Abstract
Purpose:
To describe the demographics and clinical profile of Stargardt disease in patients presenting a multitier ophthalmology hospital network in India.
Methods:
This cross-sectional hospital-based study was performed among 2,834,616 new patients presenting between August 2010 and June 2021 in our network. Patients with a clinical diagnosis of Stargardt disease in at least one eye were included as cases. The data were collected using an electronic medical record system.
Results:
Overall, 1,934 (0.069%) patients were diagnosed with Stargardt disease. Most of the patients were male (63.14%). The most common age group at presentation was during the second decade of life, with 626 (31.87%) patients. The overall prevalence was higher in patients from a higher socioeconomic status (0.077%), in those presenting from the urban geography (0.079%), and in students (0.197%). Systemic history of hypertension was seen in 56 (2.85%) patients, while diabetes mellitus was seen in (2.49%) patients. Of the 3,917 eyes, 1,910 (48.76%) eyes had moderate visual impairment (>20/70–20/200) followed by severe visual impairment (>20/200 to 20/400) in 646 (16.49%) eyes. The most commonly associated retinal signs were retinal flecks in 1,260 (32.17%) eyes, followed by RPE changes in 945 (24.13%) eyes. The most documented investigations were autofluorescence (39.85%), followed by optical coherence tomography (23.90). Cataract surgery was the commonest performed surgical intervention in (0.66%) eyes, followed by intravitreal injection in 4 (0.10%) eyes. The family history of parent consanguinity marriage was reported by 212 (10.79%) patients.
Conclusion:
Stargardt disease was seen more commonly in males presenting during the second decade of life. It is predominantly a bilateral disease, with the majority of the eyes having moderate visual impairment.
Keywords: Big data, electronic medical records, India, Stargardt disease
Stargardt disease (STGD) is the most common form of juvenile macular dystrophy.[1] It is an inherited autosomal recessive condition caused by the mutation in the adenosine triphosphate ATP binding transporter ABCA4 that facilitates the clearance of all-trans-retinaldehyde, which is generated by photon-mediated cis-trans isomerization of retinaldehyde in the photoreceptor cell.[2] When the transport activity is reduced or absent, it results in the abnormal accumulation of lipofuscin in the retinal pigment epithelium.[3] This accumulation in RPE is toxic, and it leads to photoreceptor cell degeneration.[4,5] Furthermore, STGD is distinguished by a progressive bilateral loss of central vision that can present from early childhood to late adulthood and occurs typically in the age onset of the first or second decade of life with a mean age of 15 years. Its prevalence is estimated at 1 in 8000 to 10000 populations, with deterioration of visual acuity leading to legal blindness and loss of central visual acuity.[2,6-8] The typical appearance of the fundus in STGD is characterized by progressive and symmetrical atrophy of the macula in young individuals, which is eventually surrounded by irregular, white-yellow deep flecks or spots in the posterior pole.[9] On the other hand, the clinical finding includes macular changes with progression toward a beaten bronze maculopathy, (fishtail) pisciform flecks, macular atrophy without dots, bull’s eye maculopathy, fundus flavimaculatus (retinal spots without macular atrophy), rod-cone dystrophy, retinitis pigmentosa, and end-stage fundus aspect by extensive RPE changes, choriocapillaris atrophy, with resorbed flecks and sparse pigmentation.[7,8,10,11]
The disease is known to be progressive, with irreversible loss of central vision, blind spots, wavy vision blurriness, impaired color vision, difficulty adapting to dark images, and central field scotomas.[12,13] Diagnosis of STGD is based on the family history, typical fundus appearance, fundus autofluorescence imaging, fundus fluorescein angiography, indocyanine green angiography, and full field electroretinogram.[14] Optical coherence tomography OCT and multifocal electroretinogram illustrate the changes in the outer nuclear layer, such as photoreceptor loss, RPE abnormalities, or the rare occurrence of choroidal neovascularization.[15] There is still debate about treatment; however, stem cell therapy, pharmacological strategies, and gene replacement are the latest therapeutic options to restore RPE damage or slow down the progression of the disease.[16] The success of these therapies, as in the case of Leber’s congenital amaurosis and Luxturna is essentially dependent on the stage of presentation of the disease. There is a paucity of literature on the patterns of Stargardt disease in the Indian population. The purpose of this study is to present the clinical and demographic profile of Stargardt disease at a large multitier ophthalmology network in India using electronic medical record-driven analytics. This data will help in strategizing future interventions for STGD.
Methods
Study Design, Period, Location, and Approval: This is a cross-sectional observational hospital-based study and includes all patients presenting between August 2010 and June 2021 to a multitier ophthalmology network located in India.[17] The patient or the parents or guardians of the patient filled out a standard consent form for electronic data privacy at the time of registration. None of the identifiable parameters of the patient was used for the analysis of the data or is presented in this study. The clinical data of each patient who underwent a comprehensive ophthalmic examination was entered into a browser-based electronic medical records system (eyeSmart EMR) by uniformly trained ophthalmic personnel and supervised by an ophthalmologist using a standardized template.[18] The study adhered to the Declaration of Helsinki and was approved by the Institutional Ethics Committee.
Cases: A total of 2,834,616 new patients presented to the tertiary and secondary centers of the multitier ophthalmology network during the study period. The eyeSmart EMR was screened for patients with a documented ocular diagnosis of Stargardt disease in one or both eyes. A total of 1,964 patient records were identified using this search strategy and were labeled as cases. A total of 3,917 eyes diagnosed with Stargardt disease in the above patients were further reassessed by a single specialist trained in retinal dystrophies and analyzed for clinical information.
Data Retrieval and Processing: The data of 1,964 patients included in this study were retrieved from the electronic medical record database and segregated into an Excel sheet. The columns included the data on patient demographics, clinical presentation, ocular diagnosis, and treatment information and were exported for analysis. The Excel sheet with the required data was then used for analysis using the appropriate statistical software. Standardized definitions were used for occupation and socio-economic status.[19] The visual acuity was classified according to the WHO guidelines.[20]
Statistical Analysis: Descriptive statistics using mean ± standard deviation and median with interquartile range (IQR) were used to elucidate the demographic data. All tables for age, gender, visual acuity, and clinical features were drawn by using Microsoft Excel (Microsoft Corporation 2018. Redmond, USA). Wilcoxon signed-rank tests were performed on mean values for first visual acuity, and final visual acuity. Chi-square test (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP) was used for univariate analysis to detect significant differences in the distribution of demographic features between patients with STGD and the overall population.
Results
Of the 2,834,616 new patients who presented across the eye care network during the study period, 1,964 patients were diagnosed with STGD, translating into a hospital prevalence rate of 0.069% (95%CI: ±0. 073%) or 693/million hospital patients over 10 years. The prevalence amongst students was 0.20%. The overall prevalence for the second and third decade of life was 0.22% and 0.12%, respectively. Among the 1,964 patients, 56 (2.85%) patients had hypertension, 49 (2.49%) patients are with diabetes mellitus, and 5 (0.25%) patients are with asthma.
Age: The mean age of the patients was 26.46 ± 14.61 years, while the median age was 24 (IQR: 15–36) years. The most common age group of the patients were distributed between 11 and 20 years (n = 626; 31.87%) followed by 21 and 30 years (n = 476; 24.24%). The distribution of patients in each age decade is presented in Fig. 1.
Figure 1.
Decade-wise distribution of patients with Stargardt disease
Sex: There were 1,240 (63.14%) male and 724 (36.86%) female patients. The overall distribution of disease was significantly greater in males (0.081%; 1,240/1,527,876) as compared to females (0.055%; 724/1,306,740) and was statistically significant (p=<0.01). Among the patients diagnosed with Stargardt disease, the mean and median age were 26.94 ± 14.75 and 24 (IQR: 15 to 36) years for men and 25.62 ± 14.35 and 21.5 (IQR: 14 to 35) years for women.
Urban–Rural Distribution: Of the 1,964 patients with Stargardt disease, 877 (44.65%) were from an urban locality, 875 (44.55%) were from a rural locality, and 212 (10.79%) patients presented from the metropolitan region. The overall prevalence of Stargardt disease in the urban community (0.079%; 877/1,106,990) was higher as compared to the rural (0.065%; 875/1,353,226) or metropolitan community (0.057%; 212/374,400) and was statistically significant (p=<0.00001).
Socio-economic status: Of the 1,964 patients with Stargardt disease, there were 1,545 (78.67%) patients from the lower middle class, 349 (17.77%) patients from the lower socio-economic class, 60 (3.05%) patients from the upper-middle class, and 10 (0.51%) patients from the upper class. The overall prevalence of Stargardt disease was slightly higher in the higher socio-economic strata (0.077%; 1545/2,007,912) as compared to lower socio-economic strata (0.051%; 349/682,641) and was statistically significant (p=<0.00001).
Occupation: Of the 1,964 patients with Stargardt disease, 933 (47.51%) were students; 516 (26.27%) were professionals; 248 (12.63%) were homemakers; 94 (4.79%) were agricultural workers; 63 (3.21%) were manual laborers; 20 (1.02%) were retired individuals and in the remaining 90 (4.58%) patients the occupational category was not available/applicable. The overall prevalence of Stargardt disease in students (0.197%, 933/472,770) was significantly significant (p=<0.00001) in comparison to other professions.
Laterality: Of the 1,964 patients with Stargardt disease, 3 (0.15%) were affected in the right eye, and 8 (0.41%) were affected in the left eye. In 1,953 (99.44%) patients, the affliction was bilateral in nature. In cases of unilateral documented Stargardt disease diagnosed cases (11 patients), the other eye could not be examined due to obscuring media opacity secondary to cataracts.
Presenting Family History: Among the 1,964 patients, a history of Stargardt diseases for siblings, parents, and relatives was documented in 212 (10.79%) patients, and parental consanguinity was documented in 210 (10.69%) patients.
Initial Visual Acuity: Among the 3,917 eyes, the mean LogMar initial visual acuity of the affected eyes was 0.94 ± 0.46, 522 (13.33%) eyes had mild or no visual impairment (<20/70), 1,910 (48.76%) eyes had moderate visual impairment (>20/70 to 20/200), 646 (16.49%) eyes had severe visual impairment (>20/200 to 20/400), 342 (8.73%) eyes had blindness (>20/400 to 20/1200), 7 (0.18%) eyes had blindness (>20/1200 to PL), 1 (0.03%) eye had blindness (NPL), and in 489 (12.48%) eyes the visual acuity was undetermined or unspecified.
Visual acuity – Age-wise distribution
Between age group of 0–10 years: Among the 423 eyes, the mean LogMar final visual acuity of the affected eyes was 0.85 ± 0.37, 290 (68.56%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 59 (13.95%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 74 (17.49%) eyes the visual acuity was undetermined or unspecified. The distribution of patients’ visual acuity among each age decade is presented in Fig. 2.
Figure 2.
Age-wise distribution of visual acuity – Average of LogMar of patients with Stargardt disease
Between age group of 11–20 years: Among the 1,249 eyes, the mean LogMar final visual acuity of the affected eyes was 0.93 ± 0.36, 828 (66.26%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 265 (21.22%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 156 (12.49%) eyes the visual acuity was undetermined or unspecified.
Between age group of 21-30 years: Amongthe 951 eyes, the mean LogMar final visual acuity of the affected eyes was 0.99 ± 0.48, 540 (56.78%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 293 (30.81%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 118 (12.41%) eyes the visual acuity was undetermined or unspecified.
Between age group of 31–40 years: Among the 573 eyes, the mean LogMar final visual acuity of the affected eyes was 0.97 ± 0.54, 336 (58.64%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 169 (29.49%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 68 (11.87%) eyes the visual acuity was undetermined or unspecified.
Between age group of 41–50 years: Among the 390 eyes, the mean LogMar final visual acuity of the affected eyes was 0.88 ± 0.49, 247 (63.33%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 108 (27.69%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 35 (8.97%) eyes the visual acuity was undetermined or unspecified.
Between age group of 51–60 years: Among the 136 eyes, the mean LogMar final visual acuity of the affected eyes was 0.97 ± 0.60, 136 (56.20%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 78 (32.23%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 28 (11.57%) eyes the visual acuity was undetermined or unspecified.
Between age group of 61–90 years: Among the 89 eyes, the mean LogMar final visual acuity of the affected eyes was 0.90 ± 0.48, 55 (61.80%) eyes had mild or no/moderate visual impairment (<20/70 to 20/200), 24 (26.97%) eyes had severe visual impairment and beyond (>20/200 to NPL), and in 10 (11.24%) eyes the visual acuity was undetermined or unspecified.
Spherical Equivalent – Objective: Among the 3,917 eyes, 1,626 (41.51%) eyes had emmetropia (−0.50 to +0.50 D), 1,139 (29.08%) eyes had mild myopia (> −0.50 to −3.00 D), 367 (9.37%) eyes had moderate myopia (> −3.00 to −6.00 D), 124 (3.17%) eyes had high myopia (> −6.00 D), 223 (5.69%) eyes had mild hyperopia (> +0.50 to +3.00 D), 28 (0.71%) eyes had moderate hyperopia (> +3.00 to +6.00 D), and 4 (0.10%) eyes had high hyperopia (>+6.00 D), and in 406 (10.37%) eyes values were not available.
Spherical Equivalent – Subjective: Among the 3,917 eyes, 969 (24.74%) eyes had emmetropia (−0.50 to +0.50 D), 1,387 (35.41%) eyes had mild myopia (> −0.50 to -3.00 D), 421 (10.75%) eyes had moderate myopia (> −3.00 to −6.00 D), 136 (3.47%) eyes had high myopia (> −6.00D), 393 (10.03%) eyes had mild hyperopia (> +0.50 to +3.00 D), 25 (0.64%) eyes had moderate hyperopia (> +3.00 to +6.00 D), and 10 (0.26%) eyes had high hyperopia (>+6.00 D), and in 576 (14.71%) eyes values were not available.
Retinal Manifestation: Among the 3,917 eyes, an associated RPE change was documented in 945 (24.13%) eyes, retinal flecks in 1,260 (32.17%) eyes, macular dystrophy in 495 (12.64%) eyes, macular atrophy in 316 (8.07%) eyes, beaten bronze appearance in 245 (6.25%) eyes, bulls-eye maculopathy in 268 (6.84%) eyes, foveal atrophy in 205 (5.23%) eyes, beaten metal appearance 149 (3.80%) eyes, metallic sheen flecks 144 (3.68%) eyes, yellow-white flecks 100 (2.55%) eyes, pisciform flecks 59 (1.51%) eyes, choroidal neo-vascularization 19 (0.49%) eyes, and unspecified flecks in 493 (12.59%) eyes. The types of flecks described in the retinal manifestations were based on the morphological appearance of flecks noted by the retina specialists, which can be collated under the broad category of characteristics of retinal flecks of Stargardt’s disease.
Treatment: Among the 3,917 eyes, surgical intervention was performed in 33 (0.84%) eyes. Cataract surgery was performed in 26 (0.66%) eyes, Avastin injection was given in 4 (0.10%) eyes (15/19 eyes had scarred CNV, so we decided to observe), and vitrectomy was performed in 3 (0.08%, two eyes had rhegmatogenous retinal detachment and the other had vitreous hemorrhage secondary to diabetic retinopathy), and 1,259 (59.91%) patients were referred to the center for sight enhancement (CSE), translating into 2,518 eyes.
Visual Rehabilitation: These patients were counselled for low vision aids and visual rehabilitation. Following the rehabilitative interventions or attempted interventions in 2,518 eyes, mean changes in visual acuity groups were recorded. With high contrast visual acuity, 172 eyes were now classified with mild or lesser visual impairment, 1,186 eyes had moderate visual impairment, 463 eyes had severe visual impairment, and 141 were blind. Therefore, there was a 6.83% change in the mildly impaired, 47.10% in moderately impaired, 18.39% in the severely impaired, and 5.06% in blind groups. Similarly, for low contrast visual acuity 37 eyes were now classified with mild or lesser visual impairment, 701 eyes had moderate visual impairment, 605 eyes had severe visual impairment, and 340 were blind. Therefore, there was a 1.47% change in the mildly impaired, 27.84% in the moderately impaired, 24.03% in the severely impaired, and 13.50% in blind groups.
Discussion
This study sought to describe the clinical profile and demographic distribution of Stargardt diseases in a large cohort of patients presenting to a multitier hospital network in India using electronic medical records-driven big data analytics. The primary purpose of the study was to determine the relative proportion and demographic profile of Stargardt diseases in the clinical care setup. The overall prevalence of Stargardt disease was 0.069% in patients who presented between 2010–2021 (an 11-year period). The disease is predominantly bilateral and affects males. It causes moderate visual impairment in many of the affected eyes.
STGD is a symmetrical central blinding disease with similarities to age-related macular degeneration occurring in any gender.[10] Typically, the age of onset is 10–20 years.[21] Our sample also demonstrated that most of the patients presented during the second (31.87%) and the third decade (24.24%) of life, with an average higher age of 26.46 ± 14.61 years. However, no relationship could be established between the degree of visual impairment and age of presentation. These big data analytics shows that presenting age of STGD is much less, and hospitals need to be sensitive to the young nature of these patients; there will also be an opportunistic cost involved in managing this patient subset as these are young and debilitated people needing attending support. It can be also noted that the clinical workup for STGD is time demanding, considering the need for multiple investigations, including electrophysiology. However, considering the need to diagnose these children earlier to be able to offer advanced therapy [22,23] we need to strategize an early detection as patients seem to be presenting late in India. As shown by the visual benefit attained by low vision service visits by our sample, visual rehabilitation remains the key yet in this young age group.
Limitations
A large part of our sample was not tested for genetic analysis, and all investigations were not available for detailed analysis in all the patients. Thus, the diagnosis was predominantly presumed on clinical suspicion. However, all these patients were evaluated by trained and well-experienced retinal surgeons managing retinal dystrophy. The average follow-up of the patients was 153.5 ± 438.58 days with an average of 2 ± 6.45 visits. Since this is a retrospective study, there could be selection and data collection bias.
Conclusion
In conclusion, this study sets the tone for big data embodiment in Indian literature on STGD. It shows the need for a policy review for STGD management for early detection and visual rehabilitation. Future analysis of retinal imaging should attempt to correlate clinical signs to disease features and their longitudinal evolution.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
The authors wish to acknowledge the support of our department of eyeSmart EMR and AEye team, especially Mr Ranganath Vadapalli and Mr. Mohammad Pasha.
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