Dan Milea

Monochromatic Pupillometry in Unilateral Glaucoma Discloses no Adaptive Changes Subserved by the ipRGCs

Purpose: To detect signs of a possible adaptive mechanism of the intrinsically photosensitive ganglion cells in unilateral glaucoma. Method: Eleven patients with unilateral glaucoma, classified by automated perimetry (glaucoma: mean deviation <0), were studied by monochromatic pupillometry, employing red (660u2009nm) or blue (470u2009nm) light, and by optical coherence tomography of the peripapillary retinal nerve fiber layer. The main outcome measure in pupillometry, the area under the curve (AUC), i.e., the product of pupillary contraction amplitude and time, was determined during and after light exposure in glaucomatous and unafflicted fellow eyes and compared to the AUCs of a healthy, age-matched control group. Results: The AUC to stimulation with blue light was significantly reduced in glaucomatous eyes, both during and after stimulus, compared with that of fellow, unafflicted eyes (pu2009≤u20090.014). The AUC to red light stimulation was reduced during (pu2009=u20090.035), but not after (pu2009≥u20090.072), exposure in glaucomatous eyes. In the unafflicted fellow eyes, the pupillary response to blue light did not differ from that of healthy controls. Conclusion: The pupillary response to blue light was decreased in the glaucomatous eyes of unilateral glaucoma. No difference was detected between the pupillary light response of the unafflicted fellow eyes and that of a healthy, age-matched control group. Thus no sign of an adaptive mechanism was detected, neither in the glaucomatous nor in the unafflicted fellow eyes, and consequently glaucoma appears to differ from non-arteritic anterior ischemic optic neuropathy.

Finite Element Analysis Predicts Large Optic Nerve Head Strains During Horizontal Eye Movements.

PURPOSEnWe combined finite element (FE) analysis and dynamic magnetic resonance imaging (MRI) to estimate optic nerve head (ONH) strains during horizontal eye movements, and identified factors influencing such strains. We also compared ONH strains (prelamina, lamina cribrosa, and retrolamina strains) induced by eye movements to those induced by IOP.nnnMETHODSnThe ocular globes and orbits of a healthy subject were visualized during horizontal eye movements (up to 13°), using dynamic MRI. A baseline FE model of one eye was reconstructed in the primary gaze position, including details from the orbital and ONH tissues. Finite element-derived ONH strains induced by eye movements were compared to those resulting from an IOP of 50 mm Hg. Finally, a FE sensitivity study was performed, in which we varied the stiffness of all ONH connective tissues, to understand their influence on ONH strains.nnnRESULTSnOur models predicted that, during horizontal eye movements, the optic nerve pulled the ONH posteriorly. Optic nerve head strains following a lateral eye movement of 13° were large and higher than those resulting from an IOP of 50 mm Hg. These results held true even with variations in connective tissue stiffness. We also found that stiff sclerae reduced lamina cribrosa and prelamina strains during eye movements, but stiff optic nerve sheaths significantly increased those strains.nnnCONCLUSIONSnOur models predicted high ONH strains during eye movements, which were aggravated with stiffer optic nerve sheaths. Further studies are needed to explore links between ONH strains induced by eye movements and axonal loss in glaucoma.

OPA1-related disorders: Diversity of clinical expression, modes of inheritance and pathophysiology.

Mutations in the Optic Atrophy 1 gene (OPA1) were first identified in 2000 as the main cause of Dominant Optic Atrophy, a disease specifically affecting the retinal ganglion cells and the optic nerve. Since then, an increasing number of symptoms involving the central, peripheral and autonomous nervous systems, with considerable variations of age of onset and severity, have been reported in OPA1 patients. This variety of phenotypes is attributed to differences in the effects of OPA1 mutations, to the mode of inheritance, which may be mono- or bi-allelic, and eventually to somatic mitochondrial DNA mutations. The diversity of the pathophysiological mechanisms involved in OPA1-related disorders is linked to the crucial role played by OPA1 in the maintenance of mitochondrial structure, genome and function. The neurological expression of these disorders highlights the importance of mitochondrial dynamics in neuronal processes such as dendritogenesis, axonal transport, and neuronal survival. Thus, OPA1-related disorders may serve as a paradigm in the wider context of neurodegenerative syndromes, particularly for the development of novel therapeutic strategies against these diseases.

Improved Locus‐Specific Database for OPA1 Mutations Allows Inclusion of Advanced Clinical Data

Autosomal‐dominant optic atrophy (ADOA) is the most common inherited optic neuropathy, due to mutations in the optic atrophy 1 gene (OPA1) in about 60%–80% of cases. At present, the clinical heterogeneity of patients carrying OPA1 variants renders genotype–phenotype correlations difficulty. Since 2005, when we published the first locus‐specific database (LSDB) dedicated to OPA1, a large amount of new clinical and genetic knowledge has emerged, prompting us to update this database. We have used the Leiden Open‐Source Variation Database to develop a clinico‐biological database, aiming to add clinical phenotypes related to OPA1 variants. As a first step, we validated this new database by registering several patients previously reported in the literature, as well as new patients from our own institution. Contributors may now make online submissions of clinical and molecular descriptions of phenotypes due to OPA1 variants, including detailed ophthalmological and neurological data, with due respect to patient anonymity. The updated OPA1 LSDB (http://opa1.mitodyn.org/) should prove useful for molecular diagnoses, large‐scale variant statistics, and genotype–phenotype correlations in ADOA studies.

In Vivo 3-Dimensional Strain Mapping Confirms Large Optic Nerve Head Deformations Following Horizontal Eye Movements

PurposenTo measure lamina cribrosa (LC) strains (deformations) following abduction and adduction in healthy subjects and to compare them with those resulting from a relatively high acute intraocular pressure (IOP) elevation.nnnMethodsnA total of 16 eyes from 8 healthy subjects were included. Among the 16 eyes, 11 had peripapillary atrophy (PPA). For each subject, both optic nerve heads (ONHs) were imaged using optical coherence tomography (OCT) at baseline (twice), in different gaze positions (adduction and abduction of 20°) and following an acute IOP elevation of approximately 20 mm Hg from baseline (via ophthalmodynamometry). Strains of LC for all loading scenarios were mapped using a three-dimensional tracking algorithm.nnnResultsnIn all 16 eyes, LC strains induced by adduction and abduction were 5.83% ± 3.78% and 3.93% ± 2.57%, respectively, and both significantly higher than the control strains measured from the repeated baseline acquisitions (P < 0.01). Strains of LC in adduction were on average higher than those in abduction, but the difference was not statistically significant (P = 0.07). Strains of LC induced by IOP elevations (on average 21.13 ± 7.61 mm Hg) were 6.41% ± 3.21% and significantly higher than the control strains (P < 0.0005). Gaze-induced LC strains in the PPA group were on average larger than those in the non-PPA group; however, the relationship was not statistically significant.nnnConclusionsnOur results confirm that horizontal eye movements generate significant ONH strains, which is consistent with our previous estimations using finite element analysis. Further studies are needed to explore a possible link between ONH strains induced by eye movements and axonal loss in optic neuropathies.

New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix–Saguenay

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment.

Optical coherence tomography angiography in acute non-arteritic anterior ischaemic optic neuropathy

Purpose To characterise vascular changes in eyes with acute non-arteritic anterior ischaemic optic neuropathy (NAION), using optical coherence tomography angiography (OCT-A) imaging. Methods This hospital-based observational case-control study included included five patients with acute NAION (6 eyes), within 7u2005days after onset of symptoms and 19 age-matched healthy controls (19 eyes). OCT-A (RTVue XR 100; Optovue, Fremont, California, USA), covering a 4.5×4.5u2005mm scan area, was used to evaluate peripapillary blood flow in cases and controls. The flow densities at the retinal and choroidal level were measured using the split-spectrum amplitude-decorrelation angiography algorithm. Results The mean age of the NAION and normal subjects was 69 (61–82) and 68 (58–82) years, respectively (p=0.3). At the acute stage, OCT-A disclosed global reduction of the mean peripapillary flow density in eyes with NAION (53.5±3.7%) compared with normal eyes (64.3±2.4%) (p<0.001). The mean vascular flow density was also reduced in the peripapillary choroid layer of eyes with NAION (53.2±7.8%) compared with controls (69.5±3.0%) (p<0.001). In patients (3 eyes) with resolution of optic disc oedema, a repeated OCT-A analysis (at 4–22u2005weeks) of the full segment (including retina and choroid) revealed spontaneous improvement of the average total peripapillary flow density by 8.1±2.7%. Conclusions Using OCT-A, we revealed a global and sectorial reduction of retinal and choroidal peripapillary flow densities at the acute stage of NAION, followed by partial subsequent spontaneous recovery. Further studies are needed to establish the potential value of OCT-A for evaluating NAION and other optic neuropathies.

Pupillary Responses to High-Irradiance Blue Light Correlate with Glaucoma Severity.

PURPOSEnTo evaluate whether a chromatic pupillometry test can be used to detect impaired function of intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with primary open-angle glaucoma (POAG) and to determine if pupillary responses correlate with optic nerve damage and visual loss.nnnDESIGNnCross-sectional study.nnnPARTICIPANTSnOne hundred sixty-one healthy controls recruited from a community polyclinic (55 men; 151 ethnic Chinese) and 40 POAG patients recruited from a glaucoma clinic (22 men; 35 ethnic Chinese) 50 years of age or older.nnnMETHODSnSubjects underwent monocular exposure to narrowband blue light (469 nm) or red light (631 nm) using a modified Ganzfeld dome. Each light stimulus was increased gradually over 2 minutes to activate sequentially the rods, cones, and ipRGCs that mediate the pupillary light reflex. Pupil diameter was recorded using an infrared pupillography system.nnnMAIN OUTCOME MEASURESnPupillary responses to blue light and red light were compared between control subjects and those with POAG by constructing dose-response curves across a wide range of corneal irradiances (7-14 log photons/cm(2) per second). In patients with POAG, pupillary responses were evaluated relative to standard automated perimetry testing (Humphrey Visual Field [HVF]; Carl Zeiss Meditec, Dublin, CA) and scanning laser ophthalmoscopy parameters (Heidelberg Retinal Tomography [HRT]; Heidelberg Engineering, Heidelberg, Germany).nnnRESULTSnThe pupillary light reflex was reduced in patients with POAG only at higher irradiance levels, corresponding to the range of activation of ipRGCs. Pupillary responses to high-irradiance blue light associated more strongly with disease severity compared with responses to red light, with a significant linear correlation observed between pupil diameter and HVF mean deviation (rxa0=xa0-0.44; Pxa0= 0.005) as well as HRT linear cup-to-disc ratio (rxa0= 0.61; P < 0.001) and several other optic nerve head parameters.nnnCONCLUSIONSnIn glaucomatous eyes, reduced pupillary responses to high-irradiance blue light were associated with greater visual field loss and optic disc cupping. In POAG, a short chromatic pupillometry test that evaluates the function of ipRGCs can be used to estimate the degree of damage to retinal ganglion cells that mediate image-forming vision. This approach could prove useful in detecting glaucoma.

Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy

To assess skeletal muscle weakness and progression as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD).

Dissociation of Pupillary Post-Illumination Responses from Visual Function in Confirmed OPA1 c.983A > G and c.2708_2711delTTAG Autosomal Dominant Optic Atrophy

Purpose: To test whether the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs), as evaluated by examination of the pupillary light reflex (PLR), are preserved in genetically confirmed autosomal dominant optic atrophy (ADOA). Method: Twenty-nine patients with either the c.983Au2009>u2009G (nu2009=u200914) or the c.2708_ 2711delTTAG mutation (nu2009=u200915) were examined with monochromatic pupillometry, using isoluminant (300u2009cd/m2), red (660u2009nm) or blue (470u2009nm) light, optical coherence tomography, automated visual field analysis, and with determination of best corrected visual acuity (BCVA). Since we examined two different mutations, initially we compared all outcome variables between the two, and finding no statistically significant difference, pooled them. Results: Despite a poor BCVA (56 letters, ETDRS) in the ADOA patients, their post-illuminatory pupil responses did not differ significantly from those of healthy controls (blue, pu2009=u20090.45, red, pu2009=u20090.49, t-test), and no statistically significant effect was noted of peripapillary retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, or age. Conclusion: The PLR to blue light of high luminance (300u2009cd/m2) was preserved in both c.983Au2009>u2009G and c.2708_2711delTTAG ADOA despite severe visual loss and optic nerve atrophy. The study confirms, in a large sample of two genetically homogenous groups, that the ipRGCs are spared in ADOA.