Dysflective cones: Visual function and cone reflectivity in long-term follow-up of acute bilateral foveolitis.

PURPOSE:Confocal adaptive optics scanning laser ophthalmoscope (AOSLO) images provide a sensitive measure of cone structure. However, the relationship between structural findings of diminished cone reflectivity and visual function is unclear. We used fundus-referenced testing to evaluate visual function in regions of apparent cone loss identified using confocal AOSLO images. METHODS:A patient diagnosed with acute bilateral foveolitis had spectral-domain optical coherence tomography (SD-OCT) (Spectralis HRA + OCT system [Heidelberg Engineering, Vista, CA, USA]) images indicating focal loss of the inner segment-outer segment junction band with an intact, but hyper-reflective, external limiting membrane. Five years after symptom onset, visual acuity had improved from 20/80 to 20/25, but the retinal appearance remained unchanged compared to 3 months after symptoms began. We performed structural assessments using SD-OCT, directional OCT (non-standard use of a prototype on loan from Carl Zeiss Meditec) and AOSLO (custom-built system). We also administered fundus-referenced functional tests in the region of apparent cone loss, including analysis of preferred retinal locus (PRL), AOSLO acuity, and microperimetry with tracking SLO (TSLO) (prototype system). To determine AOSLO-corrected visual acuity, the scanning laser was modulated with a tumbling E consistent with 20/30 visual acuity. Visual sensitivity was assessed in and around the lesion using TSLO microperimetry. Complete eye examination, including standard measures of best-corrected visual acuity, visual field tests, color fundus photos, and fundus auto-fluorescence were also performed. RESULTS:Despite a lack of visible cone profiles in the foveal lesion, fundus-referenced vision testing demonstrated visual function within the lesion consistent with cone function. The PRL was within the lesion of apparent cone loss at the fovea. AOSLO visual acuity tests were abnormal, but measurable: for trials in which the stimulus remained completely within the lesion, the subject got 48% correct, compared to 78% correct when the stimulus was outside the lesion. TSLO microperimetry revealed reduced, but detectible, sensitivity thresholds within the lesion. CONCLUSIONS AND IMPORTANCE:Fundus-referenced visual testing proved useful to identify functional cones despite apparent photoreceptor loss identified using AOSLO and SD-OCT. While AOSLO and SD-OCT appear to be sensitive for the detection of abnormal or absent photoreceptors, changes in photoreceptors that are identified with these imaging tools do not correlate completely with visual function in every patient. Fundus-referenced vision testing is a useful tool to indicate the presence of cones that may be amenable to recovery or response to experimental therapies despite not being visible on confocal AOSLO or SD-OCT images

Repeatability of Cone Spacing Measures in Eyes With Inherited Retinal Degenerations

PURPOSE. To determine short-term variability of adaptive optics scanning laser ophthalmoscopy (AOSLO)-derived cone spacing measures in eyes with inherited retinal degenerations (IRD) and in normal eyes. METHODS. Twenty IRD patients and 10 visually normal subjects underwent AOSLO imaging at two visits separated by no more than 1 month (NCT00254605). Cone spacing was measured in multiple macular regions in each image by three independent graders. Variability of cone spacing measures between visits, between graders, and between eyes was determined and correlated with standard clinical measures. RESULTS. Cone spacing was measured in 2905 regions. Interobserver agreement was high both in normal eyes and eyes with IRD (mean intraclass correlation coefficient [ICC] ¼ 0.838 for normal and 0.892 for eyes with IRD). Cone spacing measures were closely correlated between visits (ICC > 0.869 for both study groups). Mean relative intervisit spacing difference (absolute difference in measures divided by the mean at each region) was 4.0% for normal eyes and 4.9% for eyes with IRD. Cone spacing measures from fellow eyes of the same subject showed strong agreement for all subjects (ICC > 0.85 for both study groups). CONCLUSIONS. Adaptive optics scanning laser ophthalmoscopy-derived macular cone spacing measures were correlated between observers, visits, and fellow eyes of the same subject in normal eyes and in eyes with IRD. This information may help establish the role of cone spacing measures derived from images of the cone mosaic obtained with AOSLO as a sensitive biomarker for longitudinal tracking of photoreceptor loss during disease progression and in response to treatment. (ClinicalTrials.gov number, NCT00254605.

Heterogeneous patterns of tissue injury in NARP syndrome

Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual–spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss

Calibrating ADL-IADL scales to improve measurement accuracy and to extend the disability construct into the preclinical range: a systematic review

<p>Abstract</p> <p>Background</p> <p>Interest in measuring functional status among nondisabled older adults has increased in recent years. This is, in part, due to the notion that adults identified as 'high risk' for functional decline portray a state that is potentially easier to reverse than overt disability. Assessing relatively healthy older adults with traditional self-report measures (activities of daily living) has proven difficult because these instruments were initially developed for institutionalised older adults. Perhaps less evident, are problems associated with change scores and the potential for 'construct under-representation', which reflects the exclusion of important features of the construct (e.g., disability). Furthermore, establishing a formal hierarchy of functional status tells more than the typical simple summation of functional loss, and may have predictive value to the clinician monitoring older adults: if the sequence task difficulty is accelerated or out of order it may indicate the need for interventions.</p> <p>Methods</p> <p>This review identified studies that employed item response theory (IRT) to examine or revise functional status scales. IRT can be used to transform the ordinal nature of functional status scales to interval level data, which serves to increase diagnostic precision and sensitivity to clinical change. Furthermore, IRT can be used to rank items unequivocally along a hierarchy based on difficulty. It should be noted that this review is not concerned with contrasting IRT with more traditional classical test theory methodology.</p> <p>Results</p> <p>A systematic search of four databases (PubMed, Embase, CINAHL, and PsychInfo) resulted in the review of 2,192 manuscripts. Of these manuscripts, twelve met our inclusion/exclusion requirements and thus were targeted for further inspection.</p> <p>Conclusions</p> <p>Manuscripts presented in this review appear to summarise gerontology's best efforts to improve construct validity and content validity (i.e., ceiling effects) for scales measuring the early stages of activity restriction in community-dwelling older adults. Several scales in this review were exceptional at reducing ceiling effects, reducing gaps in coverage along the construct, as well as establishing a formal hierarchy of functional decline. These instrument modifications make it plausible to detect minor changes in difficulty for IADL items positioned at the edge of the disability continuum, which can be used to signal the onset of progressive type disability in older adults.</p

Revealing Henle's Fiber Layer Using Spectral Domain Optical Coherence Tomography

By positioning the spectral domain optical coherence tomography (SD-OCT) entrance beam away from the center of the pupil, the authors are able to directly visualize Henle's fiber layer, which contains the axons of macular photoreceptors. They present an optical model of this phenomenon and demonstrate its importance for accurately measuring outer nuclear layer thickness and for interpreting SD-OCT images containing macular pathology

Cone Structure Imaged With Adaptive Optics Scanning Laser Ophthalmoscopy in Eyes With Nonneovascular Age-Related Macular DegenerationAOSLO in Eyes With Nonneovacular AMD

PurposeTo evaluate cone spacing using adaptive optics scanning laser ophthalmoscopy (AOSLO) in eyes with nonneovascular AMD, and to correlate progression of AOSLO-derived cone measures with standard measures of macular structure.MethodsAdaptive optics scanning laser ophthalmoscopy images were obtained over 12 to 21 months from seven patients with AMD including four eyes with geographic atrophy (GA) and four eyes with drusen. Adaptive optics scanning laser ophthalmoscopy images were overlaid with color, infrared, and autofluorescence fundus photographs and spectral domain optical coherence tomography (SD-OCT) images to allow direct correlation of cone parameters with macular structure. Cone spacing was measured for each visit in selected regions including areas over drusen (n = 29), at GA margins (n = 14), and regions without drusen or GA (n = 13) and compared with normal, age-similar values.ResultsAdaptive optics scanning laser ophthalmoscopy imaging revealed continuous cone mosaics up to the GA edge and overlying drusen, although reduced cone reflectivity often resulted in hyporeflective AOSLO signals at these locations. Baseline cone spacing measures were normal in 13/13 unaffected regions, 26/28 drusen regions, and 12/14 GA margin regions. Although standard clinical measures showed progression of GA in all study eyes, cone spacing remained within normal ranges in most drusen regions and all GA margin regions.ConclusionsAdaptive optics scanning laser ophthalmoscopy provides adequate resolution for quantitative measurement of cone spacing at the margin of GA and over drusen in eyes with AMD. Although cone spacing was often normal at baseline and remained normal over time, these regions showed focal areas of decreased cone reflectivity. These findings may provide insight into the pathophysiology of AMD progression. (ClinicalTrials.gov number, NCT00254605)

Comparing Cone Structure and Function in RHO- and RPGR-Associated Retinitis Pigmentosa.

Purpose:To study cone structure and function in patients with retinitis pigmentosa (RP) owing to mutations in rhodopsin (RHO), expressed in rod outer segments, and mutations in the RP-GTPase regulator (RPGR) gene, expressed in the connecting cilium of rods and cones. Methods:Four eyes of 4 patients with RHO mutations, 5 eyes of 5 patients with RPGR mutations, and 4 eyes of 4 normal subjects were studied. Cone structure was studied with confocal and split-detector adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral-domain optical coherence tomography. Retinal function was measured using a 543-nm AOSLO-mediated adaptive optics microperimetry (AOMP) stimulus. The ratio of sensitivity to cone density was compared between groups using the Wilcoxon rank-sum test. Results:AOMP sensitivity/cone density in patients with RPGR mutations was significantly lower than normal (P &lt; 0.001) and lower than patients with RHO mutations (P &lt; 0.015), whereas patients with RHO mutations were similar to normal (P &gt; 0.9). Conclusions:Retinal sensitivity/cone density was lower in patients with RPGR mutations than normal and lower than patients with RHO mutations, perhaps because cones express RPGR and degenerate primarily, whereas cones in eyes with RHO mutations die secondary to rod degeneration. High-resolution microperimetry can reveal differences in cone degeneration in patients with different forms of RP

Comparing Cone Structure and Function in RHO- and RPGR-Associated Retinitis Pigmentosa.

Purpose:To study cone structure and function in patients with retinitis pigmentosa (RP) owing to mutations in rhodopsin (RHO), expressed in rod outer segments, and mutations in the RP-GTPase regulator (RPGR) gene, expressed in the connecting cilium of rods and cones. Methods:Four eyes of 4 patients with RHO mutations, 5 eyes of 5 patients with RPGR mutations, and 4 eyes of 4 normal subjects were studied. Cone structure was studied with confocal and split-detector adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral-domain optical coherence tomography. Retinal function was measured using a 543-nm AOSLO-mediated adaptive optics microperimetry (AOMP) stimulus. The ratio of sensitivity to cone density was compared between groups using the Wilcoxon rank-sum test. Results:AOMP sensitivity/cone density in patients with RPGR mutations was significantly lower than normal (P &lt; 0.001) and lower than patients with RHO mutations (P &lt; 0.015), whereas patients with RHO mutations were similar to normal (P &gt; 0.9). Conclusions:Retinal sensitivity/cone density was lower in patients with RPGR mutations than normal and lower than patients with RHO mutations, perhaps because cones express RPGR and degenerate primarily, whereas cones in eyes with RHO mutations die secondary to rod degeneration. High-resolution microperimetry can reveal differences in cone degeneration in patients with different forms of RP