Demyelination precedes axonal loss in the transneuronal spread of human neurodegenerative disease.

The spread of neurodegeneration through the human brain network is reported as underlying the progression of neurodegenerative disorders. However, the exact mechanisms remain unknown. The human visual pathway is characterized by its unique hierarchical architecture and, therefore, represents an ideal model to study trans-synaptic degeneration, in contrast to the complexity in neural connectivity of the whole brain. Here we show in two specifically selected patient cohorts, including (i) glaucoma patients with symmetrical bilateral hemifield defects respecting the horizontal meridian (n = 25, 14 females, 64.8 ± 10.1 years; versus 13 normal controls with similar age/sex distributions); and (ii) multiple sclerosis patients without optic radiation lesions (to avoid potential effects of lesions on diffusivity measures) (n = 30, 25 females, 37.9 ± 10.8 years; versus 20 controls), that there are measurable topographic changes in the posterior visual pathways corresponding to the primary optic nerve defects. A significant anisotropic increase of water diffusion was detected in both patient cohorts in the optic radiations, characterized by changes in perpendicular (radial) diffusivity (a measure of myelin integrity) that extended more posteriorly than those observed in parallel (axial) diffusivity (reflecting axonal integrity). In glaucoma, which is not considered a demyelinating disease, the observed increase in radial diffusivity within the optic radiations was validated by topographically linked delay of visual evoked potential latency, a functional measure of demyelination. Radial diffusivity change in the optic radiations was also associated with an asymmetrical reduction in the thickness of the calcarine cortex in glaucoma. In addition, 3 years longitudinal observation of the multiple sclerosis patient cohort revealed an anterograde increase of radial diffusivity in the anterior part of optic radiations which again was retinotopically associated with the primary damage caused by optic neuritis. Finally, in an animal model of optic nerve injury, we observed early glial activation and demyelination in the posterior visual projections, evidenced by the presence of myelin-laden macrophages. This occurred prior to the appearance of amyloid precursor protein accumulation, an indicator of disrupted fast axonal transport. This study demonstrated strong topographical spread of neurodegeneration along recognized neural projections and showed that myelin and glial pathology precedes axonal loss in the process, suggesting that the mechanism of trans-synaptic damage may be at least partially mediated by glial components at the cellular level. The findings may have broad biological and therapeutic implications for other neurodegenerative disorders.

SUCCESSFUL CLOSURE OF FULL-THICKNESS MACULAR HOLES SECONDARY TO MACULAR VITELLIFORM LESIONS.

PURPOSE: To describe the first reported cases of full-thickness macular holes secondary to vitelliform lesions that were successfully closed with vitrectomy surgery and gas tamponade. METHODS: Two female patients developed visual loss secondary to bilateral vitelliform lesions and associated full-thickness macular holes. The patients underwent 25-gauge pars plana vitrectomy, internal limiting membrane peeling, and 26% sulfur hexafluoride gas, followed by 3 days of face-down positioning. RESULTS: In both patients, the macular holes remain closed 3 and 25 months postoperatively. CONCLUSION: Vitrectomy surgery with gas tamponade may successfully close full-thickness macular holes secondary to macular vitelliform lesions.

Bleb vascularity following post-trabeculectomy subconjunctival bevacizumab: a pilot study.

BACKGROUND: To determine whether postoperative subconjunctival bevacizumab significantly alters bleb vascularity. DESIGN: A randomized, prospective interventional study. PARTICIPANTS: Forty-three eyes from 39 patients were recruited, with 21 eyes randomized to subconjunctival injections of 5-fluorouracil, and 22 eyes to combined 5-fluorouracil/bevacizumab. METHODS: All patients who underwent uncomplicated primary antimetabolite augmented trabeculectomy who subsequently required postoperative subconjunctival 5-fluorouracil injection within 4 weeks of surgery were eligible. Patients were randomized to receive subconjunctival 5-fluorouracil only (7.5 mg/0.15 mL) or 5-fluorouracil plus bevacizumab (1.25 mg/0.05 mL). MAIN OUTCOME MEASURES: Primary outcome was bleb vascularity with secondary endpoints including visual acuity, intraocular pressure, bleb morphology, complications and total numbers of 5-fluorouracil injections were recorded at baseline, week 12 and 18 months. RESULTS: At week 12, there was no significant difference between groups for visual acuity, intraocular pressure, bleb vascularity and morphology, or total number of 5-fluorouracil injections. By 18 months, 47.4% of the 5-fluorouracil/bevacizumab group exhibited central bleb avascularity compared with 21.1% of the 5-fluorouracil group (Fisher's exact test, P = 0.17). Two bleb complications (one blebitis; one suture abscess) recorded in the 5-fluorouracil/bevacizumab group. CONCLUSIONS: After a single combined injection, a trend for increased central bleb avascularity was observed, although this effect was not sufficient to reach statistical significance. This, in addition to the occurrence of two bleb-related complications in the bevacizumab group, suggests the need for a larger clinical trial to further evaluate the safety and efficacy of bevacizumab as a modulating agent in glaucoma filtration surgery.

Bilateral homonymous superior quadrantanopia after traumatic attempts to remove a cockroach impacted in the external auditory canal.

Visual field defects typically caused by lesions in the optic nerve or optic chiasm may be caused indirectly by subdural haematomas. A 61-year-old man survived transtentorial herniation caused by subdural haematomas that resulted from shaking his head in an attempt to remove a cockroach impacted in his external auditory canal. Bilateral incomplete posterior cerebral artery infarction of both inferior tips of the occipital lobe resulted in bilateral superior quadrantanopia. There are no previous reports of tentorial herniation causing this permanent outcome.

Glaucoma prevalence in Indigenous Australians.

AIM: Define the prevalence of glaucoma within the Indigenous Australian population. METHODS: Aboriginal and Torres Strait Islander adults aged ≥ 40 years were recruited from 30 randomly selected sample areas or communities. Participants were regarded to have glaucoma if they had a cup:disc ratio (CDR) of > 0.8, or missed ≥ 2 points on the Frequency Doubling Test and a CDR > 0.7 in at least one eye. RESULTS: 1189 eligible adult participants were examined, representing 72% of the target population. After excluding cases with missing or ungradable information, the authors found a 2.2% (95% CI 1.6% to 3.6%) overall prevalence of glaucoma. In univariate analyses, the odds of glaucoma increased with age (χ² trend=4.38, p < 0.001), male gender (OR 2.43, 95% CI 1.10 to 5.41), less than secondary education (OR 4.74, 95% CI 1.96 to 11.45) and self-reported history of glaucoma (OR 20.8; 95% CI 6.23 to 69.51). After a multivariate analysis, none of these attributes other than history of glaucoma remained significant. No cases of low vision (presenting visual acuity (VA) < 6/12 to ≤ 6/60) or blindness (presenting VA < 6/60) were solely attributable to glaucoma. The mean optic disc diameter was 1.93 mm (SD 0.19) for left and right eyes, while the mean CDR for right eyes was 0.44 (SD 0.15) and for left eyes 0.43 (SD 0.16). CONCLUSIONS: This population-based study examined the prevalence of glaucoma within the Indigenous Australian population, and although an infrequent cause of vision loss, definable rates of disease were seen. The results may suggest a potential introduction of Caucasian glaucoma-associated genes into this community, differently used diagnostic criteria or sampling bias compared with previous surveys.

A geometric morphometric assessment of the optic cup in glaucoma.

The morphologic appearance of the optic disc is of interest in glaucoma. In contrast to descriptive classification systems that are currently used, a quantitative approach to the analysis of optic disc morphology is required. Our goal was to determine the optimal method for quantifying optic cup shape by comparing traditional (ovality, form-factor and neuroretinal rim (NRR) width ratio) and geometric morphometric approaches. Left optic disc stereophotographs of 160 (80 normal and 80 glaucomatous (stratified by severity)) subjects were examined. The optic cup margins were stereoscopically delineated with a custom tracing system and saved as a series of discrete points. The geometric morphometric methods of elliptic Fourier analysis (EFA) and sliding semi-landmark analysis (SSLA) were used to eliminate variation unrelated to shape (e.g. size) and yield a series of shape variables. Differences in optic cup shape between normal and glaucoma groups were investigated. Discriminant functions were computed and the sensitivity and specificity of each technique determined. Receiver operator characteristic (ROC) curves were calculated for all methods and evaluated in their potential to discriminate between normal and glaucomatous eyes based on the shape variables. All geometric morphometric methods revealed differences between normal and glaucomatous eyes in optic cup shape, in addition to the traditional parameters of ovality, form-factor and NRR width ratio (p<0.0005). SSLA (minimum bending energy criterion--18 points) had the best sensitivity (83%) and area under the curve (AUC) (0.91). EFA (72 points) performed similarly well (74%, 0.89) as did the set of traditional shape-based variables (76%, 0.86). This study demonstrated that a geometric morphometric approach for discriminating between normal and glaucomatous eyes in optic cup shape is superior to that provided by traditional single parameter shape measures. Such analytical techniques could be incorporated into future automated optic disc screening modalities.

A retrospective review of the associations between amblyopia type, patient age, treatment compliance and referral patterns.

AIM: To review presenting ages, referral sources, amblyopia type and treatment compliance in children attending a typical public hospital ophthalmology clinic with no formal amblyopia screening program in place. METHODS: One hundred and twenty-seven children attending the outpatients clinics of The Children's Hospital at Westmead for amblyopia management between January 2001 and May 2003 were reviewed. Presenting age, amblyopia type, referral source, treatment prescribed and compliance achieved were analysed using means, 95% confidence intervals (CI), and Mantel-Haenszel chi2 statistic. RESULTS: General practitioners and paediatricians provided most referrals. The mean presenting age was 32.9 (95% CI 29.0-36.9) months. There was no significant association between presenting age and amblyopia type (chi2 = 6.00, P = 0.11, d.f. = 3), but a trend was found with deprivation amblyopia identified earliest, and pure anisometropic amblyopia identified latest (chi2 = 5.65, P = 0.02, d.f. = 1). Compliance to patching did not differ significantly between sexes, with calculated aggregate compliance of 67.3% (95% CI: 59-75%) for boys and 66.3% (95% CI: 60-73%) for girls. Compliance to patching also did not differ significantly between amblyopia types (chi2 = 3.61, P = 0.3, d.f. = 3). Compliance was best among younger and older children, and worst among those aged 15-30 months. There was no association between patching compliance and treatment duration. CONCLUSION: Amblyopia is a preventable form of blindness. A multidisciplinary approach must be taken. Resources and education should be targeted at general practitioners and paediatricians who have the greatest opportunities to perform amblyopia screening. Teachers are an important resource in identifying cases missed at previous informal screening opportunities. Amblyopia treatment must be intensified and individualized between the ages of 15-30 months when compliance is poorest.

Corneal arcus and hyperlipidemia: findings from an older population.

PURPOSE: To quantify the association between arcus and hyperlipidemia in an older population. DESIGN: Cross-sectional population-based study. METHODS: Arcus and serum lipids were measured in the Blue Mountains Eye Study (n = 3,654, aged >49 years). Arcus was graded as absent, partial (<180 degrees) or circumferential (> or =180 degrees). Associations between arcus and hyperlipidemia were assessed using logistic regression, adjusting for age and vascular risk factors. RESULTS: Arcus was strongly associated with age (P <.0001). After age adjustment, arcus was associated with male sex (P <.01) and diabetes (P <.02) but not with hypertension or smoking. Corneal arcus was significantly associated with progressively higher levels of total cholesterol over 5 mmol/l. Adjusted odds increased from 1.6 for cholesterol 6.0 to 6.9 mmol/l to 4.6 for cholesterol >8.0 mmol/l, and was 1.9 for high triglyceride >3.0 mmol/l. CONCLUSION: This population-based finding confirms that corneal arcus was associated with hypercholesterolemia and hypertriglyceridemia in older persons.