What's Your Diagnosis?

Routine visit leads to asymptomatic diagnosis

A 71-year-old white female presented to the clinic in May 2018 for her periodic examination with no complaints. Systemic history included sinusitis and seasonal allergies. She reported taking no medications.

Kowa color photography of right and left macula. Note the presence of drusen in each eye.
Source: Amanda S. Legge, OD

Her ocular history was remarkable for symptomatic impaired dark adaptation. Clinical findings previously included small, soft drusen more marked in the right eye than the left, and age-appropriate nuclear sclerotic cataracts that were mildly visually significant. She was taking AREDS2 supplements as recommended.

Macular OCT of the right eye showing, in this cross-sectional view, large drusen consistent with the fundus observation.

This patient was diagnosed with AMD initially in 2016 when she presented to the clinic as a new patient with subtle drusen. This clinical finding prompted dark adaptation testing, which found that her rod intercept was significantly delayed for both eyes. Dark adaptation is the only biomarker for early AMD. Although her maculae had no severe signs of drusen in 2016, the patient was diagnosed with AMD and educated on lifestyle changes, smoking cessation, weight loss, comorbid disease control, UV protection, initiation of AREDS2 supplements, Amsler grid home screening and monitoring in-office with more frequent dilated examinations.

Over time, the patient’s rod intercept time on the dark adaptation curve continued to progress. This worsening functional deficit, along with worsening drusen appearance, prompted a more careful “watchful waiting” monitoring with dilated examinations recommended every 3 months.

Macular OCT of the left eye showing choroidal neovascular invasion into the sub-RPE and subretinal spaces.

On this examination now in May 2018, the patient’s best corrected visual acuities were 20/25-1 OD and 20/25+2 OS. IOP measured with Goldmann was 14 mm Hg OD and 16 mm Hg OS.

The anterior segment was remarkable for mild ocular rosacea and meibomian gland dysfunction in both eyes. The posterior segment was remarkable for nuclear sclerotic and cortical cataracts in both eyes. The right macula showed soft drusen without retinal pigment epithelium (RPE) hypertrophy. The left macula had mild soft drusen and mild, just visible, central macular thickening as observed by indirect +66 D slit lamp biomicroscopy. An OCT was obtained of the macula to determine the etiology of macular thickening.

OCT imaging revealed moderate drusen in the right eye but with normal macular thickness. The left eye had less severe drusen but with mild subretinal fluid with central thickening compared to the right eye. Amsler grid testing was performed prior to dilation, and the patient stated that both eyes were symmetric and stable compared to previous testing, without change.

What’s your diagnosis?
See answer on next page.

Given the history and present findings, the diagnosis is consistent with choroidal neovascularization (CNV) in wet macular degeneration in the left eye, which was confirmed with fluorescein angiography. More interesting than the diagnosis itself is that the patient was diagnosed with CNV so early in the course of conversion to wet AMD that she had no symptoms, which gives the best visual outcome for the patient.

Amanda S. Legge

So, how was this diagnosed so early, and what can be done in order to diagnose more patients this early in the course of CNV development in macular degeneration?

As stated in the history, the patient had a markedly delayed dark adaptation in each eye. She was a new patient to the clinic in May 2016 when mild drusen was noted in each eye. Her original macula OCT is shown.

Baseline macular OCT of the right eye in May 2016. Note that there are small drusen, but no evidence of choroidal neovascularization.

Because drusen of any size or number is a risk factor for AMD, at the initial visit dark adaptation testing was ordered. Dark adaptation is the only functional biomarker of AMD and can be used to diagnose the disease up to 3 years before drusen are present on clinical examination (Owsley et al., 2001). The longer the dark adaptation is delayed, the more advanced the disease of macular degeneration is. As the disease becomes more advanced, the patient is more at risk for developing choroidal neovascularization, which can be quickly visually devastating if the diagnosis is not promptly made.

During her initial work-up, the macular drusen were subtle and mild, but her dark adaptation was already significantly delayed, greater than 17.91 minutes OD and greater than 13.94 minutes OS. Normal patients should complete this test earlier than 6.5 minutes. In this patient’s case, both tests were terminated by the technician, as the patient had a recent neck sprain and it was difficult for her to test for that length of time. But it is clear that both are significantly delayed, and her stage of macular degeneration is much more advanced than is visible by clinical dilated examination alone.

Dark adaptation and AMD

Dark adaptation is impaired in AMD because, clinically, the macula encompasses the most posterior region of the retina within the vascular arcades and, as a whole, has significantly more rods than cones. Rod loss is the beginning of a continuum of AMD, as rods are affected earlier and more severely than cones throughout the progression of AMD. Only much later in the disease process are cones significantly affected, which correlates with a decrease in visual acuity.

AMD speeds up the rate of rod loss due to a deposition of cholesterol wash in Bruch’s membrane, which causes a depletion of nutrient supply to the outer retina, as well as inflammation and oxidative stress. Specific to dark adaptation, vitamin A has been proven to be functionally disrupted with the development of this abnormal cholesterol layer (Owsley, McGwin, Jackson, et al., 2006). Because vitamin A is a large molecule, its transport is impaired early in the disease process, thus causing the macula to have a localized vitamin A deficiency. As is well known, vitamin A deficiency causes poor dark adaptation (Hecht et al.). This is the underlying cause of decreased dark adaptation in even early or subclinical AMD.

Baseline macular OCT of the left eye in May 2016. Note that there are small drusen, but no evidence of choroidal neovascularization

What this shows is that AMD first manifests itself through impaired dark adaptation and, thus, dark adaptation can be used to identify patients with subclinical AMD before drusen are evident. Evaluating structure and function together provides improved diagnostic accuracy and the opportunity to treat the disease earlier than by use of clinical examination of structure alone.

Our practice has been utilizing the AdaptDx (Maculogix) since 2014. It is the only commercially available dark adaptometer that is useable in a clinic setting and is well proven to be 90% specific and sensitive to AMD (Jackson et al.). An abnormal dark adaptation, and especially a significantly abnormal dark adaptation, causes me great concern for worse disease than I can appreciate clinically. Therefore, any patient with a significantly delayed dark adaptation is monitored with dilated examination and appropriate testing every 3 to 4 months.

This patient’s management

This particular patient was recommended to start AREDS2 therapy in 2016 in addition to dilated fundus examinations every 4 months, which was changed to every 3 months when her drusen worsened in size and number in late 2017. In addition, the patient was counseled about lifestyle changes in 2016 including smoking cessation, weight loss and control of comorbid disorders like hypertension, diabetes and hypercholesterolemia; UV-blocking sunglasses outdoors; and healthy diet and exercise. She was also educated and uses the Amsler grid at home monocularly three to four times per week. She was well educated about the disease of AMD and the watchful waiting monitoring at close intervals with dilated examination to detect the earliest sign of choroidal neovascularization if she ever did convert to wet AMD in her lifetime.

Rod intercept time in this patient’s initial dark adaptation test in June 2016.

It was that series of events that was able to have the patient well educated about the disease early in its process and made the patient compliant with the recommended treatment regimen. In that way, she was monitored so closely that wet AMD was diagnosed when she still had excellent vision and was asymptomatic. Even her Amsler grid findings were subjectively stable.

This patient was monitoring herself at home with the Amsler grid monocularly several times per week. An alternative to monitor for metamorphopsia in patients with high risk for conversion to wet AMD is the Foresee Home device (Notal Vision), which is based on the visual skill of hyperacuity. Patients are recommended to use the automated device daily; monthly reports are delivered to the prescribing doctor to review. If a statistically significant change is noted, the doctor is immediately alerted to bring the patient to the office for a dilated fundus examination sooner than their routinely scheduled visit.

Research has shown that 94% of patients that converted to wet AMD using the ForeseeHome device retained better than 20/40 vision compared to only 62% of patients using conventional methods. Earlier detection leads to earlier intervention, which gives better long-term outcomes.

On follow-up 9 months after initiation of anti-VEGF therapy, the patient still maintains 20/25 vision in the eye with choroidal neovascularization, and we are monitoring her right eye carefully for conversion at this time as well. This is the ultimate goal for diagnosing and treating AMD as early as it can be detected. Earlier detection allows earlier treatment, which leads to better patient outcomes, which is obvious with this clinical case.

Disclosure: Legge reports she is on the AMD Speaker Alliance for MacuLogix.

A 71-year-old white female presented to the clinic in May 2018 for her periodic examination with no complaints. Systemic history included sinusitis and seasonal allergies. She reported taking no medications.

Kowa color photography of right and left macula. Note the presence of drusen in each eye.
Source: Amanda S. Legge, OD

Her ocular history was remarkable for symptomatic impaired dark adaptation. Clinical findings previously included small, soft drusen more marked in the right eye than the left, and age-appropriate nuclear sclerotic cataracts that were mildly visually significant. She was taking AREDS2 supplements as recommended.

Macular OCT of the right eye showing, in this cross-sectional view, large drusen consistent with the fundus observation.

This patient was diagnosed with AMD initially in 2016 when she presented to the clinic as a new patient with subtle drusen. This clinical finding prompted dark adaptation testing, which found that her rod intercept was significantly delayed for both eyes. Dark adaptation is the only biomarker for early AMD. Although her maculae had no severe signs of drusen in 2016, the patient was diagnosed with AMD and educated on lifestyle changes, smoking cessation, weight loss, comorbid disease control, UV protection, initiation of AREDS2 supplements, Amsler grid home screening and monitoring in-office with more frequent dilated examinations.

Over time, the patient’s rod intercept time on the dark adaptation curve continued to progress. This worsening functional deficit, along with worsening drusen appearance, prompted a more careful “watchful waiting” monitoring with dilated examinations recommended every 3 months.

Macular OCT of the left eye showing choroidal neovascular invasion into the sub-RPE and subretinal spaces.

On this examination now in May 2018, the patient’s best corrected visual acuities were 20/25-1 OD and 20/25+2 OS. IOP measured with Goldmann was 14 mm Hg OD and 16 mm Hg OS.

The anterior segment was remarkable for mild ocular rosacea and meibomian gland dysfunction in both eyes. The posterior segment was remarkable for nuclear sclerotic and cortical cataracts in both eyes. The right macula showed soft drusen without retinal pigment epithelium (RPE) hypertrophy. The left macula had mild soft drusen and mild, just visible, central macular thickening as observed by indirect +66 D slit lamp biomicroscopy. An OCT was obtained of the macula to determine the etiology of macular thickening.

OCT imaging revealed moderate drusen in the right eye but with normal macular thickness. The left eye had less severe drusen but with mild subretinal fluid with central thickening compared to the right eye. Amsler grid testing was performed prior to dilation, and the patient stated that both eyes were symmetric and stable compared to previous testing, without change.

What’s your diagnosis?
See answer on next page.

PAGE BREAK

Given the history and present findings, the diagnosis is consistent with choroidal neovascularization (CNV) in wet macular degeneration in the left eye, which was confirmed with fluorescein angiography. More interesting than the diagnosis itself is that the patient was diagnosed with CNV so early in the course of conversion to wet AMD that she had no symptoms, which gives the best visual outcome for the patient.

Amanda S. Legge

So, how was this diagnosed so early, and what can be done in order to diagnose more patients this early in the course of CNV development in macular degeneration?

As stated in the history, the patient had a markedly delayed dark adaptation in each eye. She was a new patient to the clinic in May 2016 when mild drusen was noted in each eye. Her original macula OCT is shown.

Baseline macular OCT of the right eye in May 2016. Note that there are small drusen, but no evidence of choroidal neovascularization.

Because drusen of any size or number is a risk factor for AMD, at the initial visit dark adaptation testing was ordered. Dark adaptation is the only functional biomarker of AMD and can be used to diagnose the disease up to 3 years before drusen are present on clinical examination (Owsley et al., 2001). The longer the dark adaptation is delayed, the more advanced the disease of macular degeneration is. As the disease becomes more advanced, the patient is more at risk for developing choroidal neovascularization, which can be quickly visually devastating if the diagnosis is not promptly made.

During her initial work-up, the macular drusen were subtle and mild, but her dark adaptation was already significantly delayed, greater than 17.91 minutes OD and greater than 13.94 minutes OS. Normal patients should complete this test earlier than 6.5 minutes. In this patient’s case, both tests were terminated by the technician, as the patient had a recent neck sprain and it was difficult for her to test for that length of time. But it is clear that both are significantly delayed, and her stage of macular degeneration is much more advanced than is visible by clinical dilated examination alone.

Dark adaptation and AMD

Dark adaptation is impaired in AMD because, clinically, the macula encompasses the most posterior region of the retina within the vascular arcades and, as a whole, has significantly more rods than cones. Rod loss is the beginning of a continuum of AMD, as rods are affected earlier and more severely than cones throughout the progression of AMD. Only much later in the disease process are cones significantly affected, which correlates with a decrease in visual acuity.

PAGE BREAK

AMD speeds up the rate of rod loss due to a deposition of cholesterol wash in Bruch’s membrane, which causes a depletion of nutrient supply to the outer retina, as well as inflammation and oxidative stress. Specific to dark adaptation, vitamin A has been proven to be functionally disrupted with the development of this abnormal cholesterol layer (Owsley, McGwin, Jackson, et al., 2006). Because vitamin A is a large molecule, its transport is impaired early in the disease process, thus causing the macula to have a localized vitamin A deficiency. As is well known, vitamin A deficiency causes poor dark adaptation (Hecht et al.). This is the underlying cause of decreased dark adaptation in even early or subclinical AMD.

Baseline macular OCT of the left eye in May 2016. Note that there are small drusen, but no evidence of choroidal neovascularization

What this shows is that AMD first manifests itself through impaired dark adaptation and, thus, dark adaptation can be used to identify patients with subclinical AMD before drusen are evident. Evaluating structure and function together provides improved diagnostic accuracy and the opportunity to treat the disease earlier than by use of clinical examination of structure alone.

Our practice has been utilizing the AdaptDx (Maculogix) since 2014. It is the only commercially available dark adaptometer that is useable in a clinic setting and is well proven to be 90% specific and sensitive to AMD (Jackson et al.). An abnormal dark adaptation, and especially a significantly abnormal dark adaptation, causes me great concern for worse disease than I can appreciate clinically. Therefore, any patient with a significantly delayed dark adaptation is monitored with dilated examination and appropriate testing every 3 to 4 months.

This patient’s management

This particular patient was recommended to start AREDS2 therapy in 2016 in addition to dilated fundus examinations every 4 months, which was changed to every 3 months when her drusen worsened in size and number in late 2017. In addition, the patient was counseled about lifestyle changes in 2016 including smoking cessation, weight loss and control of comorbid disorders like hypertension, diabetes and hypercholesterolemia; UV-blocking sunglasses outdoors; and healthy diet and exercise. She was also educated and uses the Amsler grid at home monocularly three to four times per week. She was well educated about the disease of AMD and the watchful waiting monitoring at close intervals with dilated examination to detect the earliest sign of choroidal neovascularization if she ever did convert to wet AMD in her lifetime.

PAGE BREAK
Rod intercept time in this patient’s initial dark adaptation test in June 2016.

It was that series of events that was able to have the patient well educated about the disease early in its process and made the patient compliant with the recommended treatment regimen. In that way, she was monitored so closely that wet AMD was diagnosed when she still had excellent vision and was asymptomatic. Even her Amsler grid findings were subjectively stable.

This patient was monitoring herself at home with the Amsler grid monocularly several times per week. An alternative to monitor for metamorphopsia in patients with high risk for conversion to wet AMD is the Foresee Home device (Notal Vision), which is based on the visual skill of hyperacuity. Patients are recommended to use the automated device daily; monthly reports are delivered to the prescribing doctor to review. If a statistically significant change is noted, the doctor is immediately alerted to bring the patient to the office for a dilated fundus examination sooner than their routinely scheduled visit.

Research has shown that 94% of patients that converted to wet AMD using the ForeseeHome device retained better than 20/40 vision compared to only 62% of patients using conventional methods. Earlier detection leads to earlier intervention, which gives better long-term outcomes.

On follow-up 9 months after initiation of anti-VEGF therapy, the patient still maintains 20/25 vision in the eye with choroidal neovascularization, and we are monitoring her right eye carefully for conversion at this time as well. This is the ultimate goal for diagnosing and treating AMD as early as it can be detected. Earlier detection allows earlier treatment, which leads to better patient outcomes, which is obvious with this clinical case.

Disclosure: Legge reports she is on the AMD Speaker Alliance for MacuLogix.