Fundus Photography
Number: 0539
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses fundus photography.
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Medical Necessity
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Aetna considers fundus photography medically necessary for any of the following indications:
- Abnormal electro-oculogram (EOG) / infrared video-oculogram (VOG)
- Abnormal oculomotor studies
- Abnormal retinal function studies
- Abnormal visually evoked potential
- Age-related macular degeneration
- Atrophic pigmentary degeneration of the retina
- Benign neoplasm of choroid, cranial nerves, eyeball, or retina
- Carcinoma in situ of eye
- Chorioretinal inflammation, scars, and other disorders of choroid including staphyloma posticum
- Color vision deficiencies
- Congenital anomalies of posterior segment of eye
- Congenital glaucoma
- Congenital rubella
- Diabetes mellitus (diabetic retinopathy)
- Disorders of aromatic amino-acid metabolism affecting the fundus
- Disorders of globe
- Disorders of optic nerve and visual pathways
- Endophthalmitis
- Glaucoma and glaucoma suspects
- Hamartoses involving the eye
- Histoplasmosis
- Human immunodeficiency virus (HIV) disease
- Hypertensive retinopathy
- Initial baseline evaluation and periodical follow-up of individuals being treated with ethambutol (Myambutol)
- Lupus erythematosus
- Malignant neoplasm of eye
- Monitoring of cytomegalovirus (CMV) retinitis
- Monitoring of members for toxicity by anti-malarials such as chloroquine (Aralen), hydroxychloroquine (Plaquenil) and drugs acting on other blood protozoa
- Multiple sclerosis
- Other retinal disorders (e.g., macular dystrophy or inherited retinal disorders such as incontentia pigmenti) where the results of fundus photography may change the treatment of the member.
- Penetration of eyeball with magnetic or non-magnetic foreign body
- Peters anomaly
- Pseudotumor cerebri
- Retinal detachment and defects
- Rheumatoid arthritis and other inflammatory polyarthropathies
- Sickle-cell anemia
- Stickler syndrome
- Syphilitic retrobulbar neuritis
- Systemic lupus erythematosus
- Toxoplasmosis
- Tuberous sclerosis.
Note: Fundus photography of a normal retina is considered not medically necessary.
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Frequency of Testing:
Aetna considers fundus photography medically necessary no more than two times per year. Justification for more frequent testing must be documented in the medical record.
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Experimental and Investigational
The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:
- Automated color fundus photography for detection and screening of age-related macular degeneration
- Computer-aided animation and analysis of time series retinal images (e.g., MatchedFlicker) for monitoring disease progression and for all other indications
- Fundus photography for all other indications, including (not an all-inclusive list):
- Screening in asymptomatic persons without signs or symptoms of disease
- Diagnosis/evaluation of copper deficiency and mild myopia
- Posterior vitreous detachment
- Evaluation of neurofibromatosis type 1
- Non-penetrating traumatic eye injury
- Pigment dispersion syndrome
- Pilocytic astrocytoma
- Tilted optic nerve
- Tamoxifen use
- Toxocariasis
- Visual snow syndrome
- Monitoring of individuals on checkpoint inhibitors (e.g., ipilimumab and nivolumab))
- Screening for potential ocular side effects (e.g., macular edema, retinal vasculitis, and uveitis) of durvalumab (Imfinizi).
Background
Fundus photography involves the use of a retinal camera to photograph the regions of the vitreous, retina, choroid, and optic nerve. The resultant images may be either photographic or digital and become part of the member's medical record. Fundus photographs are usually taken through a dilated pupil in order to enhance the quality of the photographic record, unless unnecessary for image acquisition or clinically contraindicated.
Fundus photography is indicated to document abnormalities related to disease processes affecting the eye or to follow the progress of the disease, and is considered medically necessary for such conditions such as macular degeneration, retinal neoplasms, choroid disturbances and diabetic retinopathy, or to identify glaucoma, multiple sclerosis, and other central nervous system abnormalities.
Fundus photographs are only considered medically necessary where the results may influence the management of the patient. In general, fundus photography is performed to evaluate abnormalities in the fundus, follow the progress of a disease, plan the treatment for a disease, and assess the therapeutic effect of recent surgery (e.g., photocoagulation). Fundus photographs are not medically necessary simply to document the existence of a condition. However, photographs may be medically necessary to establish a baseline to judge later whether a disease is progressive.
A CGS Administrators, LLC Medicare Local Coverage Determination (LCD) allows coverage of fundus photography (L34399) for diagnosis of conditions such as macular degeneration. Fundus photography is usually medically necessary no more than two times per year. Fundus photography of a normal retina will be considered not medically necessary.
A First Coast Service Options, Inc. Medicare Local Coverage Determination (LCD) also allows coverage of fundus photography (L33670) and states that “fundus photos may be of value in the documentation of rapidly evolving diabetic retinopathy. In the absence of prior treatment, studies would not generally be performed for this indication more frequently than every 6 months.”
A National Government Services, Inc. Medicare Local Coverage Determination (LCD) allows coverage of fundus photography (L33567) which states that “fundus photography may be used for the diagnosis of conditions such as macular degeneration, retinal neoplasms, choroid disturbances and diabetic retinopathy, glaucoma, multiple sclerosis or other central nervous system anomalies.” It is not covered if study is performed as a “screening” service. Fundus photography is usually medically necessary no more than two times per year. Fundus photography of a normal retina will be considered not medically necessary.
Sequential series of photographs are considered medically necessary only if they document a clinically relevant condition that is subject to change in extent, appearance or size, and where such change would directly affect the management. Repeat fundus photography may be medically necessary when an examination of the fundus reveals that the disease of condition of the fundus has progressed, such that prior fundus photographs no longer depict the pathology at the present time. Repeated fundus photographs of the same disease or condition, without any meaningful change, are not considered medically necessary. In addition to disease progression, repeat fundus photographs may be necessary if there is a new disease affecting the fundus, or for planning for additional surgical treatment. Routine images to embellish the record, but a succession of which would not influence treatment, are not considered medically necessary. When performed concurrently, the medical necessity of fundus photography and scanning computerized diagnostic imaging of the posterior segment should be documented in the medical record.
Documentation in the patient's medical record should include a current, pertinent history and physical examination, and progress notes describing and supporting the covered indication for fundus photography, and pertinent prior diagnostic testing and completed report(s), including, when appropriate, previous fundus photographs. Fundus photographs should be properly labeled as to which eye they represent, the date they were taken, and the date they were reviewed. The medical records should document the findings of the fundus photography, including a description of changes from prior fundus photographs (if any), and an interpretation of those findings, and the implications of the photographic evidence, including whether any changes in the treatment plan will be instituted as a result of the photographs. Fundus photographs without an interpretation are considered not medically necessary. All documentation must be maintained in the member’s medical record. The record must be legible and include appropriate patient identification information (e.g., complete name, dates of service(s)), as well as the physician or non-physician practitioner responsible for and providing the care of the patient.
When indicated for glaucoma, the interpretation of the fundus photographs should include a report of the vertical and horizontal cup/disc ratio based upon vessel pattern and/or coloration, the presence or absence of diffuse or focal pallor, the presence or absence of asymmetry, and the presence or absence of progression regarding any of the above parameters. If the fundus photographs include red-free images, commentary on the status of the retinal nerve fiber layer should accompany the images.
The American Academy of Ophthalmology (Marmor et al, 2011) does not recommend the use of fundus photography for screening of chloroquine and hydroxychloroquine retinopathy. It is not sensitive enough for screening because recognizable bull's-eye retinopathy signifies relatively advanced chloroquine or hydroxychloroquine toxicity.
Salcone et al (2010) stated that retinopathy of prematurity (ROP) is a vision-threatening vaso-proliferative condition of premature infants worldwide. As survival rates of younger and smaller infants improve, more babies are at risk for the development of ROP and blindness. Meanwhile, fewer ophthalmologists are available for bedside indirect ophthalmoscopy screening examinations. Remote digital imaging is a promising method with which to identify those infants with treatment-requiring or referral-warranted ROP quickly and accurately, and may help circumvent issues regarding the limited availability of ROP screening providers. The Retcam imaging system is the most common system for fundus photography, with which high-quality photographs can be obtained by trained non-physician personnel and evaluated by a remote expert. It has been shown to have high reliability and accuracy in detecting referral-warranted ROP, particularly at later post-menstrual ages. Additionally, the method is generally well-received by parents and is highly cost-effective.
An UpToDate review on "Retinopathy of prematurity" (Paysse, 2012) does not mention the use of digital imaging or fundus photography. It states that "screening evaluation consists of a comprehensive eye examination performed by an ophthalmologist with expertise in neonatal disorders".
An UpToDate review on “Toxocariasis: visceral and ocular larva migrans” (Weller and Leder, 2013) does NOT mention the use of fundus imaging/photography.
Computer-aided animation and analysis of time series retinal images (e.g., MatchedFlicker) has been proposed for use in monitoring glaucoma and other retinal diseases. According to the manufacturer of the MatchedFlicker (EyeIC, Wayne, PA), the technology automatically aligns and registers two images of the same object taken at different points in time, and generates a superimposed view that is alternated back and forth (i.e., a flicker). In so doing, areas of change present between the two images appear as motion.
MatchedFlicker has been cleared by the FDA based upon 510(k) premarket notification as a class II device.
The manufacturer states that MatchedFlicker helps to improve both the speed and accuracy of image diagnostic evaluations, resulting in more efficient workflow, more accurate patient diagnosis, and ease of documentation (EyeIC, 2014).
Studies have compared computer-aided animation and analysis of time series retinal images to side-by-side comparison of photographic images in a number of retinal diseases, including detection of glaucoma and screening of premature infant eyes for retinopathy of prematurity. Clinical utility studies are ongoing.
Screening for Diabetic Retinopathy
van Ballegooie and van Everdingen (2000) stated that early detection and adequate treatment of complications of diabetes mellitus (DM) are important for many patients in maintaining independence and ability to work. Diabetic retinopathy (DR) cannot be prevented. Limitation of damage is possible by aiming for normoglycemia and normotension. While exudative as well as proliferative retinopathy can occur without any visual symptom, regular ophthalmological examination is necessary for timely laser coagulation. Fundus photography for screening is applicable under certain conditions; fluorescence angiography can be useful in patients with understood deterioration of visual acuity or diabetic maculopathy. In many patients foot disease can be prevented by simple measures: examining the foot at least once-yearly, recognition of the foot with a high level of risk, education of patient and family, adapted shoes and preventive foot care. Treatment of a foot ulcer consists of relief of mechanical pressure, repair of disturbed skin circulation, treatment of infection and edema, optimal metabolic control, frequent local wound care and education. Patients with a diabetic foot have to be thoroughly followed-up for the rest of their lives. For patients with diabetic nephropathy cardiovascular complications are the main causes of morbidity and mortality. Of all patient with DM older than 10 years, urine has to be examined for loss of albumin at least once-yearly. Treatment of nephropathy consists of non-smoking, sufficient physical exercise, reduction of over-weight, well-composed nutrition and particularly treatment of hypertension. Diagnosing cardiovascular diseases in patients with DM is in principle the same as for other patients. Treatment of hyper-cholesterolemia has to be based on an absolute risk of 20 % for cardiovascular disease in the following 10 years. The limit for treatment will be reached earlier in the presence of micro-albuminuria, persistent high HbA1c greater than 8.5 %, triglyceride concentration greater than 2.0 mmol/L, or a positive family history with myocardial infarction less than 60 years. In proven cardiovascular disease one needs to strive for optimization of the glucose metabolism, non-smoking and if necessary drug therapy.
Massin et al (2003) compared the results of fundus photography using a new non-mydriatic digital camera with the results of reference standard of Early Treatment Diabetic Retinopathy Study (ETDRS) retinal photographs, for the detection of DR. Fundus color photographs were taken with a Topcon non-mydriatic camera of 147 eyes of 74 diabetic patients, without pupillary dilation (5 overlapping fields of 45 degrees; posterior pole, nasal, temporal, superior and inferior). Three retinal specialists classified the photographs in a masked fashion, as showing no DR or mild non-proliferative DR (NPDR) not requiring referral, moderate or more severe NPDR and/or macular edema, or as non-gradable image requiring referral; ETDRS 35-mm color slides served as reference images for DR detection. For moderately severe to severe DR, the sensitivities of detection reported by the 3 observers were 92, 100 and 92 %, respectively, and the specificities, 87, 85, and 88 %, respectively. For 4 levels of DR severity (none or mild NPDR, moderate NPDR, severe NPDR and proliferative DR), the percentages of exact agreement between the 3 observers on the retinopathy grades assigned to the non-mydriatic photographs and to the ETDRS reference slides were 94.6, 93 and 87.6 %, respectively (kappa 0.60 to 0.80); 16 eyes of 9 patients (11%) were judged un-gradable by at least 1 observer. In a second series of 110 patients, evaluated in the setting of a screening procedure, fewer photographs were un-gradable (less than 6 %). The authors concluded that these findings suggested that fundus photographs taken by the Topcon TRC-NW6S non-mydriatic camera, without pupillary dilation, are suitable for DR screening.
- single-field non-mydriatic;
- 3-field non-mydriatic;
- single-field mydriatic; and
- 3-field mydriatic; followed by dilated ophthalmoscopy.
Polak and colleagues (2008) noted that the revised evidence-based guideline “Diabetic retinopathy: Screening, diagnosis and treatment” contained important recommendations concerning screening, diagnosis and treatment of DR. Regular screening and the treatment of risk factors, such as hyperglycemia, hypertension, obesity and dyslipidemia, can prevent retinopathy and slow down its development. Fundus photography is recommended as a screening method. If necessary, diagnosis by biomicroscopy and a treatment consisting of photocoagulation and/or vitrectomy should be performed by the ophthalmologist. The re-assessment of responsibilities is a vital component of the implementation of the guideline bearing in mind that the screening in particular, can be performed by personnel other than ophthalmologists.
In a cross-sectional study, Germain and associates (2011) compared the efficiency of the DR screening with digital camera by endocrinologists with that by specialist and resident ophthalmologists in terms of sensitivity, specificity, and level of "loss of chance". A total of 500 adult diabetic patients (1,000 eyes) underwent 3-field retinal photography with a digital fundus camera following pupillary dilatation; 5 endocrinologists and 2 ophthalmology residents underwent 40 hours of training on screening and grading of DR and detection of associated retinal findings. A κ test compared the accuracy of endocrinologist and ophthalmology resident screening with that performed by experienced ophthalmologists. Screening efficiency of endocrinologists was evaluated in terms of "loss of chance", namely, missed diagnoses that required ophthalmologist referrals. The mean weighted κ of DR screening performed by endocrinologists was similar to that of ophthalmology residents (0.65 versus 0.73). Out of 456 DR eyes, both endocrinologists and ophthalmology residents mis-diagnosed only stage 1 DR (36 and 14, respectively), which did not require ophthalmologist referral. There were no significant differences between endocrinologists and ophthalmology residents in terms of diabetic maculopathy and incidental findings except for papillary cupping and choroidal lesions, which were not the main purpose of the study or of the training. The authors concluded that endocrinologist with specific training for DR detection using a 3-field digital fundus camera with pupillary dilatation could perform a reliable DR screening without any loss of chance for the patients when compared with identical evaluation performed by experienced ophthalmologists.
Guigui et al (2012) reviewed the current screening methods for DR, with a focus on non-mydriatic digital fundus photography. Articles from Medline were reviewed from 1976 to November 2011 for different combinations of the words "diabetic retinopathy", "screening", "fundus photography" and "nonmydriasis". Current research has proven that pupillary dilation is not a necessary step in the fundus examination, although it reduces the number of unnecessary referrals to ophthalmologists. Automated grading systems, while saving time and reducing human error, still need refinement before they can replace manual grading by trained ophthalmologists. The authors concluded that non-mydriatic digital fundus photography with manual grading by a trained technician is an acceptable method of screening for DR.
Ku and colleagues (2013) evaluated the accuracy of grading DR using single-field digital fundus photography compared with clinical grading from a dilated slit-lamp fundus examination in Indigenous Australians living in Central Australia. Main outcome measures included sensitivity and specificity of grading using digital photography compared with the clinical gold standard of slit-lamp fundus examination. Of the 1,884 participants recruited for the study, 1,040 had self-reported DM and, of those, 360 had fundus photographs available (706 eyes) that were able to be graded. On clinical grading, 163 eyes had any DR and 51 eyes had vision-threatening DR (VTDR). The sensitivity and specificity for detecting any DR were 74 % (95 % confidence interval [CI]: 67 % to 80 %) and 92 % (95 % CI: 90 % to 94 %), respectively. The sensitivity and specificity for detecting VTDR were 86 % (95 % CI: 77 % to 96 %) and 95 % (95 % CI: 93 % to 97 %), respectively. The authors concluded that single-field digital fundus photography is a valid screening tool for DR in remote communities of central Australia and may be used to provide eye care services to this region with acceptable accuracy.
An UpToDate review on “Diabetic retinopathy: Screening” (McCulloch, 2016) states that “Ophthalmoscopy is a reasonable screening method when performed by well-trained personnel on dilated fundi. The accuracy of ophthalmoscopy is substantially lower when performed by primary care physicians. As an alternative, 7-field stereoscopic fundus photography is another acceptable method, but also requires both a trained photographer and a trained reader. Fundal photography compares favorably with ophthalmoscopy (performed by an experienced ophthalmologist, optometrist, and ophthalmic technician) …. In patients with diabetes, we recommend screening for diabetic retinopathy (DR) (Grade 1B). Screening must be performed by those with expertise and can be accomplished with dilated fundus examination or retinal photography”.
Diagnosis and Management of Diabetic Retinopathy
The Institute for Clinical Systems Improvement’s clinical practice guideline on “Diagnosis and management of type 2 diabetes mellitus in adults” (Redmon et al, 2014) stated that “A dilated eye examination for diabetic eye disease performed by an ophthalmologist or optometrist is recommended annually for patients with T2DM. Less frequent exams (every 2 to 3 years) may be considered in the setting of a normal eye exam. The role of fundus photography is still being considered but doesn't replace a comprehensive exam”.
Monitoring of Ethambutol-Induced Optic Neuropathy
Chung and associates (1989) reported the case of a 54-year old Chinese woman with miliary choroidal tuberculosis who was followed for more than 3 years. She had had tuberculous meningitis for about 1 month before an ophthalmologic examination for blurred vision OU (oculus uterque meaning both eyes). There were 50 to 60 choroidal tubercles OU which were located mostly at the posterior poles including the macular areas. The meningitis and tubercular lesions resolved with anti-tuberculous medications. In a series of fundus photographs and fluorescein angiograms, a macular subretinal neovascularization was noted in association with the tubercular lesions, which resulted in disciform maculopathy. The authors stated that this case had the largest number of tubercles reported in this century, and the association of macular subretinal neovascularization with choroidal tuberculosis has never been reported.
In a prospective, longitudinal, cohort study, Han and colleagues (2015) evaluated longitudinal analysis of peri-papillary retinal nerve fiber layer (RNFL) and peri-foveal ganglion cell-inner plexiform layer (GCIPL) thickness in patients being treated with ethambutol (EMB). This study enrolled 37 patients who were treated with EMB for pulmonary tuberculosis. Best-corrected visual acuity (BCVA), color vision test, automated perimetry, fundus photography, and RNFL and GCIPL thickness were measured at baseline and at 4 and 6 months after the start of EMB treatment, using Cirrus optical coherence tomography (OCT). Among 37 patients, EMB-induced optic neuropathy occurred in 1 patient (2.7 %). In this patient, thickening of the RFNL and thinning of the GCIPL were noted at the onset of symptoms. After discontinuation of EMB, RNFL and GCIPL thickness progressively normalized. Changes in RNFL and GCIPL thickness were not statistically significant in the 36 patients who did not exhibit EMB-induced optic neuropathy-related symptoms during follow-up (all p > 0.05). The authors concluded that thickening of the peri-papillary RNFL and thinning of the peri-foveal GCIPL is an effective quantitative and early marker for diagnosis of EMB-induced optic neuropathy.
Furthermore, the American Optometric Association recommends fundus photography for initial baseline evaluation and periodical follow-up of individuals being treated with ethambutol. .
Age-Related Macular Degeneration
The American Academy of Ophthalmology Preferred Practice Pattern on age-related macular degeneration (AAO, 2015) states: "Color fundus photographs may be obtained when angiography is performed, because they are useful in finding landmarks, evaluating serous detachments of the neurosensory retina and RPE, and determining the etiology of blocked fluorescence. Fundus photographs may also be used as a baseline reference for selected patients with advanced non-neovascular AMD and for follow-up of treated patients."
Holz and colleagues (2017) summarized the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (ARMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. A panel of retina specialists participated in a systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular ARMD was held. Main outcome measures were advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced ARMD trials. Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus auto-fluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution OCT volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular ARMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indo-cyanine green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular ARMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. The authors concluded that a multi-modal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.
Fleckenstein and associates (2018) noted that geographic atrophy (GA) is an advanced form of ARMD that leads to progressive and irreversible loss of visual function. Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the peri-foveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggested that specific characteristics may be important in predicting disease progression and outcomes. This review synthesized current understanding of GA progression in ARMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement were discussed. Overall, GA progression rates reported in the literature for total study populations ranged from 0.53 to 2.6 mm2/year (median of approximately 1.78 mm2/year), assessed primarily by color fundus photography or FAF imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multi-focality, FAF patterns, and fellow eye status. Because BCVA does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including micro-perimetry, low-luminance VA, reading speed assessments, and patient-reported outcomes. The authors concluded that understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.
Automated Color Fundus Photography for Screening and Detection of Age-Related Macular Degeneration
Peng and associates (2019) noted that in assessing the severity of age-related macular degeneration (ARMD), the Age-Related Eye Disease Study (AREDS) Simplified Severity Scale predicts the risk of progression to late ARMD. However, its manual use requires the time-consuming participation of expert practitioners. Although several automated deep learning systems have been developed for classifying CFP of individual eyes by AREDS severity score, none to-date has used a patient-based scoring system that uses images from both eyes to assign a severity score. DeepSeeNet, a deep learning model, was developed to classify patients automatically by the AREDS Simplified Severity Scale (score 0 to 5) using bilateral CFP. DeepSeeNet was trained on 58,402 and tested on 900 images from the longitudinal follow-up of 4,549 subjects from AREDS. Gold standard labels were obtained using reading center grades. DeepSeeNet simulated the human grading process by first detecting individual ARMD risk factors (drusen size, pigmentary abnormalities) for each eye and then calculating a patient-based ARMD severity score using the AREDS Simplified Severity Scale. Main outcome measures were overall accuracy, specificity, sensitivity, Cohen's kappa, and area under the curve (AUC). The performance of DeepSeeNet was compared with that of retinal specialists. DeepSeeNet performed better on patient-based classification (accuracy = 0.671; kappa = 0.558) than retinal specialists (accuracy = 0.599; kappa = 0.467) with high AUC in the detection of large drusen (0.94), pigmentary abnormalities (0.93), and late AMD (0.97). DeepSeeNet also out-performed retinal specialists in the detection of large drusen (accuracy 0.742 versus 0.696; kappa 0.601 versus 0.517) and pigmentary abnormalities (accuracy 0.890 versus 0.813; kappa 0.723 versus 0.535); but showed lower performance in the detection of late ARMD (accuracy 0.967 versus 0.973; kappa 0.663 versus 0.754). The authors concluded that by simulating the human grading process, DeepSeeNet demonstrated high accuracy with increased transparency in the automated assignment of individual patients to ARMD risk categories based on the AREDS Simplified Severity Scale. These researchers stated if these results are tested and validated by further reports of superiority across multiple datasets (ideally from different countries), it is possible that the integration of deep learning models into clinical practice might become increasingly acceptable to patients and ophthalmologists. These investigators stated that in the future, deep learning models might support eye services by reducing the time and human expertise needed to classify retinal images and might lend themselves well (through telemedicine approaches) to improving care in geographical areas where current services are absent or limited. Although deep learning models are often considered “black-box” entities (because of difficulties in understanding how algorithms make their predictions), these researchers aimed to improve the transparency of DeepSeeNet by constructing it from sub-networks with clear purposes (e.g., drusen detection) and analyzing its out-puts with saliency maps. These efforts to demystify deep learning models may help improve levels of acceptability to patients and adoption by ophthalmologists. These investigators have also analyzed the performance of several distinct training strategies; lessons from these approaches may have applicability to the development of deep learning models for other retinal diseases, such as diabetic retinopathy, and even for image-based deep learning systems outside of ophthalmology.
The authors stated that this study had several drawbacks. One current limitation of DeepSeeNet (at least in its present iteration) arose from the imbalance of cases that were available in the AREDS data-set used for its training, especially the relatively low proportion of participants with late ARMD, which likely contributed to the relatively lower accuracy of DeepSeeNet in the classification of late ARMD, that is, through the performance of LA-Net in the overall model. However, this limitation may potentially be addressed by further training using image data-sets with a higher proportion of late ARMD cases. A limitation of this data-set included the sole use of CFP because these were the only images obtained in a study that began in 1992. Other imaging techniques such as OCT and FAF images were not yet feasible or universally available. Future studies would benefit from inclusion of additional methods of imaging, and multi-modal imaging would be desirable. Another potential drawback lied in the reliance of DeepSeeNet on higher levels of image quality for accurate classification. Unlike in other studies, these investigators did not perform extensive pre-processing of images, such as the detection of the outer boundaries of the retina or normalization of the color balance and local illumination. It was possible that the use of these techniques might have improved the accuracy of the model. However, these researchers deliberately avoided extensive pre-processing to make their model as generalizable as possible. They recommended further testing of their deep learning model using other data-sets of color fundus images. Furthermore, it would be interesting for future studies to compare the accuracy of the model with that of different groups of ophthalmologists (e.g., retinal specialists, general ophthalmologists, and trainee ophthalmologists). Indeed, a recent study on grader variability for diabetic retinopathy severity using CFP suggested that retinal specialists had a higher accuracy than that of general ophthalmologists. In this study, these researchers set the bar as high as possible for the deep learning model, because they considered that the retinal specialists might have accuracy as close as possible to that of the Reading Center gradings.
Pead and colleagues (2019) stated that the rising prevalence of age-related eye diseases, especially ARMD, places an ever-increasing burden on healthcare providers. As new treatments emerge, it is necessary to develop methods for reliably assessing patients' disease status and stratifying risk of progression. The presence of drusen in the retina represents a key early feature where size, number and morphology are thought to correlate significantly with risk of progression to sight-threatening ARMD. Manual labeling of drusen on CFP by a human is labor-intensive and is where automatic computerized detection would appreciably aid patient care. These investigators evaluated current artificial intelligence methods and developments for the automated detection of drusen in the context of ARMD. The authors concluded that for automated drusen assessment to be employed in the clinic it must go beyond cross-sectional phenotyping and instead relate to real patient visual outcomes; and longitudinal studies are needed to determine if automated image grading, based on drusen detection, could accurately predict disease progression. These researchers stated that future algorithms involving drusen detection should aim to provide useful quantification to aid screening for ARMD. A screening program should stratify patients according to optimal follow-up pathway. In order for automated drusen detection to contribute to the cost-effectiveness of a screening program for ARMD, it must separate individuals with drusen associated with normal aging from patients whose drusen load progresses as well as stratifying patients with mild ARMD into those at low-risk and at high-risk of progression to severe ARMD. This would enable the ophthalmologist to select relevant patients for regular follow-up, thus improving the efficiency of patient care.
Evaluation of Eye Injury
In an observational, case-series study, Lavinsky and colleagues (2011) reported FAF and OCT findings in patients with blunt ocular trauma. A total of 6 eyes of 6 consecutive patients with blunt ocular trauma were evaluated using color fundus photography, the Heidelberg Retina Angiograph 2 (HRA2) system for FAF and OCT (Stratus OCT); 3 patients presented with secondary retinal pigment epitheliopathy that was identified as a reduced FAF plaque with interposed increased FAF granular smaller lesions. These findings were not as evident in fundus examination and color photography in 2 patients. Visual field in 1 patient showed a decreased area of sensitivity that correlated to the reduced/increased auto-fluorescent lesion. The other 3 patients had sub-retinal hemorrhage and choroidal rupture, which appeared with a reduced FAF with an increased FAF rim after resolution; OCT demonstrated a chorio-capillaris/RPE complex disruption and its resolution over time in all patients with choroidal rupture. The authors concluded that damaged RPE area was more evident and better delineated by FAF imaging compared with fundus examination and fundus photography alone. They stated that auto-fluorescence imaging might be a useful examination to show the length and severity of post-traumatic retinal lesions and it may add relevant information in the global evaluation of blunt ocular trauma complications. Moreover, OCT added valuable information to the diagnosis and progression of choroidal rupture. These researchers stated that further studies are needed to determine the predictive value of FAF in ocular blunt trauma.
An UpToDate review on “Approach to eye injuries in the emergency department” (Gardiner, 2019a) does not mention fundus photography and posterior segment scanning as management tools.
Furthermore, an UpToDate review on “Overview of eye injuries in the emergency department” (Gardiner, 2019b) states that “In patients with vitreous hemorrhage that obscures the fundus but who have a closed globe, orbital ultrasound can identify a retinal detachment”. This review does not mention “posterior segment scanning”.
Neurofibromatosis Type 1
Makino and Tampo (2013) reported a case of rare and unusual choroidal abnormalities in a 42-year old woman with systemic lupus erythematosus (SLE). Images were obtained using fundus photography, fluorescein angiography (FA), NIR imaging, and OCT. The patient had a history of SLE and central retinal artery occlusion in her right eye. Fundus examination showed no specific retino-choroidal abnormalities, with the exception of optic disc atrophy in her right eye and a peripapillary small hemorrhage in her left eye. However, NIR revealed multiple bright patchy lesions in the choroid of the posterior pole and the mid-periphery of the fundus in both eyes; OCT demonstrated irregular hyper-reflectivity at the lesion sites. The authors concluded that observed choroidal abnormalities were highly specific findings and thus, were indicative of neurofibromatosis type 1 (NF1). Since the co-existence of SLE and NF1 is extremely rare, this case provided the chance to examine the relationship between SLE and NF1.
Abdolrahimzadeh et al (2014) stated that NF1 is an autosomal dominant disorder involving aberrant proliferation of multiple tissues of neural crest origin. Retinal vascular alterations in NF1 have rarely been reported in the literature and their nature is unclear. In a retrospective study, these researchers described distinctive retinal microvascular alterations and their relationship to choroidal nodules in patients with NF1. Records of 17 consecutive patients with diagnosis of NF1, presenting Lisch nodules and choroidal alterations, and 17 age- and gender-matched healthy control patients were evaluated. Fundus photographs, NIR and enhanced depth imaging -- OCT images were reviewed. Retinal microvascular abnormalities and choroidal and retinal alterations in proximity of the retinal microvascular alterations were carefully noted. A total of 6 patients (35 %) presented distinctive microvascular abnormalities. These consisted of small, tortuous vessels with a "spiral" or "corkscrew" aspect. They were 2nd or 3rd order, small tributaries of the superior or inferior temporal vein. These vessels were all located overlying choroidal alterations as observed with NIR. Enhanced depth imaging -- OCT showed alteration of choroidal vasculature due to the presence of choroidal nodules but otherwise retinal and choroidal cross-sections were unremarkable for morphology. The authors concluded that retinal microvascular alterations overlying choroidal nodules in patients with NF1 could be considered another distinctive characteristic of the disease. Although the nature of these alterations was unclear, the authors speculated that functional disorders of vasomotor nerve cells, which originated in the embryonal neural crest could lead to their formation.
Furthermore, an UpToDate review on “Neurofibromatosis type 1 (NF1): Management and prognosis” (Korf et al, 2020) does not mention fundus photography as a management tool.
Pigment Dispersion Syndrome
According to the American Academy of Ophthalmology (AAO, 2019), pigment dispersion syndrome (PDS) occurs when the pigment rubs off the back of one’s iris. This pigment then floats around to other parts of the eye. The tiny bits of pigment can clog the eye's drainage angle, which can cause eye pressure problems. Because there are often no symptoms, PDS is usually diagnosed during a regular eye examination. During a thorough eye examination, the ophthalmologist will:
- Check the intra-ocular pressure (IOP)
- Do other tests like a gonioscopy, if PDS is suspected. This lets the ophthalmologist look at the eye's drainage angle. He or she can see if something is blocking the fluid from leaving the eye.
- These tests are the same used for a glaucoma diagnosis and will determine if one has pigmentary glaucoma. The ophthalmologist will be looking for tell-tale signs of pigment floating in the eye (including at the back of the cornea) or small sections of pigment missing from one’s iris.
The AAO does not mention fundus photography as a management tool. Pigment Dispersion Syndrome Diagnosis
Tamoxifen Users
The Prescribing Information of tamoxifen (Soltamox) notes that “Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving tamoxifen. An increased incidence of cataracts and the need for cataract surgery have also been reported. Patients should be advised to seek medical attention if they experience any visual disturbance”. However, it does not mention monitoring of vision in patients taking the drug. Prescribing Information.
Visual Snow Syndrome
According to NIH’s Genetic and Rare Diseases Information Center (GARD) webpage, visual snow syndrome is diagnosed based on the symptoms and a specific set of criteria. In order for a person to be diagnosed with visual snow syndrome, other potential causes of the symptoms must be ruled out. Most people with visual snow syndrome have normal vision tests and normal brain structure on imaging studies. Symptoms of visual snow syndrome may include:
- Tiny, snow-like dots across the visual field
- Sensitivity to light (photophobia)
- Continuing to see an image after it is no longer in the field of vision (palinopsia)
- Difficulty seeing at night (nyctalopia)
- Seeing images from within the eye itself (entoptic phenomena).
Less common symptoms may include migraines, tinnitus, and fatigue. In general, the symptoms of visual snow syndrome don't change with time. Some people with visual snow syndrome have depression or anxiety related to their symptoms. The symptoms of visual snow syndrome can start at any age, but usually occur in early adulthood. The underlying cause of visual snow syndrome is unknown. It is thought to be due to a problem with how the brain processes visual images. There is no mentioning on “fundus photography” or “scanning computerized ophthalmic diagnostic imaging, posterior segment”. Visual Snow Syndrome
There is a lack of evidence to support the use of fundus photography and scanning computerized ophthalmic diagnostic imaging for the diagnosis / management of visual snow syndrome.
Puledda et al (2020) validated the current criteria of visual snow and described its common phenotype using a substantial clinical data-base. These investigators carried out a web-based survey of patients with self-assessed visual snow (n = 1,104), with either the complete visual snow syndrome ( VSS; n = 1,061) or visual snow without the syndrome (n = 43). They also described a population of patients (n = 70) with possible hallucinogen persisting perception disorder who presented clinically with visual snow syndrome. The visual snow population had an average age of 29 years and had no sex prevalence. The disorder usually started in early life, and approximately 40 % of patients had symptoms for as long as they could remember. The most commonly experienced static was black and white. Floaters, after-images, and photophobia were the most reported additional visual symptoms. A latent class analysis showed that visual snow does not present with specific clinical endophenotypes. Severity can be classified by the amount of visual symptoms experienced. Migraine and tinnitus had a very high prevalence and were independently associated with a more severe presentation of the syndrome. The authors concluded that clinical characteristics of visual snow did not differ from the previous cohort in the literature, supporting validity of the current criteria. Visual snow likely represents a clinical continuum, with different degrees of severity. On the severe end of the spectrum, it is more likely to present with its common co-morbid conditions, migraine and tinnitus. Visual snow does not depend on the effect of psychotropic substances on the brain. This study does not mention fundus photography or scanning computerized ophthalmic diagnostic imaging as diagnostic/management tools.
Traber et al (2020) noted that visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant bilateral whole-visual field flickering or pixelation. When associated with additional visual symptoms, it is referred to as VSS. Its pathophysiology remains elusive. These researchers highlighted the visual snow literature focusing on recent clinical studies that add to the understanding of its clinical picture, pathophysiology, and treatment. Clinical characterization of VSS is evolving, including a suggested modification of diagnostic criteria. Regarding pathophysiology, 2 recent studies tested the hypothesis of dysfunctional visual processing and occipital cortex hyper-excitability using electrophysiology. Likewise, advanced functional imaging shows promise to allow further insights into disease mechanisms. A retrospective study provided Class IV evidence for a possible benefit of lamotrigine in a minority of patients. The authors concluded that scientific understanding of VSS is growing. Major challenges remain the subjective nature of the disease, its overlap with migraine, and the lack of quantifiable outcome measures, which are necessary for clinical trials. In that context, refined perceptual assessment, objective electrophysiological parameters, as well as advanced functional brain imaging studies, are promising tools in the pipeline.
Eren and Schankin (2020) stated that VSS is a debilitating disorder characterized by tiny flickering dots (like TV static) in the entire visual field and a set of accompanying visual (palinopsia, enhanced entoptic phenomena, photophobia, nyctalopia), non-visual (e.g., tinnitus) and non-perceptional (e.g., concentration problems, irritability) symptoms. Its pathophysiology is enigmatic and therapy is often frustrating. These researchers summarized the current understanding of pathophysiology and treatment of VSS. They carried out a systematic search of PubMed data-base using the key word "visual snow" and pre-defined inclusion and exclusion criteria. The results were stratified into "treatment" and "pathophysiology". In additional, these investigators performed a search with the key words "persistent migraine aura" and "persistent visual aura" and screened for mis-diagnosed patients actually fulfilling the criteria for visual snow syndrome. The reference lists of most publications and any other relevant articles known to the authors were also reviewed and added if applicable. From the 50 original papers found by searching for "visual snow, 21 were included according to the inclusion and exclusion criteria. An additional 4 publications came searching for "persistent migraine aura" or "persistent visual aura". Further publications derived from literature references resulting in a total of 20 articles for pathophysiology and 15 for treatment with some overlaps. Regarding pathophysiology, hyper-excitability of the visual cortex and a processing problem of higher order visual function were assumed; however, the location is still being debated. In particular, it is unclear if the primary visual cortex, the visual association cortex or the thalamo-cortical pathway is involved. Regarding treatment, data are available on a total of 153 VSS patients with medication mentioned for 54 resulting in a total of 136 trials. From the 44 different medications tried, only 8 were effective at least once. The best data are available for lamotrigine being effective in 8/36 (22.2 %, including 1 total response and no worsening), followed by topiramate being effective in 2/13 (15.4 %, no total response and 1 worsening). The only other medication resulting in worsening of VSS was amitriptyline according to the literature review. The others reported to be effective at least once were valproate, propranolol, verapamil, baclofen, naproxen and sertraline. The non-pharmacological approach using color filters of the yellow-blue color spectrum might also be helpful in some patients. The authors concluded that VSS is still far from being fully understood. In respect of pathophysiology, a disorder of visual processing is likely. The best pharmacological evidence exists for lamotrigine, which can be discussed off-label. As non-pharmacological option, patients might benefit from tinted glasses for everyday use.
Yoo et al (2020) noted that the findings of ophthalmic examinations have not been systematically investigated in VSS. These researchers examined the abnormal neuro-ophthalmologic findings in a patient cohort with symptoms of VSS. They retrospectively reviewed 28 patients who were referred for symptoms of visual snow to a tertiary referral hospital from November 2016 to October 2019. These investigators defined the findings of best corrected visual acuity (BCVA), visual field testing, pupillary light reflex, contrast sensitivity, full-field and multi-focal electroretinography (mf-ERG), and optical coherence tomography (OCT). A total of 20 patients (71 %) were finally diagnosed as VSS. Their additional visual symptoms included illusionary palinopsia (61 %), enhanced entoptic phenomenon (65 %), disturbance of night vision (44 %), and photophobia (65 %). A history of migraine was identified in 10 patients (50 %). The mean BCVA was less than 0.1 logarithm of the minimum angle of resolution, and electrophysiology showed normal retinal function in all patients. Contrast sensitivity was decreased in 2 of the 7 patients tested. Medical treatment was administered to 5 patients which all turned out to be ineffective. Among the 8 patients who were excluded, 1 was diagnosed with rod-cone dystrophy and another with idiopathic intra-cranial hypertension. The authors concluded that neuro-ophthalmologic findings were mostly normal in patients with VSS; retinal or neurological diseases must be excluded as possible causes of visual snow.
Stickler Syndrome
Araujo et al (2018) reported the clinical (anatomic and functional) and genetic findings of Wagner syndrome (WS) in a Portuguese family. A total of 9 members of the family agreed to be examined. All had complete clinical eye examinations. The proband and selected patients underwent color fundus photography, spectral domain optical coherence tomography (SD-OCT), automatic static white-on-white computerized perimetry, and electrophysiology assessment (flash electroretinography [ERG], multi-focal ERG [mfERG] and dark adaptometry). A pedigree was constructed based on interviews with known affected subjects. Genomic DNA samples derived from venous blood were collected from all affected family members examined. A total of 28 family members were affected. This family has the typical features of WS, namely an empty vitreous cavity with veils, mild myopia and cataract; 4 examined patients underwent vitreo-retinal surgery due to abnormal peripheral vitreo-retinal adhesions with peripheral retinal traction (n = 3). Retinal detachment was observed in 5 of the examined subjects; 4 of them occurred between the ages of 5 and 15 years. Chorio-retinal atrophy was also a frequent finding that resulted in moderate-to-severe visual field and advanced rod-cone dystrophy from younger ages, also confirmed by absence of scotopic function on dark adaptation. The macular dysfunction on mfERG was profound and of early onset. A heterozygous mutation in intron 7 of the VCAN gene (c.4004-1G > A) was found. The authors described a rare autosomal dominant vitreo-retinopathy with near complete penetrance in a Portuguese family. Abnormal peripheral vitreo-retinal adhesions, retinal detachment and chorio-retinal atrophy were present in most of the examined individuals at young ages. Early onset of advanced visual field and electrophysiologic abnormalities were observed in this family. These investigators also added relevant information to the literature by reporting their experience in surgical management of WS patients with, and at risk of, retinal detachment. Stickler syndrome (STL) was one of the keywords listed in this study.
Kjellstrom et al (2021) noted that STL is a hereditary disorder of collagen tissues causing ocular, auditory, orofacial, and joint manifestations. Ocular findings typically include vitreous degeneration, high myopia, retinal detachment, and cataract. Many subjects demonstrate sensorineural or conductive hearing loss. The inheritance is autosomal dominant with mutations in COL2A1, COL11A1, or COL11A2 or autosomal recessive due to mutations in COL9A1, COL9A2, or COL9A3. These researchers described a family with STL caused by homozygous loss-of-function mutations in COL9A2. Two brothers from a consanguineous family were examined with genetic testing, visual acuity (VA), Goldmann perimetry, full-field ERG (ffERG), mfERG, OCT, fundus auto-fluorescence (FAF), fundus photography, and pure-tone audiograms. Both subjects were homozygous for the mutation c.1332del in COL9A2. Their parents were heterozygous for the same mutation. The boys demonstrated reduced VA, vitreous changes and myopia. The proband was operated for retinal detachment and cataract in 1 eye; ffERG revealed reduced function of both rods and cones and mfERG showed reduced macular function. No morphological macular changes were found by OCT or FAF. Both brothers have severe SNHL with down-sloping audiograms but only subtle mid-face hypoplasia and no, or mild joint problems. The authors concluded that only a few families with STL caused by COL9A2 mutations have been reported. These investigators confirmed previous descriptions with a severe ocular and auditory phenotype but mild orofacial and joint manifestations. Moreover, these researchers demonstrated reduced macular and overall retinal function explaining the reduced VA in patients with STL also without retinal complications.
Xerri et al (2021) compared different clinical and spectral-domain OCT (SD-OCT) features of high myopic eyes in patients with STL with matched controls. Patients with genetically confirmed STL with axial length greater than or equal to 26 mm and controls matched for axial length were included. The following data were obtained from SD-OCT scans and fundus photography: choroidal and retinal thickness (respectively, CT and RT), peripapillary atrophy area (PAA), presence of posterior staphyloma (PS). A total of 26 eyes of 17 patients with STL and 25 eyes of 19 controls were evaluated. Compared with controls, patients with STL showed a greater CT subfoveally, at 1,000 μm from the fovea at both nasal and temporal location, and at 2,000 and 3,000 μm from the fovea in nasal location (respectively, 188.7 ± 72.8 versus 126.0 ± 88.7 μm, 172.5 ± 77.7 versus 119.3 ± 80.6 μm, 190.1 ± 71.9 versus 134.9 ± 79.7 μm, 141.3 ± 56.0 versus 98.1 ± 68.5 μm, and 110.9 ± 51.0 versus 67.6 ± 50.7 μm, always p < 0.05). Furthermore, patients with STL showed a lower prevalence of PS (11.5 % versus 68 %, p < 0.001) and a lower PAA (2.2 ± 2.1 versus 5.4 ± 5.8 mm2, p = 0.03), compared with controls. The authors concluded that the findings of this study showed that high myopic patients with STL showed a greater CT, a lower PAA and a lower prevalence of PS, compared with controls matched for axial length. They stated that these findings could be relevant for the development and progression of myopic maculopathy in patients with STL.
Furthermore, an UpToDate review on “Syndromes with craniofacial abnormalities” (Buchanan, 2021) states that “Clinical features -- The clinical features of Stickler syndrome include characteristic orofacial and ophthalmologic abnormalities, deafness, and arthritis … Early ophthalmologic examination is indicated, and follow-up is essential given the difficulty in slit-lamp examination of infants and young children”.
Diagnosis / Evaluation of Atrophic Pigmentary degeneration of the Retina
Thiele et al (2018) examined the development of central atrophy in eyes with ARMD. Six-year longitudinal multi-modal retinal imaging data (MODIAMD study) from 98 eyes of 98 subjects with non-late-stage ARMD in the study eye at baseline were analyzed for the presence of central atrophy at each annual follow-up visit. Development, manifestation, and further progression of complete retinal pigment epithelium and outer retinal atrophy (cRORA) by multi-modal imaging data were compared with atrophy detection based on CFP only. A total of 17 study eyes with development of central cRORA within 6 years (cumulative rate: 17.4 %) were identified based on multi-modal imaging. In 10 (60 %) of these eyes, presence of central manifest atrophy was initially not detectable by CFP. In 6 (35 %) eyes, central cRORA occurred by the spread of existing paracentral atrophy toward the fovea. Drusen-associated atrophy development was noted in 8 eyes. In 2 eyes, atrophy development was associated with refractile deposits, while only pigmentary changes in absence of large drusen or refractile deposits were detectable before atrophy occurrence in 1 eye. The authors concluded that the earlier and more precise detection of central cRORA by multi-modal imaging as compared to atrophy detection solely based on CFP allowed for more accurate detection and identification of different pathways for atrophy development. In accordance with previous clinical and histopathologic reports, the results confirmed that different precursor lesions may independently proceed to central cRORA in ARMD.
In an observational, longitudinal study, Wu et al (2021) compared the performance of automatically quantified OCT imaging biomarkers and conventional risk factors manually graded on CFP for predicting progression to late ARMD. This trial included a total of 280 eyes from 140 participants with bilateral large drusen. All subjects underwent OCT and CFP at baseline and were then reviewed at 6-month intervals to determine progression to late ARMD. Color fundus photographs were graded manually; and OCT scans underwent automated image analyses to quantify risk factors and imaging biomarkers, respectively, based on drusen and ARMD pigmentary abnormalities. Four predictive models for progression to late ARMD or atrophic ARMD were only developed (each including age) based on: CFP only (2 parameters); OCT biomarkers, minimal (3 parameters); OCT biomarkers, extended (7 parameters); and CFP and OCT combined (8 parameters). Main outcome measures included predictive performance for progression to late ARMD, examined based on the area under the receiver operating characteristic curve (AUC) for correctly predicting progression. The AUC for predicting late ARMD development was similar for the models based on CFP alone (model 1; 0.80), OCT alone (models 2 and 3; 0.82 for both), and when using both methods together (model 4; 0.85). Furthermore, these models also performed similarly for predicting the endpoint of atrophic ARMD only (AUC, 0.83, 0.84, 0.85, and 0.88 for models 1, 2, 3, and 4, respectively). The authors concluded that OCT imaging biomarkers could provide an automatic method of risk stratification for progression to vision-threatening late ARMD as well as manual grading of CFP.
In an observational, case-series study, Graham et al (2018) compared multi-color (MC) and traditional CFP in their ability to detect features of early and late ARMD. Fundus images captured using standard CFP and MC imaging from 33 patients attending hospital clinics and 26 participants from the pilot phase of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). Systematic grading of early and late AMD features; (hard drusen, soft drusen, reticular pseudo-drusen, pigment clumping, non-geographic atrophy hypopigmentation, atrophy, hemorrhage, and fibrosis) on CFP and MC. There were 105 eyes with gradable images for comparison. Using CFP as the gold standard, sensitivity values for MC ranged from 100 % for atrophy, non-geographic atrophy hypopigmentation, and fibrosis to 69.7 % for pigment clumping. Specificity values were high: greater than 80 % for all features. On using MC as the comparator, CFP had lower sensitivity for the detection of early ARMD features (27.8 % for reticular drusen to 77.8 % for non-geographic atrophy hypopigmentation). Analysis of OCT in discrepant cases showed better agreement with MC for all ARMD lesions, except hemorrhage and non-geographic atrophy hypopigmentation. For pigment clumping, CFP and MC were in equal agreement with OCT. The authors concluded that multi-color retinal imaging allowed for improved detection and definition of ARMD features.
Furthermore, an UpToDate review on “Age-related macular degeneration: Clinical presentation, etiology, and diagnosis” (Arroyo, 2021) states that “Fluorescein dye retinal angiography -- A fluorescein angiogram can demonstrate fluorescein coursing through the choroid and retinal vessels as well as any abnormal choroidal neovascular complex. Fluorescein dye is injected intravenously as a bolus and a rapid sequence of photographs of the retina are taken 5 seconds to 10 minutes later. Color fundus photography is often taken at the same time”.
Diagnosis / Evaluation of Hypertensive Retinopathy
Gudmundsdottir et al (2010) noted that screening for hypertensive organ damage is important in assessing cardiovascular risk in hypertensive individuals. In a 20-year follow-up of normotensive and hypertensive men, signs of end-organ damage were examined, focusing on hypertensive retinopathy. In all, 56 of the original 79 men were re-examined for hypertensive organ damage, including by digital fundus photography. The diameters of the central retinal artery equivalent (CRAE) and vein were estimated; and the artery-to-vein diameter ratio calculated. Components of metabolic syndrome were assessed; 50 % of the normotensive men developed hypertension during follow-up. Significant differences appeared in CRAE between the different blood pressure (BP) groups (p = 0.025) while no differences were observed for other markers of hypertensive organ damage. There were significant relationships between CRAE and BP at baseline (r = -0.466, p = 0.001) and at follow-up (r = -0.508, p < 0.001). A linear decrease in CRAE was observed with increasing number of components of the metabolic syndrome (beta = -3.947, R(2) = 0.105, p = 0.023). Retinal vascular diameters were closely linked to BP and risk factors of the metabolic syndrome. The authors concluded that the diversity in the development of hypertensive organ damage, with changes in retinal micro-vasculature preceding other signs of damage, should encourage more liberal use of fundus photography in assessing cardiovascular risk in hypertensive individuals.
Henderson et al (2012) noted that hypertensive retinopathy describes a spectrum of retinal changes in patients with elevated BP. It is unknown why some patients are more likely to develop acute ocular end-organ damage than others with similar BP. These investigators examined risk factors for grade III/IV hypertensive retinopathy among patients with hypertensive urgency in the emergency department (ED) and compared healthcare utilization and mortality between patients with and without grade III/IV hypertensive retinopathy. They carried out a pre-planned sub-analysis of patients who presented to a university hospital ED with diastolic BP greater than or equal to 120 mmHg and who enrolled in the Fundus Photography versus Ophthalmoscopy Trial Outcomes in the ED study. Bilateral non-mydriatic ocular fundus photographs, vital signs, and demographics were obtained at presentation. Past medical history, laboratory values, healthcare utilization, and mortality were ascertained from medical record review at least 8 months after initial ED visit. A total of 21 patients with diastolic BP of greater than or equal to 120 mmHg, 7 of whom (33 %) had grade III/IV hypertensive retinopathy, were included. Patients with retinopathy were significantly younger than those without (median of 33 versus 50 years, p= 0.02). Mean arterial pressure (165 versus 163 mmHg) was essentially equal in the 2 groups. Patients with retinopathy had substantially increased but non-significant rates of ED re-visit (57 % versus 29 %, p = 0.35) and hospital admission after ED discharge (43 % versus 14 %, p = 0.28); 1 of the patients with retinopathy died, but none without. The authors concluded that younger patients may be at higher risk for grade III/IV hypertensive retinopathy among patients with hypertensive urgency. Chronic compensatory mechanisms may have not yet developed in these younger patients. Alternatively, older patients with retinopathy may be under-represented secondary to increased mortality among these patients at a younger age (survivorship bias). Further research is needed to validate these preliminary findings.
Goyal and Agarwal (2020) reported on the case of a 23-day-old female infant who was diagnosed as having systemic hypertensive emergency; and was referred for retinal screening. The fundus examination showed bilateral intra-retinal hemorrhages and hard exudates especially at the macula. Venous looping was noted. The ocular features were suggestive of hypertensive retinopathy. Control of systemic hypertension was advised and was managed conservatively with close follow-up. Widefield fundus photography was performed at presentation and follow-up to document the change in retinopathy with control of hypertension. The hemorrhages and exudates resolved on follow-up but significant retinal pigment epithelium changes with beaten bronze appearance were noted at the area of previous oedema. The authors concluded that the presence of hypertensive retinopathy in a neonate is rare and has long-term effects on visual development.
Furthermore, an UpToDate review on “Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults” (Elliott and Varon, 2022) states that “Hypertensive retinopathy is diagnosed by ophthalmologic examination of the eyes, with identification of retinal hemorrhages, exudates, and/or papilledema”. This UTD review shows representative digital retinal fundus photographs of mild, moderate, and severe hypertensive retinopathy, as graded with the simplified classification.
Diagnosis / Evaluation of Posterior Vitreous Detachment
Yang et al (2018) examined the 10-year incidence and progression of epi-retinal membranes (ERMs). The population-based longitudinal Beijing Eye Study, which included 4,439 subjects (age of 40+ years) in 2001, was repeated in 2011 with 2,695 subjects participating (66.4 % of the survivors). The study participants underwent a detailed ophthalmic examination, including retinal photography. Assessing fundus photographs, ERMs were classified as cellophane macular reflex (CMR) without retinal folds, or as preretinal macular fibrosis (PMF) without or with retinal folds. Fundus photographs were available for 2,476 subjects with a mean age of 69.0 ± 7.8 years (range of 51 to 93 years) and mean axial length of 23.3 ± 0.9 mm (range of 19.92 to 26.33mm). The 10-year incidence of ERMs was 8.4 % (208/2,476 participants; 95 % CI: 7.4 to 9.5). ERMs developed bilaterally in 50 (24 %) individuals and unilaterally in 158 (76 %) persons. The incidence of PMFs with 2.5 % (95 % CI: 1.9 to 3.1) was lower than the incidence of CMRs with 5.9 % (95 % CI: 5.0 to 6.9). Higher 10-year incidence of ERMs was associated with older age (p < 0.001; odds ratio (OR): 1.06; 95 % CI: 1.04 to 1.09), previous cataract surgery (p = 0.003; OR: 3.32; 95 % CI: 1.51 to 7.29) and presence of a complete posterior vitreous detachment (PVD) (p = 0.02; OR: 1.84; 95 % CI: 1.12 to 3.02). In the age groups of less than 60 years, 60 to 69 years, 70 to 79 years and 80+ years, incidence of ERMs was 3.1 %, 10.0 %, 14.4 % and 10.9 %, respectively, with no significant gender difference. The authors concluded that in Chinese aged 40+ years, the 10-year incidence of ERMs (8.4 %) increased with older age, previous cataract surgery and complete PVD. The 10-year incidence was lower for PMFs (2.5 %) than for CMRs (5.9 %).
Napolitano e al (2019) stated that extracellular matrix molecular components, previously linked to multi-system syndromes include collagens, fibrillins and laminins. Recently, these researchers described a novel multi-system syndrome caused by the c.9418G>A p.(V3140M) mutation in the laminin alpha-5 (LAMA5) gene, which affects connective tissues of all organs and apparatus in a 3-generation family. In the same family, these investigators have also reported a myopic trait, which, however, was linked to the prolyl 4-hydroxylase subunit alpha-2 (P4HA2) gene. These researchers described results of investigation on vitreous changes and their pathogenesis. A total of 19 family individuals underwent complete ophthalmic examination including BCVA, fundus examination, fundus photography, IOP measurement, axial length measurement using ocular biometry, Goldmann visual field examination, standard electroretinogram (ERG), and SD-OCT. Segregation analysis of LAMA5 and P4HA2 mutations was carried out in enrolled members. The vitreous alterations fully segregated with LAMA5 mutation in both young and adult family members. Slight reduction of retinal thickness and peripheral retinal degeneration in only 2 patients were reported. The authors showed that PVD is a common trait of LAMA5 multi-system syndrome that occur as an age-unrelated trait. These researchers hypothesized that the p.(V3140M) mutation results in a reduction of retinal inner limiting membrane (ILM) stability, leading to a derangement in the macromolecular structure of the vitreous gel, and PVD. Moreover, these researchers stated that further investigations are needed to examine the role of wild type and mutated LAMA5 in the pathogenesis of PVD.
Tey et al (2021) examined if the tractional elements of pathologic myopia (PM, e.g. ,myopic traction maculopathy [MTM], posterior staphyloma [PS], and aberrant PVD) are associated with myopic macular degeneration (MMD) independent of age and axial length, among highly myopic (HM) eyes. A total of 129 individuals with 239 HM eyes from the Myopic and Pathologic Eyes in Singapore (MyoPES) cohort underwent ocular biometry, fundus photography, swept-source OCT, and ocular B-scan US. Images were analyzed for PVD grade, and presence of MTM, PS, and MMD. The χ² test was carried out to determine the difference in prevalence of MMD between eyes with and without PVD, PS, and MTM. Multi-variate probit regression analyses were carried out to ascertain the relationship between the potential predictors (PVD, PS, and MTM) and outcome variable (MMD), after accounting for possible confounders (e.g., age and axial length). Marginal effects were reported. Controlling for potential confounders, eyes with MTM have a 29.92 percentage point higher likelihood of having MMD (p = 0.003), and eyes with PS have a 25.72 percentage point higher likelihood of having MMD (p = 0.002). The likelihood of MMD increases by 10.61 percentage points per 1 mm increase in axial length (p < 0.001). Sub-analysis revealed that eyes with incomplete PVD have a 22.54 percentage point higher likelihood of having MMD than eyes with early PVD (p = 0.04). The authors concluded that this study demonstrated an association between tractional (MTM, PS, and persistently incomplete PVD) and degenerative elements of PM independent of age and axial length. These data provided further insights into the pathogenesis of MMD.
Monitoring of Individuals on Checkpoint Inhibitors (e.g., Ipilimumab and Nivolumab)
The Prescribing Informations of ipilimumab and nivolumab do not mention the need of a baseline fundus photography or their uses in monitoring patients receiving the medication.
Evaluation of Staphyloma Posticum
UpToDate reviews on “Congenital and acquired abnormalities of the optic nerve” (Golnik, 2023), and “PHACE syndrome” (Siegel, 2023) do not mention fundus photography as a management option. The former UTD review (Golnik, 2023) states that “Peripapillary staphyloma is characterized by deep fundus excavation around the disc, with an otherwise normal-appearing disc. Mild temporal pallor of the disc may be present, but the blood vessels are normal. Atrophic changes in the retinal pigment epithelium and choroid occur in the walls of the staphyloma. Occasionally, contractile movement of the walls of the staphyloma changes its shape from funnel- to tube-like. With rare exception, visual acuity is markedly reduced and cecocentral scotoma is present; cecocentral scotomas are visual field defects that include central fixation and the physiologic blind spot. Peripapillary staphyloma typically is an isolated bilateral ocular abnormality associated with axial high myopia, although it may be associated with facial capillary hemangioma. Children with peripapillary staphyloma should be seen by their ophthalmologist annually”.
The latter UTD review (Siegel, 2023) notes that “Eye anomalies -- In a prospective study of PHACE patients, 16 percent were found to have ocular anomalies. Congenital anomalies of the eye can involve the posterior or anterior segment. Posterior segment anomalies are part of the major diagnostic criteria and include persistent fetal vasculature, "morning-glory" disc, peripapillary staphyloma, and optic nerve hypoplasia”.
Evaluation of Tilted Optic Nerve
Cho et al (2020) noted that it is necessary to consider myopic optic disc tilt as it seriously impacts normal ocular parameters; however, ophthalmologic measurements are within inter-observer variability and time-consuming to get. These researchers developed and evaluated deep learning models that automatically recognize a myopic tilted optic disc in fundus photography. This study used 937 fundus photographs of patients with normal or myopic tilted disc, collected from Samsung Medical Center between April 2016 and December 2018. These investigators developed an automated computer-aided recognition system for optic disc tilt on color fundus photographs via a deep learning algorithm. They pre-processed all images with 2 image re-sizing techniques. GoogleNet Inception-v3 architecture was implemented. The performances of the models were compared with the human examiner's results. Activation map visualization was qualitatively analyzed using the generalized visualization technique based on gradient-weighted class activation mapping (Grad-CAM++). A total of 937 fundus images were collected and annotated from 509 subjects -- 397 images from eyes with tilted optic discs and 540 images from eyes with non-tilted optic discs were analyzed. These researchers included both eye data of most included patients and analyzed them separately in this study. For comparison, these investigators conducted training using 2 aspect ratios: the simple re-sized dataset and the original aspect ratio (AR) preserving dataset, and the impacts of the augmentations for both datasets were evaluated. The constructed deep learning models for myopic optic disc tilt achieved the best results when simple image-resizing and augmentation were used. The results were associated with an area under the receiver operating characteristic curve (AUC) of 0.978 ± 0.008, an accuracy of 0.960 ± 0.010, sensitivity of 0.937 ± 0.023, and specificity of 0.963 ± 0.015. The heatmaps revealed that the model could effectively identify the locations of the optic discs, the superior retinal vascular arcades, and the retinal maculae. The authors developed an automated deep learning-based system to detect optic disc tilt. The model demonstrated excellent agreement with the previous clinical criteria, and the results are promising for developing future programs to adjust and identify the effect of optic disc tilt on ophthalmic measurements.
The authors stated that this study had several drawbacks. First, these researchers compared the accuracy of the algorithm with the results based on previous criteria of tilted optic disc. In the existing literature, optic disc tilt has been classified based on observations that are based on fundus photography. Several studies have examined the optic nerve head of a patient with a myopic tilted disc using three-dimensional optical coherence tomography (3D-OCT) or observed vascular abnormalities in a patient with a tilted disc using angiography. However, these previous approaches are not used as diagnostic standards. Thus, because there are no accurate diagnostic criteria for using an objective device, this study used one of the previously published criteria that included an optic disc with a ratio of minimal to maximal disc diameter of 0.75 or less on the fundus photograph with a white semilunar patch of sclera adjacent to the optic disc. Second, these investigators analyzed only temporally tilted discs, and it should be noted that the findings of this trial might not be valid when considering non-temporally tilted discs. Third, there may be limitations associated with using both eye data in this study due to possible inter-eye correlations. In future studies, the use of single-eye data will be more desirable.
Furthermore, an UpToDate review on “Congenital and acquired abnormalities of the optic nerve” (Golnik, 2023) does not mention fundus photography as a management / therapeutic option.
Monitoring of Cytomegalovirus (CMV) Retinitis
American Academy of Ophthalmology’s EyeWiKi on “CMV retinitis” (Kim et al, 2023) noted that “Depending on the medication used, complete blood counts, chemistries, and intraocular pressure checks will be needed. Dilated eye exams should be performed at least weekly initially, then 2 weeks after induction therapy, followed by monthly thereafter while the patient is on anti-CMV treatment. Fundus photographs can be helpful to detect early relapse”.
Pilocytic Astrocytoma
An UpToDate review on “Uncommon brain tumors” (Chheda and Wen, 2023) states that ‘”Pilocytic astrocytomas (World Health Organization [WHO] grade 1) are the most common gliomas in children, with a median age at diagnosis of 8 years. They are circumscribed tumors that frequently arise in the cerebellum and present with signs and symptoms of mass effect, obstructive hydrocephalus, and increased intracranial pressure. Other common locations include the optic pathway and midline structures (e.g., hypothalamus, thalamus, brainstem, spinal cord) … On MRI, pilocytic astrocytomas are usually hyperintense on T2-weighted images and have variable T1 signal. In the posterior fossa and cerebral hemispheres, most pilocytic astrocytomas appear as a well-demarcated, expansile mass consisting of an enhancing mural nodule with a surrounding cyst. Tumors in the brainstem or optic apparatus may be solid or cystic, with variable enhancement patterns. Surrounding edema is mild or absent. For tumors in the posterior fossa in children, the degree of T2 hyperintensity associated with the solid portion of the tumor helps to distinguish pilocytic astrocytoma from medulloblastoma”. Moreover, this UTD review does not mention fundus photography as a management option.
Appendix
Note on Optomap coding: The Optos Optomap is image-assisted ophthalmoscopy for evaluation of ocular health. Optomap meets the criteria for the CPT code for fundus photography (92250).
References
The above policy is based on the following references:
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