Retinal ganglion cell dysfunction in preclinical Alzheimer's disease: an electrophysiologic biomarker signature.

The current study evaluated retinal function using electroretinography (ERG) in cognitively healthy (CH) participants with preclinical Alzheimer's disease (AD), as classified by cerebral spinal fluid (CSF) Aß42/Tau ratio. Individuals with normal retinal morphology ascertained by spectral-domain optical coherence tomography were enrolled. Full-field ERG, pattern PERG, and photopic negative response (PhNR) were performed in 29 adult participants (58 eyes). Amplitude and implicit times of the ERG wave components were analyzed. Preclinical AD participants showed marked retinal ganglion cell dysfunction relative to controls. The PhNR was significantly diminished in preclinical AD relative to controls. PhNR amplitude and N95 implicit time differentiated CH individuals with CSF biomarkers of AD pathology with 87% sensitivity and 82% specificity. These quantitative electrophysiologic findings expand our understanding of early retinal functional changes that precede cognitive decline in AD. Retinal ganglion cell dysfunction, as detected by ERG, may be a clinically useful, non-invasive in vivo biomarker for early disease detection, which is necessary for ultimately pursuing early intervention.

Association of Preclinical Alzheimer Disease With Optical Coherence Tomographic Angiography Findings.

Importance: Biomarker testing for asymptomatic, preclinical Alzheimer disease (AD) is invasive and expensive. Optical coherence tomographic angiography (OCTA) is a noninvasive technique that allows analysis of retinal and microvascular anatomy, which is altered in early-stage AD. Objective: To determine whether OCTA can detect early retinal alterations in cognitively normal study participants with preclinical AD diagnosed by criterion standard biomarker testing. Design, Setting, and Participants: This case-control study included 32 participants recruited from the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St Louis, Missouri. Results of extensive neuropsychometric testing determined that all participants were cognitively normal. Participants underwent positron emission tomography and/or cerebral spinal fluid testing to determine biomarker status. Individuals with prior ophthalmic disease, media opacity, diabetes, or uncontrolled hypertension were excluded. Data were collected from July 1, 2016, through September 30, 2017, and analyzed from July 30, 2016, through December 31, 2017. Main Outcomes and Measures: Automated measurements of retinal nerve fiber layer thickness, ganglion cell layer thickness, inner and outer foveal thickness, vascular density, macular volume, and foveal avascular zone were collected using an OCTA system from both eyes of all participants. Separate model III analyses of covariance were used to analyze individual data outcome. Results: Fifty-eight eyes from 30 participants (53% female; mean [SD] age, 74.5 [5.6] years; age range, 62-92 years) were included in the analysis. One participant was African American and 29 were white. Fourteen participants had biomarkers positive for AD and thus a diagnosis of preclinical AD (mean [SD] age, 73.5 [4.7] years); 16 without biomarkers served as a control group (mean [SD] age, 75.4 [6.6] years). The foveal avascular zone was increased in the biomarker-positive group compared with controls (mean [SD], 0.364 [0.095] vs 0.275 [0.060] mm2; P = .002). Mean (SD) inner foveal thickness was decreased in the biomarker-positive group (66.0 [9.9] vs 75.4 [10.6] µm; P = .03). Conclusions and Relevance: This study suggests that cognitively healthy individuals with preclinical AD have retinal microvascular abnormalities in addition to architectural alterations and that these changes occur at earlier stages of AD than has previously been demonstrated. Longitudinal studies in larger cohorts are needed to determine whether this finding has value in identifying preclinical AD.

Retinal vessel diameter and estimated cerebrospinal fluid pressure in arterial hypertension: the Beijing Eye Study.

BACKGROUND: Hypertensive retinal microvascular abnormalities include an increased retinal vein-to-artery diameter ratio. Because central retinal vein pressure depends on cerebrospinal fluid pressure (CSFP), we examined whether the retinal vein-to-artery diameter ratio and other retinal hypertensive signs are associated with CSFP. METHODS: Participants of the population-based Beijing Eye Study (n = 1,574 subjects) underwent measurement of the temporal inferior and superior retinal artery and vein diameter. CSFP was calculated as 0.44 × body mass index (kg/m(2)) + 0.16 × diastolic blood pressure (mm Hg) - 0.18 × age (years) - 1.91. RESULTS: Larger retinal vein diameters and higher vein-to-artery diameter ratios were significantly associated with higher estimated CSFP (P = 0.001) in multivariable analysis. In contrast, temporal inferior retinal arterial diameter was marginally associated (P = 0.03) with estimated CSFP, and temporal superior artery diameter was not significantly associated (P = 0.10) with estimated CSFP; other microvascular abnormalities, such as arteriovenous crossing signs, were also not significantly associated with estimated CSFP. In a reverse manner, higher estimated CSFP as a dependent variable in the multivariable analysis was associated with wider retinal veins and higher vein-to-artery diameter ratio. In the same model, estimated CSFP was not significantly correlated with retinal artery diameters or other retinal microvascular abnormalities. Correspondingly, arterial hypertension was associated with retinal microvascular abnormalities such as arteriovenous crossing signs (P = 0.003), thinner temporal retinal arteries (P < 0.001), higher CSFP (P < 0.001), and wider retinal veins (P = 0.001) or, as a corollary, with a higher vein-to-artery diameter ratio in multivariable analysis. CONCLUSIONS: Wider retinal vein diameters are associated with higher estimated CSFP and vice versa. In arterial hypertension, an increased retinal vein-to-artery diameter ratio depends on elevated CSFP, which is correlated with blood pressure.

Anti-endothelial serum antibodies in a patient with Susac's syndrome.

BACKGROUND: Susac's syndrome (SS) is a rare arteriopathy affecting the microvasculature of the brain, retina, and inner ear, resulting in encephalopathy, branch retinal artery occlusion and hearing loss. Anecdotal reports exist on SS being associated with a humoral immune response against endothelial cells. However, no original data has ever been published. OBJECTIVE: To analyze serum and CSF from a patient with SS for the presence of CNS auto-antibodies and, if present, to further characterize such antibodies immunologically. METHODS: Serum and CSF samples were examined by indirect immunofluorescence on adult mouse cerebrum, cerebellum, brain stem, and inner ear tissue sections, and IgG subclasses were determined. RESULTS: Anti-endothelial antibodies were found at a titre of 1:960 in serum but not CSF. Antibodies belonged to the complement activating IgG1 subclass. Glucocorticoid treatment resulted in a decrease of titres (1:480), though the antibodies remained clearly detectable. CONCLUSION: Our finding of anti-endothelial cell antibodies in a patient with SS is important in the light of previous pathological data suggesting that SS is associated with endothelial damage. Larger serological studies are now warranted to assess systematically the frequency and relevance of auto-antibodies in SS.

Lupus retinopathy associated with a high IFN-alpha level in the cerebrospinal fluid.

An 18-year-old woman who presented with photosensitivity, butterfly rash and acute visual disturbance was diagnosed as SLE with retinopathy. The level of IFN-alpha in the cerebrospinal fluid (CSF) was markedly elevated. Her visual acuity recovered with high-dose prednisolone therapy. IFN-alpha in the CSF also reduced to within the normal range. The mechanism causing lupus retinopathy is not clearly understood. Although the association between lupus retinopathy and a high level of IFN-alpha has not been reported, the injection of IFN-alpha is known to frequently cause retinopathy in hepatitis patients. We discuss the possibility of IFN-alpha causing retinopathy in SLE patients.

Necrotising herpetic retinopathy in patients with advance HIV disease.

OBJECTIVES: To describe the presenting features, clinical and laboratory diagnosis, response to treatment, and outcome of necrotising herpetic retinopathy (NHR) in HIV infected patients. METHODS: Retrospective case records/laboratory data review of five HIV infected patients presenting to the specialist HIV/AIDS unit at UCL Hospitals, London from April 1994 to August 1996 with a clinical diagnosis of NHR. RESULTS: All patients had advanced HIV disease with a median CD4 count of 20.10(6)/1. Three patients had cutaneous varicella zoster virus (VZV) infection within the preceding 8 weeks. All had uniocular loss of visual acuity; one also had headache and another ocular pain. All had typical retinal appearances. VZV DNA was detected in cerebrospinal fluid of four patients (and in vitreous fluid of one of the four) and in vitreous fluid of one other. One patient refused therapy and rapidly became blind. Four patients received intravenous foscarnet with intravenous aciclovir for 6 weeks: three subsequently received oral famciclovir and one oral valaciclovir; two patients also had intravitreal injections of foscarnet. In none of the four did treatment bring about improvement in visual acuity, but in all four visual loss from retinitis was halted. CONCLUSIONS: NHR occurs in HIV infected patients with advanced HIV disease and is strongly associated with evidence of VZV infection. With aggressive use of antiviral drugs the outcome is not uniformly poor.

Primary ocular malignant lymphoma associated with the acquired immune deficiency syndrome.

A 42-year-old man who was human immunodeficiency virus (HIV)-positive complained of floaters in his right eye, which had existed for 1 week, followed by loss of central vision. Results of ophthalmoscopic examination disclosed confluent yellowish-white retinochoroidal infiltrates with perivascular sheathing, which were more prominent superiorly in the right eye. Approximately 10 small, white, intraretinal and choroidal lesions were observed in the nasal periphery of the left eye. Results of cytologic examination of the vitreous of the right eye showed neoplastic cells characteristic of large cell type malignant lymphoma. Shortly thereafter, cytologic examination of the cerebrospinal fluid also showed large cell malignant lymphoma. Magnetic resonance imaging (MRI) showed a mass involving the left cerebellar hemisphere. After bilateral whole-eye radiation therapy, there was complete resolution of the lymphomatous retinochoroidal infiltrates in both eyes. The ophthalmologic and neurologic manifestations of acquired immune deficiency syndrome (AIDS) are discussed. The authors believe this is the first report of ocular malignant lymphoma occurring in a patient with AIDS.

Spinal fluid pleocytosis in acute posterior multifocal placoid pigment epitheliopathy.

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a disorder of the fundus frequently characterized by sudden onset of bilateral, marked visual loss associated with yellowish-white, ill-defined placoid lesions of the retina. Most cases show a rapid resolution with restoration of vision to normal or near-normal levels. We evaluated an 11-year-old boy with presumed APMPPE who showed a mononuclear cell pleocytosis on spinal fluid examination.