Finally, to achieve the greatest reduction in dose exposure, room-shielding
336
equipment must be combined with personal protective devices. These include
337
protective aprons, thyroid shields, gloves and eyewear for physicians [44]. The use
338
of lead eyewear that is properly fitted and has lateral eye shielding can reduce eye
339
lens dose by a factor of 2.1 for the tube side eye, and 0.8 for the non-tube side eye
340
[48]. Unfortunately, evidence suggests poor compliance with only 25% of
341
interventionalists and 36% of cardiologists wearing glasses during the procedures
342
[41]. Although current technology has the ability to provide major protective benefits
343
to physicians, ineffective protocols and poor compliance needs to be addressed in
344
future guidelines.
345 346
b) Proficiency and treatment procedure: 13
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
347
Without comprehensive evidence-based guidelines, effective dose monitoring tools
348
and the use of appropriate protective equipment and dose-reducing strategies,
349
physicians are at risk of pathological manifestations from their occupational radiation
350
exposure. This might impact on the physician’s professional proficiency, quality of life
351
and career span [6]. For example, because of their central position, PSCCs may
352
cause significant visual impairment and decrease contrast sensitivity and present a
353
specific surgical group of patients that is likely to be younger than the majority of
354
"senile" cataract patients [49].
355 356
CONCLUSION
357
Throughout this paper, the numerous potential risk factors of cataractogenesis were
358
presented, and the pathogenesis of radiation-induced cataracts was reviewed. A
359
brief parallel was made between radiation-induced cataractogenesis and
360
oncogenesis, two process that share multiple similarities. The recent IRCP
361
guidelines changes were described, and the studies which led to these changes
362
were presented. Future areas of research include the study of specific genetic traits
363
that could potentially affect an individual’s vulnerability to radiation, and more precise
364
and homogeneous ophthalmologic diagnostic tools for the diagnosis of PSC
365
cataracts. In the current interventional radiology field, there is an urgent need to
366
recognize that there is no safe dose of radiation. Will we one day see Posterior
367
Chamber Cataracts as the canary in the cold mine? In order to prevent the
368
detrimental effects of occupational radiation on health workers, there must be a strict
369
worldwide application of the recent lower radiation threshold guidelines, a more
370
effective means of monitoring radiation exposure, and finally, the consistent use of
371
appropriate radiation protection strategies.
14
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
372
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373
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Kloeze, C., et al., Editor's choice--Use of disposable radiation-absorbing surgical
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van Rooijen, B.D., et al., Efficacy of radiation safety glasses in interventional radiology. Cardiovasc Intervent Radiol, 2014. 37(5): p. 1149-55.
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492 493 494 495 496 497 498 499 500 18
501 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
502 503 504 505 506 507 508 509 510 511
Table 1. Our search strategy for exploring the relevant literature.
512 513 514 515 516
Table 2. Protective measures to decrease radiation exposure in interventional
517
radiology.
518 Passive
Personal protection
Protective glasses Lead apron Lead gloves Thyroid shield
Room-specific protection
Suspended screens Suspended drapes Disposable shielded drapes
Active
Operator-specific
Decrease length of
strategies
fluoroscopy Decrease frame rate Use collimation Avoid magnification Decrease number of DSA acquisitions Increase distance between 19
patient and source 1 2 3 4 5 6 7 8 9 10 11 519 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Decrease distance between patient and image receptor Increase distance between operator and source if possible
20
520 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Figure Legends
521 522 523
Figure 1. Normal lens showing (1) lens capsule, (2) peripheral lens fiber, (3) nucleus
524
with higher concentration of lens fibers, (4) iris, (5) cornea, (6) ciliary body, (7)
525
artifact.
526 527
Figure 2. Posterior sub-capsular cataract showing (1) presence of a layer of
528
epithelial cells under the posterior capsule which have migrated from the equatorial
529
cells, (2) the lens fibers still maintain some normal appearance.
530 531
Figure 3. Posterior sub-capsular cataract with (1) epithelial cells under the posterior
532
lens capsule that have migrated from the equator or lens bow cells, (2) artifacts.
533 534
Figure 4. Nuclear cataract showing (1) lens fibers have lost their concentric
535
lamination giving rise to homogenous eosinophilic appearance, (2) separation of lens
536
fibers during slide processing, (3) artifact.
537 538
Figure 5. Search Strategy
21
Figure 1 Click here to download high resolution image
Figure 2 Click here to download high resolution image
Figure 3 Click here to download high resolution image
Figure 4 Click here to download high resolution image
Figure 5
Records identified through database search of keywords: (n=455)
Full text articles available: (n=297)
Articles excluded upon review of abstract: (n=99)
Exclusion due to non-English language: (n=10)
Exclusion due to publication prior to the years 1950-2016: (n=2)
Articles included upon review of abstract: (n=198)
Exclusion due to the lack of subject matter on radiationinduced cataracts pathogenesis, lens dose monitoring or radiation protection strategies: (n=87)
Full text articles assessed and included as part of review: (n=49)
Full text articles assessed and excluded due to the lack of subject matter on radiationinduced cataracts pathogenesis, lens dose monitoring or radiation protection strategies: (n=149)
Table1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Table 2. Protective measures to decrease radiation exposure in interventional radiology.
Passive
Personal protection
Protective glasses Lead apron Lead gloves Thyroid shield
Room-specific protection
Suspended screens Suspended drapes Disposable shielded drapes
Active
Operator-specific
Decrease length of
strategies
fluoroscopy Decrease frame rate Use collimation Avoid magnification Decrease number of DSA acquisitions Increase distance between patient and source Decrease distance between patient and image receptor Increase distance between operator and source if possible
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
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