WO2019236868A1

WO2019236868A1 - Devices and methods for detecting vision impairments

Info

Publication number: WO2019236868A1
Application number: PCT/US2019/035821
Authority: WO
Inventors: Mathew W. MACCUMBER
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-06-08
Filing date: 2019-06-06
Publication date: 2019-12-12
Anticipated expiration: 2020-12-08

Abstract

Devices and methods for detecting night blindness in a subject, comprising illuminating a first image on a display device using a light source so that the first image has a first luminance, determining whether the subject can see the first image, illuminating a second image on the display device using the light source so that the second image has a second luminance that is different than the first luminance, and determining whether the subject can see the second image. The first or second image can have a luminance within a range of from approximately 10-8 cd/m2 to approximately 10-1 cd/m2.

Description

DEVICES AND METHODS FOR DETECTING VISION IMPAIRMENTS

RELATED CASES AND INCORPORATION BY REFERENCE

[0001] The present application claims priority to and also incorporates by reference herein in its entirety U.S. Patent Application No. 62/682,684, filed on June 8, 2018, titled DEVICES AND METHODS FOR EARLY MARKER OF RETINAL DYSTROPHY OR VITAMIN A DEFICIENCY, and U.S. Patent Application No. 62/695,666, filed on July 9, 2018, titled DEVICES AND METHODS FOR EARLY MARKER OF RETINAL DYSTROPHY OR VITAMIN A DEFICIENCY, as if fully set forth herein.

BACKGROUND OF THE DISCLOSURE

Field

[0002] Arrangements disclosed herein relate to devices and methods for detecting vision impairments, for example, screening devices and methods for detecting night blindness.

Description of the Related Art

[0003] Night blindness, or nyctalopia, refers to impaired visual function in dark or dim lighting due to faulty function of rod cells in the retina and is commonly associated with deficiencies in vitamin A metabolism and dietary intake. There are two types of photoreceptors in the human retina - rods and cones. Rods are responsible for vision at low light levels (scotopic vision). Rods do not mediate color vision, and have a low spatial acuity. Cones are active at higher light levels (photopic vision), are capable of color vision, and are responsible for high spatial acuity. The light levels where both cones and rods are operational are called mesopic.

[0004] In developing or undeveloped communities, vitamin A deficiency accounts for the leading cause of preventable childhood blindness, affecting 1/3 of children under age four worldwide per UNICEF report. Earlier detection or diagnosis is very important, as it often permits more preservation of vision if the condition is treated early. Dean Emeritus Alfred Sommer, ophthalmologist and world’s expert on this topic confirms there no easy screening test for night blindness due to vitamin A deficiency. In cases where night blindness is caused by vitamin A deficiency, such condition is preventable with vitamin A supplementation. But, only 64% of such cases were treated in 2016, per UNICEF. A need exists, therefore, for an easy to administer, low cost screening test for night blindness so that night blindness can be diagnosed and treated at an earlier stage of the disease.

[0005] In the developed world, nyctalopia is one of the earliest symptoms of retinal pigment epithelium 65-kD protein (RPE65)-associated and other genetically-acquired retinal dystrophies, ranging from the less severe congenital stationary night blindness to the more severe Leber's congenital amaurosis (LCA). Mutations in the gene encoding RPE65 result in the inability to properly metabolize vitamin A in photoreceptors, leading to dysfunction and atrophy of rod cells. RPE65 mutations have been identified in 10-15% of LCA cases, and recent clinical trials have yielded a gene therapy voretigene neparvovec, trade name Luxturna (TM), targeted at early-onset LCA candidates with RPE65 mutations. In addition to LCA, retinitis pigmentosa, a spectrum of eye disorders causing progressive vision loss, often presents in childhood with initial nyctalopia related to inherited RPE65 and other gene mutations and worsens to include scotomas in the peripheral field, and later, within the central vision. In all cases, early diagnosis and identification of both vitamin A deficiency-related nyctalopia and inherited retinal diseases can prove vital to early treatment for the maintenance of vision and the prevention of progressive vision loss.

[0006] Diagnosis of night blindness is generally made by dark adaptation or electroretinography (ERG). Dark adaptometry is not a feasible method of detecting night blindness in children under age 6 and ERG often requires anesthesia, particularly for children under age 4, making it less suitable or infeasible for many children. Additionally, without suitable testing, young children typically do not even know or realize that they may have night blindness and it may not be noticed by parents or caregivers thus leading to delay in diagnosis.

SUMMARY OF NON-LIMTONG EMBODIMENTS

[0007] Disclosed herein are arrangements of screening devices and methods for detecting night blindness, which can optionally be low cost and easy to administer. Such devices and methods can be used to screen and diagnose patients with significant vision problems, including night blindness due to inherited retinal disease, and also to identify children and pregnant mothers who are vitamin A deficient and, who, therefore, are in need of vitamin A supplementation. The devices and methods disclosed herein can also be used to screen and diagnose patients for retinal dystrophies (RP, LCA), and can provide alternatives to dark adaptometry and electroretinography (ERG) which are much more labor intensive to administer, impractical in many areas of the world, and difficult if not impossible to administer to children under the age of six. The devices and methods disclosed herein can be particularly important for the diagnosis and treatment of significant types of vision problems in children, where current testing protocols and equipment are typically infeasible and ineffective.

[0008] Arrangements disclosed herein can use fluorescent or phosphorescent images with a light source in a dimly lit or unlit room to screen for night blindness. A patient can be placed in a dark or dimly lit room, and the patient is adapted to the darkness or dimness. The patient can then then screened for night blindness. As part of the screening, one or more fluorescent or phosphorescent images can be shown to the patient. It can be determined whether or not the patient can see the fluorescent or phosphorescent images based on simple gestures from the subject or responses to questions regarding the location and/or description of the images. Luminance of images can be varied in intensity to better determine dark adaptation threshold. A series of images, which can be of varying luminance, fluorescent intensity, and/or phosphorescent intensity (such as, for example, sequentially decreasing intensity, sequentially increasing intensity, or in a random order) can be shown to the patient to determine which images the patient or subject can see and to determine the severity of any impairments in the subject. In some arrangements herein, using a series of images of varying intensity, a cut-off point can be determined for what level of fluorescent or phosphorescent intensity is visible to the patient, and the degree of night blindness can be determined for the patient. In some arrangements, an image from a smartphone, computer monitor, tablet, or other electronic device can be presented to the subject.

[0009] Any arrangements of the devices and methods disclosed herein can be administered by healthcare as well as non-healthcare personnel for screening (e.g., parents or teachers). Positive patients can then optionally be tested for dark adaptation, ERG changes, genetic testing, or vitamin A level, as indicated.

[0010] Any of the embodiments disclosed herein can have any of the, or any combination of any of the components, features, or details of any of the following arrangements. [0011] Arrangement 1. A method of detecting night blindness in a subject, comprising:

illuminating a first image on a display device using a light source so that the first image has a first luminance;

determining whether the subject can see the first image;

illuminating a second image on the display device using the light source so that the second image has a second luminance that is different than the first luminance; and determining whether the subject can see the second image;

wherein at least one of the first luminance and the second luminance is within a range of from approximately 10 ⁶ cd/m² to approximately 10° cd/m².

[0012] Arrangement 2. The method of arrangement 1, wherein at least one of the first and second images comprises a fluorescent ink.

[0013] Arrangement 3. The method of any one of the previous arrangements, wherein the first image comprises a fluorescent ink at a first density and the second image comprises a fluorescent ink at a second density, the second density being different than the first density so that the second luminance is different than the first luminance.

[0014] Arrangement 4. The method of any one of the previous arrangements, wherein at least one of the first and second images comprises a fluorescent ink at a density of from 2% to 45%.

[0015] Arrangement 5. The method of any one of the previous arrangements, wherein the light source emits only an ultraviolet light.

[0016] Arrangement 6. The method of any one of the previous arrangements, wherein the first image is positioned at a first position on the display device and the second image is positioned at a second position on the display device, wherein the second position is different than the first position.

[0017] Arrangement 7. The method of any one of the previous arrangements, comprising illuminating at least five images on the display device.

[0018] Arrangement 8. The method of any one of the previous arrangements, comprising illuminating at least seven images on the display device. [0019] Arrangement 9. The method of any one of the previous arrangements, comprising sequentially illuminating at least five images on the display device wherein each image has a different luminance and displays a different object.

[0020] Arrangement 10. The method of any one of the previous arrangements, comprising covering one of the subject’s eyes.

[0021] Arrangement 11. The method of any one of the previous arrangements, wherein the display device comprises a plurality of test plates having a low reflectivity and luminance.

[0022] Arrangement 12. The method of any one of the previous arrangements, wherein the display device comprises a plurality of sheets of paper each having a matte black color which each display an image.

[0023] Arrangement 13. The method of any one of the previous arrangements, comprising illuminating a phosphorescent image on a test plate using a UV light source.

[0024] Arrangement 14. The method of any one of the previous arrangements, wherein the display device comprises an image that has 100% ink density.

[0025] Arrangement 15. The method of any one of the previous arrangements, wherein the display device comprises a digital display and illuminating the image on the display device using a light source comprises displaying the image on the digital display.

[0026] Arrangement 16. The method of any one of the previous arrangements, wherein at least one of the first luminance and the second luminance image is within a scotopic range.

[0027] Arrangement 17. The method of any one of the previous arrangements, wherein at least one of the first luminance and the second luminance image is within a range of from approximately 10 ⁸ cd/m² to approximately 10 ² cd/m².

[0028] Arrangement 18. The method of any one of the previous arrangements, wherein at least one of the first luminance and the second luminance image is within a range of from approximately 10 ⁴ cd/m² to approximately 10 ² cd/m².

[0029] Arrangement 19. The method of any one of the previous arrangements, wherein at least one of the first luminance and the second luminance image is within a range of from approximately 10 ⁴ cd/m² to approximately 10 ² cd/m². [0030] Arrangement 20. The method of any one of the previous arrangements, comprising placing the subject in a dark or dimly lit room for a predetermined amount of time before illuminating the first image.

[0031] Arrangement 21. The method of any one of the previous arrangements, comprising placing the subject in a dark or dimly lit room for at least 15 minutes before illuminating the first image.

[0032] Arrangement 22. The method of any one of the previous arrangements, further comprising testing the patient for one or more of dark adaptation, ERG changes, genetic testing, and/or vitamin A level.

[0033] Arrangement 23. The method of any one of the previous arrangements, further comprising treating the patient with voretigene neparvovec based on the determined degree of night blindness.

[0034] Arrangement 24. The method of any one of the previous arrangements, further comprising treating the patient with beta-carotene or vitamin A based on the determined degree of night blindness.

[0035] Arrangement 25. A system for detecting a vision impairment in a subject, comprising:

a display device configured to sequentially display a plurality of images thereon;

a light source configured to illuminate the plurality of images so that at least one of the plurality of images has a luminance within a range of from approximately

10 ⁶ cd/m² to approximately 10° cd/m².

[0036] Arrangement 26. The device of arrangement 25, wherein the plurality of images comprises a first image and a second image and the device is configured such that the first image has a luminance that is different than a luminance of the second image when the light source illuminates the first and second images.

[0037] Arrangement 27. The device of any one of arrangements 25-26, wherein the plurality of images comprises a first image having a first opacity and a second image having a second opacity and wherein the second opacity is different that the first opacity.

[0038] Arrangement 28. The device of any one of arrangements 25-27, wherein the light source is coupled with the display device using a tether having a predetermined length. [0039] Arrangement 29. The device of any one of arrangements 25-28, wherein at least one of the plurality of images comprises a fluorescent ink.

[0040] Arrangement 30. The device of any one of arrangements 25-29, comprising a first image comprising a fluorescent ink having a first density and a second image comprising a fluorescent ink having a second density, the second density being different than the first density so that the second luminance is different than the first luminance.

[0041] Arrangement 31. The device of any one of arrangements 25-30, wherein at least one of the plurality of images comprises a fluorescent ink having a density of from 2% to 45%.

[0042] Arrangement 32. The device of any one of arrangements 25-31 , wherein the light source emits only an ultraviolet light.

[0043] Arrangement 33. The device of any one of arrangements 25-32, wherein the display device comprises a plurality of test plates having low reflectivity and luminance.

[0044] Arrangement 34. The device of any one of arrangements 25-33, wherein the display device comprises a plurality of sheets of paper each having a matte black color which each display an image.

[0045] Arrangement 35. The device of any one of arrangements 25-34, wherein the display device comprises a digital display.

[0046] Arrangement 36. The device of any one of arrangements 25-35, wherein at least one of the plurality of images is within a scotopic range.

[0047] Arrangement 37. A method for early detection of night blindness, comprising:

presenting a first image to a user via an interface, the first image having a first luminance, fluorescence or phosphorescence intensity;

receiving a first input from the user, wherein the first input is provided by the user based on a visual response of the user to the first luminance, fluorescence or phosphorescence intensity;

presenting a second image to the user via the interface, the second image having a second luminance, fluorescence or phosphorescence intensity; receiving a second input from the user, wherein the second input is provided by the user based on a visual response of the user to the second luminance, fluorescence or phosphorescence intensity; and

based on the first user input and the second user input, determining a degree of night blindness in the user.

[0048] Arrangement 38. The method of arrangement 37, further comprising testing the patient for one or more of dark adaptation, ERG changes, genetic testing, and/or vitamin A level.

[0049] Arrangement 39. The method of arrangement 37 or 38, further comprising treating the patient with voretigene neparvovec based on the determined degree of night blindness.

[0050] Arrangement 40. The method of arrangement 37 or 38, further comprising treating the patient with beta-carotene or vitamin A based on the determined degree of night blindness.

BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 is a photograph of a non-limiting arrangement of a screening device, wherein an image of a cat is displayed by the display device.

[0052] Figure 2 is a photograph of the arrangement of the screening device shown in Figure 1, wherein an image of a dog is displayed by the display device.

[0053] Figure 3 is a photograph of the arrangement of the screening device shown in Figure 1, wherein an image of a dog having a higher luminance than the dog image shown in Figure 2 is displayed by the display device.

[0054] Figure 4 is a photograph of the arrangement of the screening device shown in Figure 1, wherein an image of an owl is displayed by the display device.

[0055] Figure 5 is a photograph of the arrangement of the screening device shown in Figure 1, wherein an image of an owl having a low luminance is displayed by the display device.

[0056] Figure 6 is a photograph of the arrangement of the screening device shown in Figure 5, wherein the image of the owl displayed by the display device is being illuminated by a light source. [0057] Figure 7 is a photograph of the arrangement of the screening device shown in Figure 1, wherein an image of a dog having a low luminance is displayed by the display device.

[0058] Figure 8 is a photograph of the arrangement of the screening device shown in Figure 7, wherein the image of the dog displayed by the display device is being illuminated by a light source.

[0059] Figure 9 shows the results from a screening test performed by seven different subjects.

DETAILED DESCRIPTION

[0060] Disclosed herein are various arrangements of vision impairment screening devices and methods (referred to herein as vision screening devices or methods or diagnosis devices and methods) for the diagnosis of significant vision problems. The vision screening device and method arrangements disclosed herein provide an important solution for diagnosing vision impairments that are difficult and/or infeasible to detect using current equipment and methodologies. Such devices and methods disclosed herein can be particularly important for children under the age of six or for children with language impairments, for which current testing protocols and devices are generally ineffective for detecting.

[0061] Some arrangements are directed to an easy in-office or in the field test for night blindness to detect inherited retinal disease, vitamin A deficiency, and/or other vision impairments. Based on preliminary luminance testing of the vision screening devices and methods disclosed herein, arrangements of such devices and methods are very effective in detecting and diagnosing patients for nyctalopia, or night blindness. Such arrangements can be used to identify children at young ages with night blindness due to inherited retinal disease and/or vitamin A deficiency. Earlier detection could mean earlier initiation of treatment, which could be vital in the management and prevention of progressive vision loss.

[0062] In any arrangements, the patient can be a mammal - optionally a human patient. The vision screening devices and methods disclosed herein can be used for any person and generally at any age range. The vision screening devices and methods can be applied to patients at any age, or at ages of 15 years and below, or 8 years and above, 7 years and above, 6 years and above, 5 years and above, 4 years and above, 3 years and above, 2 years and above, or 1 year and above. In some arrangements, the vision screening devices and methods can be applied to any patient who is a child, or optionally to any patient who can communicate, or to any patient can communicate at a basic level verbally or non-verbally, such as through finger and/or hand gestures. Any arrangements of the vision screening devices and methods can be applied to any patient who can communicate or signal the existence of an object under testing conditions, including children who are 2 years old or younger. Therefore, arrangements disclosed herein can be used for diagnosing vision impairments in a subject who is under 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age. In some arrangements, the methods and devices provided herein can allow a parent, caregiver, or medical practitioner such as a doctor, physician or nurse, to detect night blindness in the patient. In some arrangements, a method is provided for detecting, identifying, or diagnosing whether a patient or child has night blindness. In some arrangements, the method identifies a patient not having night blindness.

[0063] In some arrangements, for example in the arrangement shown in Figures 1- 9, the screening device 100 can include a display device 102 having one or more (or, optionally, a plurality of) test plates 104 (also referred to herein as pages or plates) and a light source 106. In some arrangements, the test plates 104 can be made using any suitable substrate such as paper, cardboard, plastic, or otherwise, and can have a dark color, such as black, brown, purple, maroon, magenta, gray, or any such color that has a low reflectivity (for example, matte black). Optionally, any background color can be used, including but not limited to grey, dark grey, dark blue, or brown. The test plate 102 can optionally be made using a thick or stiff sheet of paper (for example and without limitation, a 100 lb dull white cover sheet, or from an 80 lb to 110 lb sheet of paper), thin sheet of cardboard, or even thinner paper or plastic sheets. In any arrangements, the test plate can comprise a paper substrate having one or more or two or more coats of matte black ink (optionally, a UV black ink) thereon, or three or more coats of black ink thereon, or wherein the substrate of the paper or the background ink or coating is configured to prevent the ink used for the image from bleeding into the background ink or substrate or from blurring at the edges. Optionally, the background ink or substrate can be a low emissivity or low reflectivity ink, such as a matte black ink that reflects approximately 3% or less of the light that it receives, or approximately 5% or less, or from approximately 2% or less to approximately 10% or more, of the light that it receives, or between any values within these ranges. [0064] Each of the test plates 104 can have one or more images or objects 108 on a first surface of the test plate or page. The plurality of test plates or pages 104 can optionally be bound together in a book, with a binding of metal wire coil, plastic coil, adhesive binding, or using any other suitable binding materials or methods. The images can be optionally be painted or printed on one or more of the test plates 104 in any desired location and/or size. For example, on a first test plate, a first image can be of an owl and can be printed in an upper left portion of the page. The image(s) can optionally be in an upper middle portion, an upper right portion, a middle left portion (i.e., vertically centered, but on left side of the page), a middle portion, a middle right portion, a lower left portion, a lower middle portion, and/or a lower right portion. Any arrangements of the screening device 100 can have more than one image 108 on a test plate, including two or more images, three or more images, four or more images, or more, each at a different location on the test plate.

[0065] In any arrangements of the vision screening devices and methods disclosed herein, any of the objects printed on the pages can be animals or other living creatures or things including but not limited to trees, insects, fish, reptiles, or otherwise, any shapes such as ovals, circles, squares, triangles, rectangles, pentagons, hexagons, or other polygons, articles of fruit or vegetables such as bananas, oranges, apples, pineapples, or any other desired type of food, any desired objects such as houses, vehicles, or otherwise. The images can also optionally be numbers, letters, or other characters.

[0066] In any arrangements, one or more of the images can comprise phosphorescent ink (such as, for example, a glow-in-the-dark ink), fluorescent ink, or otherwise, of any desired color. In any arrangements, the ink used for the images can be a fluorescent UV yellow ink, or can optionally be any desired color. A satin, aqueous coating can be applied over at least one of the UV ink used for the images and the ink used for the background.

[0067] Alternatively, in any arrangements, which can have any of the features, components, or other details of any other arrangements disclosed herein, the images can be presented on light emitting displays, such as images on a black or dark background on a tablet, a computer monitor or television screen, a liquid crystal display (LCD), a light emitting diode (LED) display, or other electronic device. In digital or electronic arrangements, the mobile phone or other device can have a neutral density filter over the display if, for example, the lowest luminance setting on mobile phone or other device is higher than the optimal luminance range for the testing. Different filters can be used to display or test different luminance ranges, and the brightness of the electronic device can also be adjusted to display or test different luminance ranges. An interactive smartphone app can measure a dark adaptation threshold of the patient by showing one or more images via a user interface, and receiving user input based on whether or not the user can see the images.

[0068] In any digital or electronic arrangements, a neutral density filter (which, in any arrangements disclosed herein, can be a lOOOx or other neutral density filter) can be applied over the display of the electronic device to reduce the light emitted by the display of the electronic device to generate a dimmer image for the test. Any arrangements of the digital test device can have any of the layout details, luminance parameters, image size, and other components, parameters, or details of any of the non-digital vision screening devices and methods arrangements disclosed herein.

[0069] In some arrangements, the vision screening devices and methods can include a black-background photopaper book with commonly-recognized animals printed using a range of fluorescent ink densities. In any arrangements, the ink can be a fluorescent UV ink, as mentioned above. A commonly available UV light calibrated and dimmed with filters can be used to reduce the amount of light reflected (luminance) of the fluorescent ink to within wavelengths detected by human vision photoreceptors. The ink density of any of the images can be one or more of the following densities: 2%, 5%, 10%, 12%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, and/or 100%, including any values between those listed. In some arrangements, the ink densities less than 100% can be achieved using a halftone printing process, or other process wherein the ink density can be decreased. For example and without limitation, a size of the dots on the test plate used to create the images can be decreased so as to decrease the ink density of the image. Screens can be used to achieve lower densities in the half-tone process.

[0070] Optionally, in some arrangements, the ink can be diluted using diluting agents or substances, which can optionally be water. As used herein, a 50% density ink would include 50% undiluted ink and 50% diluting agent by volume, and a 2% density ink would include 2% undiluted ink and 98% diluting agent by volume. The diluting agent can be any suitable diluting agent for fluorescent UV ink, optionally water. [0071] In any embodiments disclosed herein, a level of luminance of the image can be varied by increasing or decreasing the ink density, and/or by increasing or decreasing an intensity of the light source directed to the image. For example and without limitation, the cat image 108 of the display device 102 shown in Figure 1 has a higher ink density than the dog image 108 of the display device 102 shown in Figure 2 such that, under the same illumination by the light source 106, the cat image 108 will have a higher luminance than the dog image 108. Optionally, the ink density can correlate with an opacity level or with a luminance level of the images. For example, in any arrangements disclosed herein, the display device can be configured to display a plurality of images, each of which can have any of the following opacity or luminance levels: 2%, 5%, 10%, 12%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, and/or 100% (or any value therebetween), wherein 100% is the highest luminance that can be achieved for the particular ink being used and results from the undiluted ink.

[0072] In any arrangement disclosed herein, the display device 102 can have a plurality of images 108 arranged sequentially on a plurality of test plates 104 of the display device 102. Optionally, each of the sequentially arranged images can have an increasing (or decreasing) level of ink density, opacity and/or luminance or a decreasing level of ink density, opacity and/or luminance, or can be arranged randomly with respect to density, opacity and/or luminance. Optionally, in any arrangements disclosed herein, the display device 100 can also have a one or more images at 100% ink density so that a user can learn what the images look like prior to being exposed to the lower luminance images under testing conditions.

[0073] In some arrangements, there can be a direct correlation between luminance and ink density percentages. Luminance ranges at the lowest ink density percentage (2%) can approach thresholds of rod photoreceptor sensitivity (the photoreceptors used to see in the dark), indicating that the vision screening devices and methods arrangements disclosed herein can be used to differentiate rod from cone function.

[0074] Any arrangements of the vision screening devices and methods disclosed herein (whether analog, paper based, or digital such as using a tablet, computer, or otherwise) can have luminance values or intensities that are in the lower mesopic or scotopic vision ranges. Given that mesopic vision is also commonly affected in inherited retinal diseases, including some images that test for both cone and rod function (i.e., within the mesopic range) may be beneficial for further screening use. [0075] In any arrangements, the light source 104 can be a portable UV light source such as, without limitation, a small UV flashlight. The light source 104 can optionally be a 395 nm UV flashlight, or optionally a 398 nm UV flashlight, or any UV light source between about 350 nm and about 450 nm.. In any arrangements, the light source (which can include one or more neutral density filters) can configured to produce light at wavelengths (for example, in scotopic range) that rods are sensitive to, and which cones are not as sensitive to or not able to detect. In any arrangements, the light source 104 can optionally comprise a 395 nm UV flashlight having a neutral density filter or other optical dimmer on it to reduce the brightness or intensity of the light source 104. The light source can optionally use a 385 nm wavelength UV bulb. In any arrangements, the luminance levels can be reduced to be within or close to rod-exclusive, or scotopic, luminance ranges using the fluorescent ink, a 395 nm UV light source, and a 1 OOOx neutral density filter. In any arrangements, the light source can have a lOOOx, a 2000x, or from a 500x or less to a 3 OOOx or more neutral density filter.

[0076] Accordingly, any arrangements of the vision screening devices and methods disclosed herein can be configured to provide an image having a luminance within a scotopic range, or within a lower mesopic, or within a lower mesopic and/or scotopic range, or from approximately 10 ⁶ cd/m² (or as low as 10 ⁸ cd/m²) to approximately 10° cd/m², or from approximately 10 ⁴ cd/m² to approximately 10 ¹ cd/m², or from approximately 10 ³ cd/m² to approximately 10 ¹ cd/m², or from approximately 10 ⁴ cd/m² to approximately 10 ¹ cd/m², or from or to any values within any of the foregoing ranges.

[0077] The light source 104 can optionally be coupled with the plurality of test plates 102 using a tether 112, which can be a string, a chain, a thin strap, or other material. The tether 112 can have a predetermined or standardized length, such as approximately 10 inches (approximately 25 cm), or from approximately 8 inches to approximately 14 inches or more, or from approximately 8 inches to approximately 20 inches or more, or between any values within these ranges. The tether 112 can optionally be substantially non-stretchable and/or non-elastic so as to provide a maximum distance (or predetermined distance) that the light source 104 can be moved away from the test plate 102 so that the light source 104 can be a fixed distance from every test plate 102 for consistency by moving the light source 104 away from the test plate until the tether 112 is taut. In this configuration, when a user or administrator of the test performs the test, the light source 104 can be positioned to shine light from the light source 104 on the image 108 from a set and consistent distance by moving the light source 104 away from the test plate 102 as far as the tether 112 will permit. Therefore, in any arrangements, the light source 104 can be configured to illuminate the one or more images on any of the test plates, with the light source being at a predetermined distance from the test plate or object.

[0078] Any arrangements of the vision screening devices and methods disclosed herein can include one or more of the following steps, in any desired combination:

1. In lighted conditions, explain to the subject (and the parent or guardian if

necessary) that the subject will be undergoing a test to assess the subject’s ability to see in low lighting conditions. Show the subject the first three example test plates at the beginning of the test book and explain to the subject that they will sit in the dark for a predetermined amount of time (which can be 22 minutes, or from 15 - 30 minutes, or from 20 - 25 minutes) and will be asked to perform the test, which will include identifying objects on the pages.

a. The first three example test plates can have a thicker layer of ink on the test plates so as to be more visible and identifiable, for instructional purposes (i.e., to facilitate explaining the steps of the test).

2. Acclimate the subject’s eyes to darkness in an unlit or, optionally, a very dimly lit room for a predetermined amount of time, which can be for approximately 22 minutes, or from approximately 15 minutes - approximately 30 minutes, or from approximately 15 to approximately 20 minutes. This can maximize rod cell sensitivity.

a. Can optionally advise the subject (and the parent or guardian if necessary) that he or she will sit in the dark for the predetermined amount of time to adapt his or her eyes to the darkness.

3. Cover or instruct the subject to cover a first eye of the subject to block the

subject’s vision through the first eye. The first eye can be the left eye or, alternatively, the right eye.

a. An eye patch, an occluder, the patient’s hand, or other device or object can optionally be used to selectively block the subject’s eye. b. In some arrangements, the subject can use both eyes for the test. Illuminate the first object printed on the first test plate using the UV light source, with the UV light source at a predetermined distance from the test plate or object. a. In some arrangements, the predetermined distance can be approximately 25 cm, or from approximately 20 cm or less to approximately 50 cm or more.

b. A string, tether, or other object coupling the light source to the test book can have a predetermined length which can, when fully extended, position the light source at the predetermined distance.

c. Optionally, the any arrangements of the devices or methods disclosed herein can be configured such that the luminance level of the image is within the lower mesopic range or, optionally, in the scotopic range. d. The UV light should not be shined in the subject’s eyes.

Instruct the subject to examine the first test plate and point to or otherwise identify the location of the first object printed on the first test plate.

a. The first object can have a first level of opacity or any desired level of opacity.

Instruct the subject to name or describe (if possible) the first object on the first test plate.

Repeat steps 4-6 for the second test plate, the third test plate, the fourth test plate, the fifth test plate, the six test plate, and/or the seventh test plate.

a. Any arrangements of the vision screening devices and methods disclosed herein can have seven test plates, or from four or less to ten or more test plates, or any desired number of test plates in total or in the first section. Record the results for each test plate including which eye was tested and whether the subject correctly identified the object and/or the location of the object.

Uncover or instruct the subject to uncover the first eye and to cover a second eye of the subject to block the subject’s vision through the second eye. The second eye can be the right eye or whichever eye was not covered earlier in the test. Illuminate the eighth object printed on the eighth test plate using the UV light source, as done for the preceding test plates. 11. Instruct the subject to examine the eighth test plate and point to or otherwise identify the location of the eighth object printed on the eighth test plate. a. The eighth object can have any desired level of opacity.

12. Instruct the subject to name or describe (if possible) the first object on the first test plate.

13. Repeat steps 10-12 for the ninth test plate, the tenth test plate, the eleventh test plate, the twelfth test plate, the thirteenth test plate, and/or the fourteenth test plate.

a. Any arrangements of the vision screening devices and methods disclosed herein can have seven test plates, or from four or less to ten or more test plates, or any desired number of test plates in total or in the second section of the test book.

14. Record the results for each test plate including which eye was tested and whether the subject correctly identified the object and/or the location of the object.

[0079] In some arrangements, wherein an ink density or luminance level is as low as 2%, subjects with healthy eyesight should be able to correctly identify 6 of 7 of the images for each eye, since the 2% luminance image may be difficult for most healthy eyes to detect. In such arrangements, if less than 6 of the 7 images are seen by the subject, the subject may have night blindness, the severity of which can be determined by the number of images that were not detected and the luminance level of such images.

[0080] Any arrangements of the protocol or steps for using or applying the vision screening devices and methods can be modified for use with subjects with communication impairments or deficiencies by providing other verbal and non-verbal cues and/or instructions to instruct the subject how to proceed with the use of the vision screening devices and methods. Any devices disclosed herein can be low cost and, therefore, affordable and feasible for use in poorer countries or poorer populations.

[0081] Optionally, any of the steps described above can be modified or adapated (within the scope of one of ordinary skill in the art or as described herein) to be performed using a digital display device or other electronic device that can have a digital display, as described in more detail above. For example, a liquid crystal display (LCD) and/or a light emitting diode (LED) display can be used as the display device in any arrangements disclosed herein, which display device can be configured to display the images at any desired varying levels of luminance. In any arrangements, the electronic device can be configured such that any of the steps of the method or protocol performed above can be performed using the electronic device.

[0082] Figure 9 shows the results from a screening test performed or taken by seven different subjects. The arrangement of a screening device used for the test had seven different images. The light source used for the test was a 395 nm wavelength ultraviolet light with a lOOOx neutral density filter. The test results reveal that all seven subjects identified the 45% ink density image displayed by the display device of the screening device and that none of the subjects was able to identify the 2% ink density image. Notably, the test results reveal the accuracy of the arrangements of the screening test devices and methods disclosed herein in diagnosing subjects with advanced cone-rod dystrophy. In particular, subjects #4 and #7, both of whom have advanced cone-rod dystrophy, were not able to see any of the images having an ink density less than 45% and, therefore, were correctly diagnosed using an arrangement of the screening device of this disclosure.

[0083] As mentioned, in some cases, night blindness can be caused by a homozygous mutation in Retinal pigment epithelium-specific 65 kDa protein (also known as retinoid isomerohydrolase or RPE65). In some arrangements, the patient can have a homozygous mutation in RPE65 that causes a disease that includes night blindness. Voretigene neparvovec (LUXTURNA) is currently FDA approved for children 1 year of age or older. Early diagnosis of night blindness or homozygous RPE65 mutations by the methods or devices provided herein can permit preservation of vision that would be lost by later detection of the night blindness or homozygous RPE65 mutations. In some arrangements, a child or adult patient is treated with voretigene neparvovec. The treatment can be based on a detection or diagnosis of night blindness by the methods or devices described herein. The treatment can include a dose of voretigene neparvovec at about 1.5 x 10¹¹ vector genomes (vg), including doses ranging from about 1.5 x 10⁷ to about 1.5 x 10¹³ vg. In some arrangements, the dose of voretigene neparvovec is administered in liquid diluent such as sterile water or saline solution at total volume of 0.3 mL (e.g., about 0.1 to about 1.0 mL). In some arrangements, the dose of voretigene neparvovec is injected into one eye of the patient. In some arrangements, the dose of voretigene neparvovec is injected into a second eye of the patient. In some arrangements, the injection is subretinal. In some arrangements, the diluent includes sterile water containing 180 mM sodium chloride, 10 mM sodium phosphate, and/or 0.001% Poloxamer 188, and may be at pH 7.3.

[0084] In some case, the condition can be caused by a vitamin A deficiency, which can be treated with beta-carotene or vitamin A. Beta-carotene or vitamin A can be provided to the patient at a dose of 25,000, 15,000, 5,000, 2500, 1000, 500, 250, 100, or 50 IU/kg body weight. Optionally, multiple doses of vitamin A can be provided. For example, an easy to use screening test for night blindness as provided herein helps identify children in need of vitamin A supplementation, advantageously, at an earlier time-point that other methods currently in practice, which allows for a potentially improved prognosis based on an earlier administration of therapy.

[0085] In some cases, the night blindness can be caused by Leber’s congnital amaurosis, retinitis pigmentosa, retinal detachment, a medication such as a phenothiazine, Oguchi disease, pathological myopia, a cataract (peripheral cortical), a refractive surgery (LASIK, photorefractive keratectomy, or radial keratotomy), Sorsby's Fundus Dystrophy (macular degeneration), vitamin A deficiency, choroideremia, glaucoma, or any combination of such diseases. Some arrangements of the methods and devices disclosed herein enable or include diagnosis, identification, and/or treatment of the cause of the night blindness.

[0086] In some cases, a drug, supplement, vitamin, or treatment is provided based on whether a patient is identified to have night blindness as provided herein. In some cases, the drug, supplement, vitamin, or treatment can be provided once, twice, three times, four times, or five times per day. One or more doses of the drug, supplement, vitamin, or treatment are provided over a course of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. One or more doses of the drug, supplement, vitamin, or treatment can be provided over a course of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 months. One or more doses of the drug, supplement, vitamin, or treatment can be provided over a course of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 years. In some arrangements, the drug, supplement, vitamin, or treatment can be provided by injection, intravenously, subcutaneously, intradermally, or orally, which can be provided as a pill, capsule, or liquid. [0087] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the arrangements of the invention(s).

[0088] It is contemplated that various combinations or subcombinations of the specific features and aspects of the arrangements disclosed above may be made and still fall within one or more of the inventions. Further, the disclosure herein of any particular feature, aspect, method, property, characteristic, quality, attribute, element, or the like in connection with an arrangement can be used in all other arrangements set forth herein. Accordingly, it should be understood that various features and aspects of the disclosed arrangements can be combined with or substituted for one another in order to form varying modes of the disclosed inventions. Thus, it is intended that the scope of the present inventions herein disclosed should not be limited by the particular disclosed arrangements described above. Moreover, while the invention is susceptible to various modifications, and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the various arrangements described and the appended claims. Any methods disclosed herein need not be performed in the order recited. The methods disclosed herein include certain actions taken by a practitioner; however, they can also include any third-party instruction of those actions, either expressly or by implication. For example, actions such as“administering an antigen-binding protein” include“instructing the administration of an antigen-binding protein.” In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0089] The ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof. Language such as“up to,”“at least,”“greater than,”“less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or“approximately” include the recited numbers. For example,“about 90%” includes “90%.”

[0090] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term‘including’ should be read to mean‘including, without limitation,’‘including but not limited to,’ or the like.

[0091] The indefinite article“a” or“an” does not exclude a plurality. The term “about” as used herein to, for example, define the values and ranges of molecular weights means that the indicated values and/or range limits can vary within ±20%, e.g., within ±10%. The use of“about” before a number includes the number itself. For example,“about 5” provides express support for“5”. Numbers provided in ranges include overlapping ranges and integers in between; for example a range of 1-4 and 5-7 includes for example, 1-7, 1-6, 1-5, 2- 5, 2-7, 4-7, 1, 2, 3, 4, 5, 6 and 7.

Claims

WHAT IS CLAIMED IS:

1. A method of detecting night blindness in a subject, comprising:

determining whether the subject can see the first image;

2. The method of claim 1, wherein at least one of the first and second images comprises a fluorescent ink.

3. The method of any one of the previous claims, wherein the first image comprises a fluorescent ink at a first density and the second image comprises a fluorescent ink at a second density, the second density being different than the first density so that the second luminance is different than the first luminance.

4. The method of any one of the previous claims, wherein at least one of the first and second images comprises a fluorescent ink at a density of from 2% to 45%.

5. The method of any one of the previous claims, wherein the light source emits only an ultraviolet light.

6. The method of any one of the previous claims, wherein the first image is positioned at a first position on the display device and the second image is positioned at a second position on the display device, wherein the second position is different than the first position.

7. The method of any one of the previous claims, comprising illuminating at least five images on the display device.

8. The method of any one of the previous claims, comprising illuminating at least seven images on the display device.

9. The method of any one of the previous claims, comprising sequentially illuminating at least five images on the display device wherein each image has a different luminance and displays a different object.

10. The method of any one of the previous claims, comprising covering one of the subject’s eyes.

11. The method of any one of the previous claims, wherein the display device comprises a plurality of test plates having a low reflectivity and luminance.

12. The method of any one of the previous claims, wherein the display device comprises a plurality of sheets of paper each having a matte black color which each display an image.

13. The method of any one of the previous claims, comprising illuminating a phosphorescent image on a test plate using a UV light source.

14. The method of any one of the previous claims, wherein the display device comprises an image that has 100% ink density.

15. The method of any one of the previous claims, wherein the display device comprises a digital display and illuminating the image on the display device using a light source comprises displaying the image on the digital display.

16. The method of any one of the previous claims, wherein at least one of the first luminance and the second luminance image is within a scotopic range.

17. The method of any one of the previous claims, wherein at least one of the first luminance and the second luminance image is within a range of from approximately 10 ⁸ cd/m² to approximately 10 ² cd/m².

18. The method of any one of the previous claims, wherein at least one of the first luminance and the second luminance image is within a range of from approximately 10 ⁴ cd/m² to approximately 10 ² cd/m².

19. The method of any one of the previous claims, wherein at least one of the first luminance and the second luminance image is within a range of from approximately 10 ⁴ cd/m² to approximately 10 ² cd/m².

20. The method of any one of the previous claims, comprising placing the subject in a dark or dimly lit room for a predetermined amount of time before illuminating the first image.

21. The method of any one of the previous claims, comprising placing the subject in a dark or dimly lit room for at least 15 minutes before illuminating the first image.

22. The method of any one of the previous claims, further comprising testing the patient for one or more of dark adaptation, ERG changes, genetic testing, and/or vitamin A level.

23. The method of any one of the previous claims, further comprising treating the patient with voretigene neparvovec based on the determined degree of night blindness.

24. The method of any one of the previous claims, further comprising treating the patient with beta-carotene or vitamin A based on the determined degree of night blindness.

25. A system for detecting a vision impairment in a subject, comprising:

10 ⁶ cd/m² to approximately 10° cd/m².

26. The device of claim 25, wherein the plurality of images comprises a first image and a second image and the device is configured such that the first image has a luminance that is different than a luminance of the second image when the light source illuminates the first and second images.

27. The device of any one of claims 25-26, wherein the plurality of images comprises a first image having a first opacity and a second image having a second opacity and wherein the second opacity is different that the first opacity.

28. The device of any one of claims 25-27, wherein the light source is coupled with the display device using a tether having a predetermined length.

29. The device of any one of claims 25-28, wherein at least one of the plurality of images comprises a fluorescent ink.

30. The device of any one of claims 25-29, comprising a first image comprising a fluorescent ink having a first density and a second image comprising a fluorescent ink having a second density, the second density being different than the first density so that the second luminance is different than the first luminance.

31. The device of any one of claims 25-30, wherein at least one of the plurality of images comprises a fluorescent ink having a density of from 2% to 45%.

32. The device of any one of claims 25-31, wherein the light source emits only an ultraviolet light.

33. The device of any one of claims 25-32, wherein the display device comprises a plurality of test plates having low reflectivity and luminance.

34. The device of any one of claims 25-33, wherein the display device comprises a plurality of sheets of paper each having a matte black color which each display an image.

35. The device of any one of claims 25-34, wherein the display device comprises a digital display.

36. The device of any one of claims 25-35, wherein at least one of the plurality of images is within a scotopic range.

37. A method for early detection of night blindness, comprising:

presenting a second image to the user via the interface, the second image having a second luminance, fluorescence or phosphorescence intensity;

receiving a second input from the user, wherein the second input is provided by the user based on a visual response of the user to the second luminance, fluorescence or phosphorescence intensity; and

38. The method of claim 37, further comprising testing the patient for one or more of dark adaptation, ERG changes, genetic testing, and/or vitamin A level.

39. The method of claim 37 or 38, further comprising treating the patient with voretigene neparvovec based on the determined degree of night blindness.

40. The method of claim 37 or 38, further comprising treating the patient with beta- carotene or vitamin A based on the determined degree of night blindness.

41. A method of detecting night blindness in a subject substantially as hereinbefore described or shown in the accompanying drawings.

42. A device configured to diagnose night blindness in a subject substantially as hereinbefore described or shown in the accompanying drawings.