Search

Purpose: To investigate the clinical and molecular genetic features of childhood-onset Leber hereditary optic neuropathy (LHON) to gain a better understanding of the factors influencing the visual outcome in this atypical form of the disease., Design: Retrospective cohort study., Methods: We retrospectively included 2 cohorts of patients with LHON with onset of visual loss before the age of 12 years from Italy and the United Kingdom. Ophthalmologic evaluation, including best-corrected visual acuity, orthoptic evaluation, slit-lamp biomicroscopy, visual field testing, and optical coherence tomography, was considered. Patients were classified based on both the age of onset and the pattern of visual loss., Results: A total of 68 patients were stratified based on the age of onset of visual loss: group 1 (<3 years): 14 patients (20.6%); group 2 (≥3 to <9 years): 27 patients (39.7%); and group 3 (≥9 to ≤12 years): 27 patients (39.7%). Patients in group 2 achieved a better visual outcome than those in group 3. Patients in groups 1 and 2 had better mean deviation on visual field testing than those in group 3. The mean ganglion cell layer thickness on optical coherence tomography in group 2 was higher than those in groups 1 and 3. Patients were also categorized based on the pattern of visual loss as follows: Subacute Bilateral: 54 patients (66.7%); Insidious Bilateral: 14 patients (17.3%); Unilateral: 9 patients (11.1%); and Subclinical Bilateral: 4 patients (4.9%)., Conclusions: Children who lose vision from LHON before the age of 9 years have a better visual prognosis than those who become affected in later years, likely representing a "form frustre" of the disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the safety profile of lenadogene nolparvovec (Lumevoq) in patients with Leber hereditary optic neuropathy., Design: Pooled analysis of safety data from 5 clinical studies., Methods: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination, and systemic immune responses against rAAV2/2., Results: Almost all patients (95.2%) received 9 × 10 10 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients; none were serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%), and were of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally., Conclusions: Lenadogene nolparvovec had a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this retrospective, interventional, longitudinal small case series, we looked at the visual effects of pharmacologic intervention with 4-aminopyridine (4-AP) in chronic Leber's Hereditary Optic Neuropathy (LHON) patients who are non-responders to idebenone. We illustrate, as examples, the visual progression of three LHON patients with 4-AP as add-on therapy to idebenone. Each patient had a different primary LHON mutation and was treated with idebenone within one year of onset. No response to idebenone at 300 mg orally three times a day ranged from less than one year to 2.5 years, and the addition of 4-AP at 10 mg orally two times a day ranged from 24 to 29 months. Outcome measures included best-corrected distance visual acuity, color vision, automated perimetry, the average retinal nerve fiber layer (RNFL) thickness, and the full-field photopic negative response (PhNR) amplitude. The 19-year-old man with the LHON mutation 11778A > G had no response to the addition of 4-AP to idebenone. The 27-year-old man with the LHON mutation 3460A > G experienced a significant response to 4-AP. Finally, the 40-year-old man with the LHON mutation 14484 T > C had a milder response. Although this case series was too small to demonstrate the efficacy of idebenone with add-on 4AP, it allowed us to consider a new hypothesis that neuronal activity generated from 4-AP can add more potential for visual recovery in LHON patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing both to image and non-image-forming (NIF) functions of the eye. They convey light signal to the brain to modulate circadian entrainment, sleep, alertness, cognition, brightness perception and coarse vision. Given that rods and cones also contribute to all these impacts of light, isolating mRGC visual and NIF roles in humans is challenging so that mRGC functions remains to be fully characterized. Here, we evaluated light-driven visual and cognitive brain responses in Leber's Hereditary Optic Neuropathy (LHON), an inherited optic neuropathy that is characterized by a selective relative sparing of the melanopsin-expressing retinal ganglion cells (mRGCs). Twelve patients and twelve matched healthy controls (HC) were enrolled in a functional brain magnetic resonance imaging (fMRI) protocol including visual and visual-cognitive paradigms under blue (480 nm) and red (620 nm) light exposures. Primary visual cortex activation was detected in LHON patients; in particular higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with the relative mRGC sparing demonstrated in LHON and support the mRGC contribution to both non-visual and visual brain functions, with potential implication for visual rehabilitation in hereditary optic neuropathy patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues., Cases Presentation: The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris. The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI., Discussion: Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity., Conclusion: The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features., (Copyright © 2021 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Purpose: Patients afflicted with clinically significant vitreous floaters suffer from vision-degrading myodesopsia, characterized by impairment in contrast sensitivity function (CSF) and decreased quality of life. This study determined the cost-effectiveness of limited vitrectomy for this condition., Design: Retrospective, interventional case series and third-party insurer cost-utility analysis., Methods: Sixty-seven patients suffering from unilateral vitreous floaters (20 non-myopic patients with posterior vitreous detachment [PVD]; 17 myopic patients [>-2 diopters] without PVD; 30 myopic patients with PVD) completed the National Eye Institute Visual Function Questionnaire (VFQ-39) and were tested with best-corrected visual acuity (BCVA) and CSF measurements before and after limited vitrectomy. A reference case cost-utility analysis was performed., Results: The mean VFQ-39 increased 19% (P < 0.00001) after surgery, with general vision improving 27% for the entire group and 37% for non-myopic PVD (P < 0.00001 for each). VFQ-39 correlations with time tradeoff utilities indicated a 14.4% improvement in quality of life. Mean BCVA improved 13.5% postoperatively (P < 0.00001) and CSF improved 53% (P < 0.00001). The incremental patient value gain conferred by limited vitrectomy was 2.38 quality-adjusted life-years (QALYs), and the average cost-utility ratio in 2018 U.S. real dollars was $1,574/QALY., Conclusions: Limited vitrectomy for vision-degrading myodesopsia is clinically effective, in that it improves BCVA, CSF, and patient well-being. It is also highly cost-effective ($1,574/QALY), with an average cost-utility ratio vs. no therapy that is superior to cataract surgery ($2,262/QALY), amblyopia therapy ($2,710/QALY), and retinal detachment repair ($45,304/QALY). Myopic patients without PVD had the lowest cost-utility ratio of all ($1,338/QALY)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To study the macular microvascular networks in patients affected by chronic Leber hereditary optic neuropathy (LHON) using optical coherence tomography angiography (OCTA), and to quantify these changes in different macular sectors., Design: Prospective cross-sectional study., Methods: Patients with a clinical and molecularly confirmed diagnosis of LHON (affected patients in the chronic stage) were enrolled from the neuro-ophthalmology clinic at the Doheny-UCLA. Patients and controls underwent a complete ophthalmologic evaluation, including imaging with OCTA., Results: Twenty-nine eyes from 15 LHON patients (14 male) and 20 eyes from 20 healthy subjects (13 male) were included in the analysis. Mean age was 32.0 ± 14.2 years (range 16-49 years) in the LHON group and 34.2 ± 10.1 years (range 23-48 years) in the control group (P = .552). In the parafoveal region, the vessel length density was lower in LHON patients, at both the SCP (9.1% ± 0.5% and 9.3% ± 0.4%, P = .041) and DCP (9.4% ± 0.5% and 9.8% ± 0.3%, P = .008) levels. In the sectorial analysis, vascular changes remained significant only in the parafoveal nasal and inferior regions. Univariate linear regression analysis demonstrated that the strongest associations with visual acuity were with parafoveal SCP perfusion density (R 2  = .276, P = .045) and parafoveal SCP vessel length density (R 2  = .277, P = .044)., Conclusions: LHON eyes have SCP and DCP changes that are mainly confined to the nasal and inferior parafoveal sectors that correspond to the papillomacular bundle. Furthermore, visual loss is associated with the SCP flow impairment, but not with the OCT-detectable structural damage., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive RGCs deputed to non-image forming functions of the eye such as synchronization of circadian rhythms to light-dark cycle. These cells are characterized by unique electrophysiological, anatomical and biochemical properties and are usually more resistant than conventional RGCs to different insults, such as axotomy and different paradigms of stress. We also demonstrated that these cells are relatively spared compared to conventional RGCs in mitochondrial optic neuropathies (Leber's hereditary optic neuropathy and Dominant Optic Atrophy). However, these cells are affected in other neurodegenerative conditions, such as glaucoma and Alzheimer's disease. We here review the current evidences that may underlie this dichotomy. We also present our unpublished data on cell experiments demonstrating that melanopsin itself does not explain the robustness of these cells and some preliminary data on immunohistochemical assessment of mitochondria in mRGCs., (Copyright © 2017 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Purpose: To assess the peripapillary retinal nerve fiber and macular retinal ganglion cell (RGC) loss in patients with dominant optic atrophy (DOA) stratified by OPA1 mutation type., Design: Cross-sectional study., Methods: We studied 39 patients from 28 pedigrees with DOA harboring heterozygous mutations in the OPA1 gene along with 45 age-matched healthy subjects. The retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) of patients with DOA were evaluated by optical coherence tomography (OCT) and compared to those of controls. Patients' eyes were divided into 4 groups based on increasing severity of visual loss (DOA1 to DOA4) and were stratified by OPA1 mutation type., Results: The average thicknesses of the RNFL and GC-IPL were smaller in patients with DOA than in healthy controls (P < 0.0001). RNFL analysis showed a significant reduction of the average, superior and inferior quadrants thicknesses in the DOA4 group compared to the DOA1 group (P = 0.001, P = 0.002 and P = 0.001, respectively). GC-IPL analysis showed a significant thinning in the superotemporal and superior sectors in the patients with DOA2 compared to those with DOA1 (P = 0.046 and P = 0.04, respectively). Stratifying by mutation type, average, superior and nasal RNFL thinning was significantly more severe in missense mutations and had a presumed dominant-negative effect compared to mutations causing haploinsufficiency., Conclusions: The present study demonstrates that in DOA, loss of macular RGCs is the earliest pathologic event, better reflected by GC-IPL measurements, whereas RNFL thickness is a measure of spared axons in late stages of the disease. Thus, mild cases (DOA2) show significant macular RGC loss as opposed to substantial maintenance of RNFL thickness, which is significantly decreased only in severe cases (DOA4). A clear genotype/phenotype correlation emerged, stratifying OCT measures by OPA1 mutation type, missense mutations being the most severe., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS, testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four "quadrants": superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the temporal and inferior quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A 48-year-old woman presented with painless bilateral vision loss that began in the left eye and responded to steroids, followed by vision loss in the right eye one day after completing her steroid taper. Diagnosis was complicated by a positive screening test for Leber hereditary optic neuropathy and a negative workup for demyelinating disease. Steroid-dependent optic neuropathies such as autoimmune optic neuropathy and chronic relapsing inflammatory optic neuropathy were considered in the differential. Seven months after initial presentation, the patient developed a new periventricular white matter lesion, lesions on her cervical and thoracic spinal cord, bilateral leg weakness, and sensory loss consistent with multiple sclerosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To investigate relationships between contrast sensitivity (CS), color vision, and retinal nerve fiber layer (RNFL) among people with human immunodeficiency virus (HIV) infection; to evaluate the effect of time since diagnosis of HIV infection on RNFL thickness., Design: Noninterventional cross-sectional study., Methods: We evaluated 102 eyes of 57 HIV-infected individuals without ocular opportunistic infections. Peripapillary RNFL thickness was determined with spectral-domain optical coherence tomography in 4 quadrants. CS was measured with the Pelli-Robson technique (expressed as logCS); color vision was measured with the Lanthony desaturated 15-hue technique (expressed as color confusion index [C-index], with higher scores indicating worse color vision). Correlations between values were assessed using Spearman correlation coefficients., Results: Median RNFL thickness (average of 4 quadrants) was 102.9 μm (range, 75.0-134.7 μm). Median logCS was 1.90 (range, 1.25-1.95). Median C-index was 1.58 (range, 0.96-4.07). Temporal RNFL thickness was correlated with logCS (r=0.295, P=.003) and C-index (r=-0.338, P=.0005). Time since diagnosis of HIV infection was shorter for those with thick average RNFL than for those with thin average RNFL (P=.18)., Conclusions: Both worse CS and worse color vision are correlated with thinning of the temporal RNFL, with possible threshold effects. Increased prevalences of abnormal CS and abnormal color vision in this population are therefore likely attributable to neuroretinal compromise. This pattern of structural and functional losses may reflect preferential damage to small-caliber axons in the maculopapillary bundle, possibly associated with mitochondrial dysfunction, providing a potential disease mechanism for HIV-associated "neuroretinal disorder.", (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate vitreomacular relations in different stages of age-related macular degeneration (AMD) without the influence of genetics and environmental factors., Design: Retrospective, observational case series., Methods: This was a multicenter study consisting of 29 previously untreated subjects with active exudative (wet) AMD in one eye and active nonexudative (dry) AMD in the fellow eye who were compared with 10 previously untreated subjects with end-stage geographic atrophy in one eye and an end-stage fibrotic (disciform) scar in the fellow eye. All subjects were studied with ultrasonography to identify the presence of posterior vitreous detachment (PVD) and by optical coherence tomography to detect vitreomacular adhesion (VMA)., Results: The incidence of PVD in eyes with nonexudative AMD was 20 (69%) of 29, compared with 6 (21%) of 29 with active exudative AMD (P = .002). VMA was present in 11 (38%) of 29 of eyes with exudative AMD and in only 3 (10%) of 29 eyes with nonexudative AMD (P = .008). The incidence of PVD in geographic atrophy was 7 (70%) of 10, compared with 4 (40%) of 10 with disciform scar (P = .44). VMA was present in 2 (20%) of 10 eyes with disciform scars and in 0 (0%) of 10 eyes with geographic atrophy (P = .48)., Conclusions: PVD may protect against exudative AMD, whereas VMA may promote exudative AMD. This phenomenon is not evident in end-stage disease because of an increased incidence of PVD and a decreased incidence of VMA in eyes with disciform scars. Genetic and environmental factors do not seem to influence these observations.

Purpose: To evaluate early changes in the central retinal response in human immunodeficiency virus (HIV)-positive patients without infectious retinitis using multifocal electroretinography (mfERG)., Design: Case control study., Methods: We evaluated three cohorts: HIV-negative controls and two groups of HIV-positive patients separated according to their nadir CD4 counts (>or= 100 cells/mm(3) and < 100 cells/mm(3) for a minimum of six months). mfERG first-order kernels (FOKs) and second-order kernels (SOKs) were analyzed separately by areas of rings, quadrants, and individual hexagons for each cohort., Results: Of 103 hexagon locations of FOK results, there were no significant differences in amplitudes of P1 and N1 across the groups (.05 < P < .50), although there was a trend for an overall reduction in the amplitudes. Similarly, latency N1 did not differ (.28 < P < .95). There were significantly delayed latencies of P1 between cohorts across 103 hexagons in both kernels. SOK results also showed significant delay in latencies of P1 and a trend of reduced P1 amplitudes across studied locations among cohorts (.24 < P < .08)., Conclusions: The results demonstrate widespread delay in latency in HIV-positive patients, especially in those with prolonged low (below 100 cells/mm(3)) CD4 nadir counts. These findings suggest early diffuse dysfunction of the inner retina results from severe HIV disease even in the HAART era.

Purpose: To evaluate the prevalence and risk factors for vision loss in patients with clinical or immunologic AIDS without infectious retinitis., Design: A prospective, multicenter cohort study of patients with AIDS., Methods: One thousand three hundred and fifty-one patients (2,671 eyes) at 19 clinical trials centers diagnosed with AIDS but without major ocular complications of HIV. Standardized measurements of visual acuity, automated perimetry, and contrast sensitivity were analyzed and correlated with measurements of patients' health and medical data relating to HIV infection. We evaluated correlations between vision function testing and HIV-related risk factors and medical testing., Results: There were significant (P<.05) associations between measures of decreasing vision function and indices of increasing disease severity, including Karnofsky score and hemoglobin. A significant relationship was seen between low-contrast sensitivity and decreasing levels of CD4+ T-cell count. Three percent of eyes had a visual acuity worse than 20/40 Snellen equivalents, which was significantly associated with a history of opportunistic infections and low Karnofsky score. When compared with external groups with normal vision, 39% of eyes had abnormal mean deviation on automated perimetry, 33% had abnormal pattern standard deviation, and 12% of eyes had low contrast sensitivity., Conclusions: This study confirms that visual dysfunction is common in patients with AIDS but without retinitis. The most prevalent visual dysfunction is loss of visual field; nearly 40% of patients have some abnormal visual field. There is an association between general disease severity and less access to care and vision loss. The pathophysiology of this vision loss is unknown but is consistent with retinovascular disease or optic nerve disease.

Purpose: To report the ophthalmologic characteristics of a newly identified seven-generation pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy consisting of 328 living individuals, 111 of whom are maternally related., Design: Observational population cohort study., Methods: This prospective study of a large Brazilian Leber hereditary optic neuropathy pedigree was carried out as a field investigation in Brazil. We describe the ophthalmologic findings of 192 eyes from 96 maternally related individuals of this pedigree. Spouses were used as control subjects. We conducted comprehensive neuro-ophthalmologic examinations with psychophysical tests, Humphrey visual fields, and fundus photographs. We also correlated the ophthalmologic findings with the previously published epidemiologic assessment of risk factors., Results: We examined 76 carriers and 20 affected individuals. The affected individuals showed severe disease with a mean visual acuity of 2.04 logarithm of the minimal angle of resolution and without evidence of recovery. All the affected individuals showed diffuse optic atrophy with a cup-to-disk ratio greater than 0.5 in 55% of cases. Moreover, among Affected individuals, smokers had a poorer visual acuity (P =.002). Among carriers there were several subclinical abnormalities, including microangiopathy, swelling of nerve fibers, and visual field abnormalities that did not correlate with tobacco or alcohol consumption., Conclusions: Our results demonstrate a significant influence of environmental risk factors, particularly smoking, for developing Leber hereditary optic neuropathy and for the severity of its clinical expression. However, smoking did not correlate with the subclinical abnormalities detected in carriers. Moreover, subclinical abnormalities were equally distributed between gender.

Purpose: To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial DNA (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON)., Design: Observational population cohort study., Methods: A prospective investigation of an entire Brazilian LHON family., Setting: A field investigation by an international team conducted in a remote part of Brazil., Study Population: We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls., Observation Procedures: We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis., Results: We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common (P <.01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group (P <.05)., Conclusions: Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.

Vision is much more than just resolving small objects. In fact, the eye sends visual information to the brain that is not consciously perceived. One such pathway entails visual information to the hypothalamus. The retinohypothalamic tract (RHT) mediates light entrainment of circadian rhythms. Retinofugal fibers project to several nuclei of the hypothalamus. These and further projections to the pineal via the sympathetic system provide the anatomical substrate for the neuro-endocrine control of diurnal and longer rhythms. Without the influence of light and dark, many rhythms desynchronize and exhibit free-running periods of approximately 24.2-24.9 hours in humans. This review will demonstrate the mechanism by which the RHT synchronizes circadian rhythms and the importance of preserving light perception in those persons with impending visual loss.

Purpose: To determine the effect of human immunodeficiency virus (HIV) infection on topographic measures of the optic disk and the retinal nerve fiber layer., Methods: A cross-sectional study at the Acquired Immunodeficiency Syndrome (AIDS) Ocular Research Unit at the University of California, San Diego. Retinal nerve fiber layer thickness at the optic nerve head was evaluated using the Heidelberg Retinal Tomograph, a confocal scanning laser tomograph in 38 HIV-positive and 24 age-matched HIV-negative subjects., Results: HIV-positive patients without CMV retinitis showed significant differences from HIV-negative normal controls in a number of measures of the retinal nerve fiber layer. This indicated a loss of retinal ganglion cells in HIV-positive patients without retinitis. HIV-positive patients with CMV retinitis were worse in most measurements than both HIV-negative controls and HIV-positive patients without CMV., Conclusions: Significant thinning of the retinal nerve fiber layer occurs in HIV-positive patients without infectious retinopathy, and there are further changes in the optic disk associated with CMV retinitis. Confocal scanning laser tomography may be of use in the diagnosis of early HIV-associated visual function loss.

Axonal degeneration and diminution of the axonal population in the optic nerve have been documented in aging and in various neuro-ophthalmic conditions. We applied morphometric techniques to the postmortem examination of optic nerves obtained from patients with acquired immunodeficiency syndrome. Twelve optic nerves (eight from patients with AIDS and four from age-matched control eyes) were stained with paraphenylenediamine and morphometrically analyzed with a computer-assisted image and measurement system. Degeneration was often severe and was scattered throughout all of the AIDS-affected optic nerves. In the AIDS-affected optic nerves, the mean axonal population was markedly lower than the mean obtained from normal optic nerves (880,000 vs 1,507,000). Despite the approximate 40% loss of axons, mean axonal diameters were not markedly different, suggesting that no particular class of axon was especially susceptible to AIDS-associated degeneration. The extent and pattern of axonal loss in optic nerves of patients with AIDS suggest that the changes may not only be secondary to damage at the retina, but may reflect an AIDS-associated primary optic neuropathy.

Patients with human immunodeficiency virus infection may have noninfectious and infectious retinopathies, as well as clinical symptoms consistent with optic nerve dysfunction. Noninfectious acquired immunodeficiency syndrome-related retinopathy is seen in most patients with AIDS. Morphologic studies have shown that the number of retrobulbar optic nerve fibers in patients with AIDS is decreased compared to the number of optic nerve fibers in normal control eyes. To determine whether these patients had a visual dysfunction consistent with damage to the macula and optic nerve, 78 subjects (156 eyes) were studied using color-vision and contrast-sensitivity testing. The Farnsworth-Munsell 100-Hue color-vision test was performed on all subjects and age-corrected color-vision scores for all groups were compared. A significant decrease in color discrimination was found in the patients with AIDS (P less than .001). Contrast-sensitivity testing disclosed a deficit of contrast threshold in patients with AIDS at four of five spatial frequencies and in patients with AIDS-related complex at three of the five spatial frequencies examined. This study demonstrated a functional visual deficit in eyes without retinitis consistent with dysfunction of the macula or optic nerve in patients with AIDS.

We studied two cases of bilateral visual loss secondary to an optic neuropathy in patients with cryptococcal meningitis. In both cases a history of visual loss after the onset of an episode of cryptococcal meningitis was elicited. Visual fields were consistent with optic nerve disease. The patients' visual loss appeared to be the result of perineuritic adhesive arachnoiditis. Although no surgical interventions were carried out in our patients, medical or surgical intervention may be useful to prevent or relieve constrictive arachnoiditis and preserve vision in selected patients.

We examined five patients with Alzheimer's disease who complained of poor vision. Two patients had mild Alzheimer's disease; they complained of problems with reading and of "bumping into things," yet both had normal visual acuities. One patient with moderate Alzheimer's disease had abnormal eye movements, visual-evoked potentials, and contrast sensitivity. The other two patients had severe Alzheimer's disease. Despite difficulties in performing the examination, we were able to see moderate impairments in visual acuity and visual fields, as well as marked dyschromatopsia, severe deficits in contrast sensitivity, and markedly abnormal eye movements and visual-evoked potentials.

We compared the tear pH values of 44 normal, healthy volunteers, 20 patients with ocular disorders other than rosacea, seven patients with untreated, active ocular rosacea, and five patients with tetracycline-treated ocular rosacea. The group with untreated, active ocular rosacea had significantly more alkaline tear pH values than the other groups tested. In patients with tetracycline-treated ocular rosacea, tear pH values were not significantly different from those of normal subjects.

We examined ten patients from a consecutive series of 73 patients with either isolated cytomegalovirus papillitis or limited cytomegalovirus retinitis contiguous with the optic disk. Patients with peripheral retinitis and other areas of retinitis were excluded. All patients were treated with ganciclovir. Two distinct types of cytomegalovirus infection of the peripapillary area were identified. Type I was characterized by spread of limited retinitis to the optic disk margin, good central visual acuity, and permanent arcuate and altitudinal visual field defects that enlarged and became more complete as the retinitis progressed toward the disk. Type II appeared to be a true cytomegalovirus infection of the optic nerve characterized by primary, isolated papillitis with peripapillary retinitis, an early afferent pupillary defect, and good initial visual acuity, which rapidly deteriorated despite prompt antiviral therapy. Peripapillary cytomegalovirus retinitis appears to be an important and underreported cause of visual morbidity in patients with AIDS.