The role of lamina cribrosa tissue stiffness and fibrosis as fundamental biomechanical drivers of pathological glaucoma cupping.

The primary biomechanical driver of pathological glaucomatous cupping remains unknown. Finite element modeling indicates that stress and strain play key roles. In this article, primarily a review, we utilize known biomechanical data and currently unpublished results from our lab to propose a three-stage, tissue stiffness-based model to explain glaucomatous cupping occurring at variable levels of translaminar pressure (TLP). In stage 1, a short-term increase in TLP gradient induces a transient increase in lamina cribrosa (LC) strain. Beyond a critical level of strain, the tissue stiffness rises steeply provoking cellular responses via integrin-mediated mechanotransduction. This early mechanoprotective cellular contraction reduces strain, which reduces tissue stiffness by return of the posteriorly deflected LC to baseline. In stage 2 a prolonged period of TLP increase elicits extracellular matrix (ECM) production leading to fibrosis, increasing baseline tissue stiffness and strain and diminishing the contractile ability/ability to return to the baseline LC position. This is supported by our three-dimensional collagen contraction assays, which show significantly reduced capacity to contract in glaucoma compared with normal LC cells. Second, 15% cyclic strain in LC cells over 24 h elicits a typical increase in ECM profibrotic genes in normal LC cells but a highly blunted response in glaucoma LC cells. Stage 3 is characterized by persistent fibrosis causing further stiffening and inducing a feed-forward ECM production cycle. Repeated cycles of increased strain and stiffness with profibrotic ECM deposition prevent optic nerve head (ONH) recoil from the new deflected position. This incremental maladaptive modeling leads to pathological ONH cupping.

Longitudinal reproducibility of spectral domain optical coherence tomography in children with physiologic cupping and stable glaucoma.

PURPOSE: To determine whether Spectralis (Heidelberg, Germany) spectral domain optical coherence tomography (SD-OCT) measurements are reproducible over time in children with physiologic cupping and stable glaucoma. METHODS: Subjects were identified from a subset of participants in an earlier retrospective study conducted by our group and included children (<18 years of age) with physiologic cupping and stable primary congenital glaucoma (PCG) having had at least 2 SD-OCTs over a period of more than 1 between April 2010 and September 2015. Thicknesses of average peripapillary retinal nerve fiber layer (pRNFL) and six individual sectors and volumes of three segmented retinal layers and total retina were measured. Spectralis review software was used for segmentation. Intraclass correlation coefficients (ICC) and coefficient of variation (COV) were calculated. RESULTS: A total of 35 eyes of 35 children were included: 15 eyes had physiologic cupping; 20 eyes, PCG. Mean ages at initial SD-OCT were 11.2 ± 3.3 years and 9.7 ± 3.3, respectively; mean intervals between first and last imaging were 2.2 ± 1.1 and 3.0 ± 1.4 years, respectively. ICCs across three visits for both groups for average and sectoral pRNFL thicknesses were 0.887-0.997 and for segmented retinal volumes were 0.806-0.993. ICCs for total retinal volume for physiologic cupping and PCG were 0.993 and 0.954, respectively. COVs for average pRNFL thickness were 0.9% and 1.7%, respectively. For all other measurements, COVs ranged from 0.3% to 5.4%. CONCLUSIONS: Reproducibility of longitudinal SD-OCT measurements for average pRNFL thickness in children with stable glaucoma over about 2 years is comparable to short-term reproducibility (COV) in normal children (1.16%) and normal and glaucoma adults (1.62%-3.4%).

Changes in the optic nerve head induced by horizontal eye movements.

PURPOSE: To investigate the effect of eye movement on the optic nerve head (ONH) using swept-source optical coherence tomography (SS-OCT), and to measure the degree of ONH changes. METHODS: We enrolled 52 healthy subjects, 20 to 40 years of age, and performed a prospective observational study. Both ONH and macula were imaged simultaneously using wide volume scan of the SS-OCT in the primary and different gaze positions. Horizontal eye movements were used to obtain OCT images in abducted and adducted eyeball positions. Multilateral 3-dimensional registration was used to process and analyze the images to measure the degree of ONH changes. RESULTS: The mean axial length (AXL) was 25.73 ± 1.42mm and the mean spherical equivalents was -4.49 ± 2.94 D (The proportion of high myopia was 39.4%). Significant morphologic changes were observed in the ONH during both abduction and adduction. In abduction, the overall ONH tissues were elevated, and the mean area of elevation was 115,134 ± 9,424 µm2 (p<0.001). In adduction, the mean areas from two perspectives, which were nasal or temporal, and peripapillary tissues or optic nerve cupping were 95,277 ± 73,846 µm2, 34,450 ± 44,948 µm2, -108,652 ± 91,246 µm2, and -30,581 ± 46,249 µm2, respectively. Elevation in abduction (overall, nasal cup segment, and temporal cup segment; R = 0.204, 0.195 and 0.225, p = 0.038, 0.047 and 0.021, respectively) and elevation of nasal peripapillary segments in adduction were positively correlated with AXL (R = 0.346, p<0.001). CONCLUSION: We found significant morphologic changes in the ONH in both abduction and adduction and these changes were associated with AXL. Considering these morphologic changes as physical properties, it allows a better understanding of the biomechanical characteristics of the ONH.

Quantitative analysis of optic disc color.

PURPOSE: To evaluate the reproducibility of ImageJ software in analyzing the color of the optic disc. METHODS: One hundred twelve normal participants (56 males and 56 females) were enrolled in this study. The image of the optic disc was taken using Kowa digital disc photo-graphy, and the gray scales of the nasal rim (NR), brightest cupping center (BCC) and largest inferior retinal vein (IRV) were calculated using histogram in ImageJ. Three different observers calculated the gray scales three separate times. Reproducibility was assessed using the interclass correlation coefficient (ICC). RESULTS: The mean age of the participants was 50.6 years old (range, 11 to 82 years). The mean gray scales of the nasal rim were 91.81, 94.91, and 93.24; those of the brightest cupping center were 174.84, 179.94, and 177.76; and those of the largest inferior retinal vein were 61.85, 53.48, and 56.73 for observers 1, 2, and 3, respectively. Inter-observer reproducibility for NR, BCC and IRV was considered good based upon ICC values of 0.944, 0.860, and 0.789 for observers 1, 2, and 3, respectively. Significant age-related differences between the values of the brightest cupping center were noted, and the gray scale score was decreased in the older participants (p < 0.001). CONCLUSIONS: The gray scale of the brightest cupping center diminished with age. ImageJ can be a useful objective tool with high reproducibility in the analysis of optic disc color.

Change in optic nerve head topography in healthy volunteers: an 11-year follow-up.

AIM: To study longitudinal changes in optic nerve head (ONH) topography in healthy volunteers. METHODS: One eye each of 36 healthy volunteers was prospectively followed for 11 (7-13) years with the Heidelberg Retina Tomograph I (HRT I). All eyes had normal visual fields, non-glaucomatous ONHs, no defects on red-free nerve fibre layer photographs and intraocular pressure (IOP) <22 mm Hg. During the follow-up, no eye developed glaucoma; visual fields remained normal, and no longitudinal changes appeared in nerve fibre layers assessed from red-free photographs or ONHs assessed from stereophotographs. The median baseline and follow-up IOPs were comparable (15 mm Hg, range 10-20 mm Hg; and 16 mm Hg; range 10 to 22 mm Hg, respectively; p=0.38). Images were re-evaluated with HRT III and ONHs graded as normal, borderline or glaucomatous with the Moorfield Regression Analysis (MRA). RESULTS Significant changes in HRT parameters indicating increased ONH cupping were detected in cup area (p=0.013), cup-to disc area ratio (p=0.015), rim area (p=0.015), mean cup depth (p=0.006) and cup shape measure (p<0.001). With the MRA classification, nine eyes (9/31, 29%) had changed for the worse in the global or any of the sector classifications. CONCLUSION: Age-dependent changes occur in ONH topography detectable with the HRT.

Quantitative Analysis of Optic Disc Color

PURPOSE: To evaluate the reproducibility of ImageJ software in analyzing the color of the optic disc. METHODS: One hundred twelve normal participants (56 males and 56 females) were enrolled in this study. The image of the optic disc was taken using Kowa digital disc photo-graphy, and the gray scales of the nasal rim (NR), brightest cupping center (BCC) and largest inferior retinal vein (IRV) were calculated using histogram in ImageJ. Three different observers calculated the gray scales three separate times. Reproducibility was assessed using the interclass correlation coefficient (ICC). RESULTS: The mean age of the participants was 50.6 years old (range, 11 to 82 years). The mean gray scales of the nasal rim were 91.81, 94.91, and 93.24; those of the brightest cupping center were 174.84, 179.94, and 177.76; and those of the largest inferior retinal vein were 61.85, 53.48, and 56.73 for observers 1, 2, and 3, respectively. Inter-observer reproducibility for NR, BCC and IRV was considered good based upon ICC values of 0.944, 0.860, and 0.789 for observers 1, 2, and 3, respectively. Significant age-related differences between the values of the brightest cupping center were noted, and the gray scale score was decreased in the older participants (p < 0.001). CONCLUSIONS: The gray scale of the brightest cupping center diminished with age. ImageJ can be a useful objective tool with high reproducibility in the analysis of optic disc color.

Effects of contralateral electroacupuncture on brain function: a double-blind, randomized, pilot clinical trial.

OBJECTIVES: The aim of this study was to ascertain the effects of contralateral acupuncture on brain function using blind-spot mapping. DESIGN AND PARTICIPANTS: Forty (40) healthy volunteers in whom the right-side blind spot was larger than the left-side one-which indicates lower left-brain function-were randomly assigned into the following two groups in which electroacupuncture was applied to: (1) the contralateral ST36 acupuncture point (right side), and (2) the ipsilateral ST36 acupuncture point (left side). OUTCOME MEASURE: Blind-spot perimetry length was the outcome measure. RESULTS: Electroacupuncture to the contralateral side decreased the blind-spot perimetry length by 5.0 (-9.3 to 0.9) [median (interquartile range, IQR)], whereas that to the ipsilateral side increased the length by 4.5 (-3.7 to 7.8) [median, IQR]. There was significant difference in this length between the two groups (p < 0.05). CONCLUSIONS: These results suggest that electroacupuncture application increased or decreased the brain function- as assessed by changes to the blind spot-depending on the treatment side: Contralateral-side treatment has a better effect than ipsilateral-side treatment on brain function. However, further randomized studies that include both right- and left-side-enlarged subjects with a sham needle are needed to convincingly show the effects of contralateral acupuncture on brain function.

A history of the optic nerve and its diseases.

We will trace the history of ideas about optic nerve anatomy and function in the Western world from the ancient Greeks to the early 20th century and show how these influenced causal theories of optic nerve diseases. Greek and Roman humoral physiology needed a hollow optic nerve, the obstruction of which prevented the flow of visual spirit to and from the brain and resulted in blindness. Medieval physicians understood that the presence of a fixed dilated pupil indicated optic nerve obstruction, preventing the passage of visual spirit, and that cataract surgery in such cases would not restore sight. During the Renaissance, the organ of vision was transferred from the lens to the optic nerve, which was generally believed to be on the axis of the eye. The acuity of central vision (at the optic disc) was explained by the concentration of visual spirit where the optic nerve met the retina. The growth of anatomy and influence of mechanical philosophy from the 17th century led to visual spirit being replaced with the concept of nerve force, which later became associated with electricity travelling along nerve fibres. This coincided with discourse about the nature of the nervous system and a shift in orientation from understanding illness holistically in terms of an individual's humoral imbalance to the concept of organ-based diseases. Both the microscope and the ophthalmoscope allowed visualisation of the optic nerve, but problems of interpretation persisted until conceptual transformations in medical science were made.

An aura of confusion: 'seeing auras-vital energy or human physiology?' Part 1 of a three part series.

The first of three papers that considers claims made for the perception or detection of vital energy. Many systems of Complementary and Alternative Medicine (CAM) assume the existence of a vital force that mediates therapeutic efficacy, for example chi or qi in Traditional Chinese medicine. Vital energy directly perceived or imaged that surrounds living organisms is frequently termed the aura. This paper aims to show how phenomena that arise as a consequence of the normal functioning of the human visual system can be inappropriately offered as support of claims for the direct perception of vital energy or the aura. Specifically, contrast and complementary colour phenomena, entoptic phenomena and the deformation phosphene, the 'flying corpuscle effect', the blind spot and the 'reverse telescope effect' are explained and discussed.

Changes in brain function after manipulation of the cervical spine.

OBJECTIVE: To ascertain whether manipulation of the cervical spine is associated with changes in brain function. DESIGN: Physiological cortical maps were used as an integer of brain activity before and after manipulation of the cervical spine in a large (500 subjects), double-blind controlled study. SETTING: Institutional clinic Participants: Adult volunteers. INTERVENTION: Five hundred subjects were divided into six comparative groups and underwent specific manipulation of the second cervical motion segment. Blinded examiners obtained reproducible pre- and postmanipulative cortical maps, which were subjected to statistical analysis. MAIN OUTCOME MEASURES: Brain activity was demonstrated by reproducible circumferential measurements of cortical hemispheric blind-spot maps before and after manipulation of the second cervical motion segment. Twelve null hypotheses were developed. The critical alpha level was adjusted in accordance with Bonferroni's theorem to .004 (.05 divided by 12) to reduce the likelihood of wrongly rejecting the null hypothesis (i.e., committing a Type I error). RESULTS: Manipulation of the cervical spine on the side of an enlarged cortical map is associated with increased contralateral cortical activity with strong statistical significance (p < .001). Manipulation of the cervical spine on the side opposite an enlarged cortical map is associated with decreased cortical activity with strong statistical significance (p < .001). Manipulation of the cervical spine was specific for changes in only one cortical hemisphere with strong statistical significance (p < .001). CONCLUSIONS: Accurate reproducible maps of cortical responses can be used to measure the neurological consequences of spinal joint manipulation. Cervical manipulation activates specific neurological pathways. Manipulation of the cervical spine may be associated with an increase or a decrease in brain function depending upon the side of the manipulation and the cortical hemisphericity of a patient.

Changes in the optic disc over a five-year interval: the Beaver Dam Eye Study.

PURPOSE: To determine the relationship of change in vertical optic disc cupping to change in intraocular pressure over a five-year interval. METHODS: Non-simultaneous stereoscopic photographs were taken of optic discs of participants in the baseline and follow-up examinations of The Beaver Dam Eye Study cohort. Optic discs and cups were measured and other disc features were graded according to a standard protocol by trained graders. Intraocular pressures were measured by Goldmann applanation tonometry. RESULTS: Change in pressure was significantly associated with change in vertical cup-to-disc ratio. Incident disc hemorrhage, flattened temporal rim, notching, cup reaching disc margin, and undercutting were not significantly associated with change in intraocular pressure. CONCLUSION: Change in intraocular pressure in this adult population was associated with increased optic disc cupping. This finding, if confirmed, would lend support to the practice of periodic follow-up of older adults who have shown changes in their intraocular pressure.

Gray crescent in the optic nerve head.

Twenty-nine patients had a slate-gray crescent within the peripheral tissue of the optic nerve head. Twenty-five of the patients were black; an examination of 100 consecutive black patients revealed the gray crescent in 12 cases. The gray crescents were usually bilateral and were most often located along the temporal or inferotemporal disk margin. Failure to recognize the anatomic location of the gray crescent may lead to misdiagnosis of disk cupping.