age - related maculopathy ( arm ) , also known as age - related macular degeneration , affects approximately 30 million people worldwide . in the united states ,
there are an estimated 13 million people with some vision loss from arm , including two million with the most severe late - stage of the disease .
fortunately , there are an increasing number of effective treatments for late - stage disease , such as pegaptabnib ( macugen ; pfizer ) and ranibizumab ( lucentis ; genetech ) . however , treatment of advanced arm often results in less than optimal patient outcomes because moderate to severe irreversible vision loss has already occurred before stabilization .
the treatment of the disease in its earliest stages is the best strategy to preserve the patient s vision , which may be only mildly disturbed as measured by high contrast visual acuity measured under high luminance conditions .
the disease s slow progression hampers the feasibility of clinical trials because currently accepted endpoints of acuity and fundus appearance are relatively insensitive to the disease s progression through its earliest stages .
these endpoints require clinical trials to have large sample sizes or long follow - up durations to evaluate efficacy of a potential treatment .
clinical trials evaluating early treatments are impractical because of the constraints current endpoints impose on trial design .
while patients with early arm typically have good best - corrected visual acuity , impaired night vision is a prominent self - reported problem [ 13 ] .
anatomical studies of donor eyes have documented significant rod dysfunction and photoreceptor drop out in comparison to cone photoreceptors .
histopathological studies have found arm - related lesions in the rpe and bruch s membrane , which are generally invisible to clinical inspection [ 5 , 6 ] .
not surprisingly , these insults to the photoreceptors and the rpe , which supports the photoreceptors , disrupt vision .
early arm patients exhibit moderate to severe impairment of rod - mediated dark adaptation and scotopic visual sensitivity even in the absence of visual acuity loss [ 7 , 8 ] .
rod - mediated dark adaptation appears to be more impaired in early arm patients than photopic visual sensitivity , scotopic visual sensitivity , acuity , and contrast sensitivity .
advanced arm patients exhibit impaired cone - mediated dark adaptation [ 912 ] and early arm patients exhibit photostress impairment [ 13 , 14 ]
. however , rod - mediated dark adaptation appears to be more affected than cone - mediated dark adaptation at least outside the fovea in early arm patients .
rod - mediated dark adaptation impairment is modestly reversible with vitamin a supplementation , whereas cone - mediated dark adaptation impairment is not .
a pilot retrospective study suggests that the rod - mediated dark adaptation impairment is detectable at least 4  years before the lesions associated with the disease are clinically apparent ( unpublished data ) .
these findings suggest that dark adaptation impairment is a sensitive marker of early arm and raises the possibility that it may used to predict progression .
the utility of dark adaptometry as a clinical outcome measure or practical diagnostic tool is hampered by a long test duration , high participant burden , and lack of standardized dark adaptometers .
dark adaptation protocols used in prior research require up to 90  minutes , and typically more than 100 threshold estimates are made . the long duration and number of thresholds measurements
the goal of this study was to develop a short - duration dark adaptation protocol that minimized patient fatigue , increased operator ease of use , and maintained the high sensitivity and specificity of research protocols .
the protocol evaluated in this study has three distinct differences compared with prior research protocols : ( 1 ) the bleaching light intensity was significantly reduced to shorten the duration necessary to measure sensitivity recovery ; ( 2 ) the stimulus was located within the area of greatest rod dysfunction to enhance the sensitivity of the test for detection of early disease ; and ( 3 ) the speed of dark adaptation was estimated using a parameter that is robust to the shape of the dark adaptation function , which can be variable with disease severity .
this protocol was implemented using a new dark adaptometer , the adaptdx , developed in collaboration with apeliotus technologies , inc .
the institutional review board of the university of alabama at birmingham approved this study . written informed consent
was obtained from all participants after the nature and possible consequences of the study were explained .
normal adults and early to intermediate arm patients were recruited from the comprehensive ophthalmology and retina services of the department of ophthalmology , university of alabama at birmingham .
inclusion criteria were as follows : ( 1 ) participants were 20 to 45  years old for the young normal group and participants were at least 55  years of age for the old normal and arm groups ; and ( 2 ) best - corrected distance visual acuity of 20/100 or better in at least one eye .
if both eyes qualified , the eye with the better acuity was enrolled as the test eye .
if the acuities were the same , the right eye was enrolled as the test eye .
exclusion criteria were as follows : ( 1 ) medical record or a general health interview indication of glaucoma , optic neuropathy or any ocular conditions other than arm , or refractive error ( spherical equivalent ) having an absolute value > 6 diopters ; ( 2 ) neurological diseases such as alzheimer s disease , parkinson s disease , history of stroke or multiple sclerosis ; ( 3 ) diabetes ; and/or ( 4 ) inability to perform the psychophysical task used to measure dark adaptation .
best - corrected distance visual acuity was measured for each eye using the edtrs chart and expressed as logmar .
the patient s test eye is dilated to 6  mm diameter , and corrective lenses are introduced as appropriate for the 30-cm viewing distance to correct for blur .
an infrared camera located behind the fixation light continuously monitors the patient s test eye and displays an image of the eye on a personal computer - based operator control screen .
the operator centers the patient s test eye to the red fixation light with the help of a reticule displayed on the image of the eye .
the patient s test eye is bleached by exposure to a photoflash ( 0.25  ms duration , 6.38 log scot td second intensity ) while the patient is focused on the fixation light .
the flash of light passes through a diffuser and 4-diameter aperture centered at 5 on the inferior visual meridian to provide a uniform focal bleach surrounding the area to be tested during sensitivity recovery measurements .
the patient focuses on the fixation light , and responds that a stimulus light is present by pushing a button .
the stimulus light is a 1.7 circular test spot located at 5 on the inferior visual meridian . to focus on rod - mediated function ,
a stimulus wavelength of 500  nm was used , which is near the peak of rod sensitivity .
sensitivity is estimated using a three - down / one - up modified staircase threshold estimate procedure .
starting at a relatively high intensity ( 5.00  cd / m ) , stimulus lights are presented every two or three seconds for a 200-ms duration .
if the patient does not respond within 2 seconds of stimulus onset , the stimulus light intensity remains unchanged on successive stimulus presentations until the patient responds .
if the patient indicates that the stimulus is visible , the intensity is decreased for each successive presentation in steps of 0.3 log units until the patient stops responding that the stimulus is visible . after the patient indicates that the stimulus light is invisible by not pressing the button
while the stimulus light is present , the intensity of the target is increased for each successive presentation in 0.1 log unit steps until the patient responds that the stimulus light is once again visible .
successive threshold measurements start with the stimulus intensity 0.2 log units brighter than the previous threshold measurement .
threshold measurements are made about once a minute for the duration of the measurement protocol ; thus about 20 threshold measurements are made during the 20-minute test . 

the bleaching light ( not shown ) is presented through an aperture co - localized with the stimulus light the patient s view of the adaptdx . the bleaching light ( not shown )
is presented through an aperture co - localized with the stimulus light because arm patients can exhibit several differently shaped dark adaptation functions , the  rod intercept  ,
the rod intercept is the amount of time after bleach offset required for the patient s sensitivity to recover to a stimulus intensity of 5    10 cd / m ( i.e. ; 4.0 log units ) .
this light level was chosen because it typically is achieved late in the second component of rod - mediated dark adaptation and is therefore completely mediated by rod function .
each subject s dark adaptation function is plotted and the rod intercept is estimated by linear interpolation .
patients with normal rod recovery will have shorter rod intercepts than those with impaired dark adaptation .
stereoscopic 30 photographs were taken with a ff450 plus zeiss fundus camera for all participants more than 54  years old .
photographs were evaluated using the age - related eye disease study ( areds ) severity scale for age - related macular degeneration   by two independent graders who were masked to the clinical and functional characteristics of the participants .
group assignment to normal or arm was based on the areds severity score of the test eye .
these steps are indicative of normal ( step 1 ) , borderline arm ( our terminology ) ( step 2 ) , early arm ( steps 36 ) , intermediate arm ( steps 79 ) , and advanced arm ( steps 10 and 11 ) .
the study population consisted of eight normal young adults ( mean age  =  32.6  years old ) , nine normal old adults ( mean age  =  73.1  years old ) and 17 arm patients ( mean age  =  75.1  years old ) .
the old normal and arm groups had similar ages ( p  =  0.42 ) and test eye acuities ( p  =  0.14 ) ( table  1 ) .
fellow eye acuity was higher on average for old normal adults than arm patients ( p  =  0.01 ) .
arm patients exhibited substantially slower dark adaptation compared with normal old adults ; whereas the dark adaptation speed was essentially the same for the young and old normal participants .
representative dark adaptation functions for a young normal adult , an early arm patient and an intermediate arm patient are shown in fig .  2 .
the rod intercept for arm patients ( mean  =  17.20  min , sd  =  3.8 ) was on average twice as long as the rod intercept for normal old adults ( mean  =  8.73  min , sd  =  1.9 ) ( p  <  0.0001 ) .
nine of the 17 arm patients failed to obtain the criterion sensitivity within the 20-minute protocol , and were assigned a rod intercept of 20  min ; thus the substantial difference between these averages actually understates the relative impairment between the two groups .
the rod intercept for normal young adults ( mean  =  8.2  min , sd  =  1.4 ) was statistically indistinguishable from normal old adults ( p  =  0.76 ) . 

2representative dark adaptation curves of a normal adult ( closed circles ) , early arm patient ( open triangles ) , and intermediate arm patient ( open circles)table  1participant demographics  young normal ( n  =  8)old normal ( n  =  9)arm ( n  =  17)age ( years ) , mean ( sd)32.6 ( 5.3)73.1 ( 4.8)75.1 ( 6.4)gender , % ( n)female100 ( 8)66.7 ( 6)52.9 ( 9)male0 ( 0)33.3 ( 3)47.1 ( 8)race , % ( n)white62.5 ( 5)88.9 ( 8)100 ( 17)african american25.0 ( 2)11.1 ( 1)0 ( 0)asian12.5 ( 1)0 ( 0)0 ( 0)visual acuity , logmar mean ( sd)tested eye.02 ( 0.4).04 ( .12).14 ( .19)fellow eye.05 ( 0.1).14 ( .21).52 ( .40 ) representative dark adaptation curves of a normal adult ( closed circles ) , early arm patient ( open triangles ) , and intermediate arm patient ( open circles ) participant demographics each subject s dark adaptation was classified as normal or impaired based whether the participant s speed of dark adaptation as measured by the rod intercept fell within the normal reference range ( mean  2  sd ) of the normal old adults . the upper limit of the normal reference range was 12.5  minutes . individuals with rod intercepts
participants with a rod intercept 12.5 were classified as having normal dark adaptation . using this criterion , 15 of the 17 arm patients
all nine normal adults fell within the normal reference range for a diagnostic specificity of 100% .
the sensitivity and specificity of our 20-minute study protocol compares favorably to that of a previously used 90-minute research protocol ( 85% sensitivity ; 100% specificity ) , despite the considerable shortening of the test .
furthermore , it is useful to examine the two false negative results ( those arm patients classified with normal dark adaptation ) . both were for participants with an areds fundus grade of 2 .
one of these patients exhibited three drusen of 63  m scattered throughout the central 3,000  m of the macula .
the sensitivity of the test is 100% for those arm patients with an areds grade 3 and higher .
the rod intercept for borderline arm patients ( areds fundus grade 2 ) was , on average , 5.1  minutes slower than the normal old adult s rod intercept .
the rod intercept for early arm patients ( areds fundus grades 3 to 5 ) was , on average , yet another 3.4  minutes slower than borderline arm patients . finally , all of the intermediate and late arm patients ( areds fundus grades  6 ) failed to reach the rod intercept within the 20-minute test time . 

table  2dark adaptation impairment increased with disease severity  young normalold normalborderline armearly armintermediate armadvanced armsample size895651areds fundus graden / a123,4,56,7,8,910rod intercept , min mean ( sd)8.2 ( 1.4)8.7 ( 1.9)13.8 ( 4.4)17.2 ( 2.7)20 ( ) 20 ( ) fundus photography and grading was not performed on young normal group.all subjects failed to reach the rod intercept within the 20-minute test duration .
dark adaptation impairment increased with disease severity fundus photography and grading was not performed on young normal group .
using a 20-minute , rod - mediated dark adaptation protocol , arm patients exhibited a dramatic slowing of dark adaptation in comparison with normal old adults .
the magnitude of the impairment was similar to that previously measured using a 90-minute research protocol . as expected , reducing the bleaching light shortened the duration of the test , and moving the stimulus to an area of greater rod dysfunction preserved the sensitivity and specificity of the protocol .
the magnitude of the dark adaptation impairment exhibited by early arm patients suggests that a rapid diagnostic screening test having a duration of less than 10  minutes is feasible .
retest reliability was found to be quite high ( intraclass r  =  0.95 ) in a separate , preliminary study of 40 normal adults and arm patients ( data not shown ) .
perhaps more intriguing , the increase in the amount of rod - mediated dark adaptation impairment with increasing disease severity as assessed by the areds severity system for arm allows the possibility of using dark adaptation as a clinical outcome measure .
previously , we evaluated another short - duration protocol developed for the sst-1 dark adaptometer ( lkc technologies , inc ) for the detection of early arm .
the sst-1 is a manual dark adaptometer that uses an abbreviated protocol , typically 20 to 30  minutes .
the adaptdx and the sst-1 exhibit markedly different response characteristics . whereas the adaptdx shows no difference with aging but is highly sensitive to arm , the sst-1 discriminates aging effects but is insensitive to arm .
an important difference between the protocols is that the sst-1 measures the sensitivity recovery of the entire retina , instead of just the macula or a portion of the macula .
we have developed a short duration protocol that can sensitively and specifically detect early arm .
the impaired night vision encountered in early arm is a clinically significant problem similar to acuity impairment encountered in late arm . as such
, we believe dark adaptation is a suitable primary endpoint to evaluate efficacy of treatments aimed at early arm .
 dark adaptometry may be a useful diagnostic test and clinical trial endpoint for age - related maculopathy ( arm ) because impaired night vision is a hallmark of early arm . 
 a novel dark adaptometer , the adaptdx , was evaluated for the detection of arm . 
 the adaptdx incorporates a 20-minute protocol optimized for the detection of arm . 
 arm patients ( n  =  17 ) exhibited substantial dark adaptation impairment compared with normal adults ( n  =  17 ) . 
 the diagnostic sensitivity was 88% and the specificity was 100% . 
 the diagnostic test characteristics of the adaptdx are similar to previously reported studies using 60- to 120-minute protocols . 