Inner Nuclear Layer Thickening Is Inversley Proportional to Retinal Ganglion Cell Loss in Optic Neuritis

Aim

To examine the relationship between retinal ganglion cell loss and changes in the inner nuclear layer (INL) in optic neuritis (ON).

Methods

36 multiple sclerosis (MS) patients with a history of ON and 36 age and sex-matched controls underwent Optical Coherence Tomography. The paramacular retinal nerve fiber layer (RNFL), combined ganglion cell and inner plexiform layers (GCL/IPL) and inner nuclear layer (INL) thickness were measured at 36 points around the fovea. To remove inter-subject variability, the difference in thickness of each layer between the ON and fellow eye of each patient was calculated. A topographic analysis was conducted.

Results

The INL of the ON patients was thicker than the controls (42.9µm versus 39.6µm, p=0.002). ON patients also had a thinner RNFL (27.8µm versus 32.2µm, p<0.001) and GCL/IPL (69.3µm versus 98.1µm, p<0.001). Among the controls, there was no correlation between RNFL and GCL/IPL as well as RNFL and INL, but a positive correlation was seen between GCL/IPL and INL (r=0.65, p<0.001). In the ON group, there was a positive correlation between RNFL and GCL/IPL (r=0.80, p<0.001) but a negative correlation between RNFL and INL (r=-0.61, p<0.001) as well as GCL/IPL and INL (r=-0.44, p=0.007). The negative correlation between GCL/IPL and INL strengthened in the ON group when inter-subject variability was removed (r=-0.75, p<0.001). Microcysts within the INL were present in 5 ON patients, mainly in the superior and infero-nasal paramacular regions. While patients with microcysts lay at the far end of the correlation curve between GCL/IPL and INL (i.e. larger INL and smaller GCL/IPL compared to other patients), their exclusion did not affect the correlation (r= -0.76, p<0.001).

Conclusions

INL enlargement in MS-related ON is associated with the severity of GCL loss. This is a continuous relationship and patients with INL microcysts may represent the extreme end of the scale.     

Correlation of Retinal Nerve Fibre Layer Thickness and Spontaneous Retinal Venous Pulsations in Glaucoma and Normal Controls

Purpose

To study the relationship between amplitude of spontaneous retinal venous pulsatility (SRVP) and retinal nerve fibre layer (RNFL) thickness in glaucomatous eyes, and to determine if this parameter may be a potential marker for glaucoma severity.

Method

85 subjects including 50 glaucoma (21 males, 67±10 yrs) and 35 normals (16 males, 62±11 yrs) were studied. SRVP amplitude was measured using the Dynamic Vessel Analyser (DVA, Imedos, Germany) at four regions of the retina simultaneously within one disc diameter from the optic disc—temporal-superior (TS), nasal-superior (NS), temporal-inferior (TI) and nasal-inferior (NI)). This was followed by RNFL thickness measurement using spectral domain optical coherence tomography (Spectralis OCT). The correlation between SRVP amplitude and corresponding sectoral RNFL thickness was assessed by means of non-linear regression (i.e. logarithmic). Linear regression was also applied and slopes were compared using analysis of covariance (ANCOVA).

Results

Greater SRVP amplitude was associated with thicker RNFL. Global SRVP amplitude was significantly lower in glaucoma eyes compared with normals (p<0.0001). The correlation coefficient of the linear regression between RNFL and SRVP at TS, NS, TI and NI quadrants in the glaucoma group were r = 0.5, 0.5, 0.48, 0.62. Mean SRVP amplitude and RNFL thickness for TS, NS, TI and NI quadrants were 4.3±1.5, 3.5±1.3, 4.7±1.6, 3.1±1 μm and 96±30, 75±22, 89±35 and 88±30 μm, respectively. The ANCOVA test showed that the slope of linear regression between the four quadrants was not significant (p>0.05). Since the slopes are not significantly different, it is possible to calculate one slope for all the data. The pooled slope equals 10.8 (i.e. RNFL = 10.8SRVP+41).

Conclusion

While SRVP was present and measurable in all individuals, the amplitude of SRVP is reduced in glaucoma with increasing RNFL loss. Our findings suggest the degree of SRVP may be an additional marker for glaucoma severity. Further studies are needed to determine the mechanism of reduction in SRVP, and whether changes can predict increased risk of progression.     

Parallel Changes in Structural and Functional Measures of Optic Nerve Myelination after Optic Neuritis

IntroductionVisual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON.MethodsThirty acute ON patients were studied at 1,3,6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further.ResultsBoth latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94ms of latency delay.ConclusionA strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination.     

Comparison of Longitudinal In Vivo Measurements of Retinal Nerve Fiber Layer Thickness and Retinal Ganglion Cell Density after Optic Nerve Transection in Rat

Purpose

To determine the relationship between longitudinal in vivo measurements of retinal nerve fiber layer thickness (RNFLT) and retinal ganglion cell (RGC) density after unilateral optic nerve transection (ONT).

Methods

Nineteen adult Brown-Norway rats were studied; N = 10 ONT plus RGC label, N = 3 ONT plus vehicle only (sans label), N = 6 sham ONT plus RGC label. RNFLT was measured by spectral domain optical coherence tomography (SD-OCT) at baseline then weekly for 1 month. RGCs were labeled by retrograde transport of fluorescently conjugated cholera toxin B (CTB) from the superior colliculus 48 hours prior to ONT or sham surgery. RGC density measurements were obtained by confocal scanning laser ophthalmoscopy (CSLO) at baseline and weekly for 1 month. RGC density and reactivity of microglia (anti-Iba1) and astrocytes (anti-GFAP) were determined from post mortem fluorescence microscopy of whole-mount retinae.

Results

RNFLT decreased after ONT by 17% (p<0.05), 30% (p<0.0001) and 36% (p<0.0001) at weeks 2, 3 and 4. RGC density decreased after ONT by 18%, 69%, 85% and 92% at weeks 1, 2, 3 and 4 (p<0.0001 each). RGC density measured in vivo at week 4 and post mortem by microscopy were strongly correlated (R = 0.91, p<0.0001). In vivo measures of RNFLT and RGC density were strongly correlated (R = 0.81, p<0.0001). In ONT- CTB labeled fellow eyes, RNFLT increased by 18%, 52% and 36% at weeks 2, 3 and 4 (p<0.0001), but did not change in fellow ONT-eyes sans CTB. Microgliosis was evident in the RNFL of the ONT-CTB fellow eyes, exceeding that observed in other fellow eyes.

Conclusions

In vivo measurements of RNFLT and RGC density are strongly correlated and can be used to monitor longitudinal changes after optic nerve injury. The strong fellow eye effect observed in eyes contralateral to ONT, only in the presence of CTB label, consisted of a dramatic increase in RNFLT associated with retinal microgliosis.     

Optic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes

Magnetisation transfer ratio (MTR) can reveal the degree of proton exchange between free water and macromolecules and was suggested to be pathological informative. We aimed to investigate changes in optic nerve MTR over 12 months following acute optic neuritis (ON) and to determine whether MTR measurements can predict clinical and paraclinical outcomes at 6 and 12 months. Thirty-seven patients with acute ON were studied within 2 weeks of presentation and at 1, 3, 6 and 12 months. Assessments included optic nerve MTR, retinal nerve fibre layer (RNFL) thickness, multifocal visual evoked potential (mfVEP) amplitude and latency and high (100%) and low (2.5%) contrast letter acuity. Eleven healthy controls were scanned twice four weeks apart for comparison with patients. Patient unaffected optic nerve MTR did not significantly differ from controls at any time-point. Compared to the unaffected nerve, affected optic nerve MTR was significantly reduced at 3 months (mean percentage interocular difference = −9.24%, p = 0.01), 6 months (mean = −12.48%, p<0.0001) and 12 months (mean = −7.61%, p = 0.003). Greater reduction in MTR at 3 months in patients was associated with subsequent loss of high contrast letter acuity at 6 (ρ = 0.60, p = 0.0003) and 12 (ρ = 0.44, p = 0.009) months, low contrast letter acuity at 6 (ρ = 0.35, p = 0.047) months, and RNFL thinning at 12 (ρ = 0.35, p = 0.044) months. Stratification of individual patient MTR time courses based on flux over 12 months (stable, putative remyelination and putative degeneration) predicted RNFL thinning at 12 months (F _2,32 = 3.59, p = 0.02). In conclusion, these findings indicate that MTR flux after acute ON is predictive of axonal degeneration and visual disability outcomes.     

Optic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes

Background

Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS).

Objectives

To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months.

Methods

Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction.

Results

Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated.

Conclusions

These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.     

Microcystic Inner Nuclear Layer Changes and Retinal Nerve Fiber Layer Defects in Eyes with Glaucoma

Objective

To examine microcystic inner nuclear layer (INL) changes in glaucomatous eyes and to determine associated factors.

Design

Retrospective, cross-sectional, observational study.

Methods

Two hundred seventeen eyes of 133 patients with primary open angle glaucoma (POAG), 41 eyes of 32 patients with preperimetric glaucoma and 181 normal eyes of 117 subjects were ultimately included. Microcystic INL lesions were examined with infrared fundus images and with 19 vertical spectral domain optical coherence tomography (SD-OCT) images in the macular area.

Results

Microcystic INL changes were observed in 6.0% of eyes with POAG, but none of the normal eyes or eyes with preperimetric glaucoma showed microcystic INL changes. The proportion of eyes with advanced glaucoma was significantly larger (P = 0.013) in eyes with microcystic lesions than without. The visual field mean deviation (MD) slope was also significantly worse (P = 0.027) in eyes with microcystic lesions. No significant differences were observed in age, sex, refraction, axial length, intraocular pressure, or MD value between eyes with and without microcystic INL lesions. In several cases, microcystic INL lesions occurred along with glaucomatous visual field progression. The retinal nerve fiber layer (RNFL) thickness (P = 0.013) and ganglion cell layer (GCL) + inner plexiform layer thickness (P = 0.023) were significantly lower in areas with microcystic lesions than without. The INL was also significantly thicker (P = 0.002) in areas with microcystic lesions.

Conclusions

Microcystic INL lesions in glaucomatous eyes are closely associated with RNFL and GCL thinning and correlated with worse MD slope. These INL lesions may indicate focal and progressive damage in glaucoma.     

Retinal Nerve Fiber and Optic Disc Morphology in Patients with Human Immunodeficiency Virus Using the Heidelberg Retina Tomography 3

Purpose

To use novel confocal scanning ophthalmoscopy technology to test hypothesis that HIV-seropositive patients without history of retinitis with a history of a low CD4 count are more likely to have damage to their retinal nerve fiber layer (RNFL) when compared to patients with high CD4 count. In addition, we compared optic disc morphologic changes with glaucoma.

Design

Cross-sectional study.

Participants and Controls

171 patients were divided into four groups. The control group consisted of 40 eyes of 20 HIV-seronegative patients. The second group consisted of 80 eyes of 41 HIV-positive patients whose CD4 cell count never dropped below 100 (1.0 x 10⁹/L). The third group consisted of 44 eyes of 26 HIV-positive patients with a history of low CD4 counts <100. Fourth group consisted of 79 eyes of 79 patients with confirmed glaucoma who served as positive controls.

Testing

Confocal scanning laser ophthalmoscopy was performed with the Heidelberg Retina Tomograph (HRT3) and data were analyzed with HRT3, software (Heyex version 1.5.10.0).

Main Outcome Measures

Disc area, cup area, cup volume, rim volume, mean cup depth, maximum cup depth, cup-to-disc ration, mean RNFL thickness, and RNFL cross-sectional area.

Results

Analysis of the global optic nerve and cup parameters showed no difference in disk area among the four groups. There was also no difference in cup, rim volume, mean cup depth, or maximum cup depth among the first three groups but they were all different from glaucoma group. The RNFL was thinner in glaucoma and both HIV-positive groups compared to HIV-seronegative subjects. The cross sectional RNFL area was thinner in both high and low CD4 HIV-positive groups compared to HIV-seronegative group in the nasal and temporal/inferior sectors, respectively. Glaucoma group showed thinning in all sectors.

Conclusions

HIV retinopathy results in retinal nerve fiber layer loss without structural optic nerve supportive tissue change. RNFL damage may occur early in HIV disease by mechanism different than in glaucoma.     

Letter to the Editor: Seasonal Pattern of Births in Patients with Optic Neuritis

Attentional processes are fundamental to good cognitive functioning of human operators. The purpose of this study was to analyze the activity of neuronal networks involved in the orienting attention and executive control processes from the perspective of diurnal variability. Twenty-three healthy male volunteers meeting magnetic resonance (MR) inclusion criteria performed the Stroop Color-Word task (block design) in the MR scanner five times/day (06:00, 10:00, 14:00, 18:00, 22:00 h). The first scanning session was scheduled 1–1.5 h after waking. Between MR sessions, subjects performed simulated driving tasks in stable environmental conditions, with controlled physical activity and diet. Significant activation was found in brain regions related to the orienting attentional system: the parietal lobe (BA40) and frontal eye-fields (FEFs). There were also activations in areas of the executive control system: the fronto-insular cortex (FIC), dorsal anterior cingulate cortex (dACC), presupplementary motor area (preSMA), supplementary motor area (SMA), basal ganglia, middle temporal (MT; BA21), and dorsolateral prefrontal cortex (DLPFC), as a part of the central executive network. Significant deactivations were observed in the rostral anterior cingulate cortex (rACC), posterior cingulate cortex (PCC), superior frontal gyrus (SF), parietal lobe (BA39), and parahippocampal that are thought to comprise the default mode network (DMN). Additionally, the activated regions included bilaterally lingual gyrus and fusiform gyrus. The insula was bilaterally deactivated. Visual attention controlled by the goal-oriented attention system and comprising top-down and bottom-up mechanisms, activated by Stroop-like task, turned out to be prone to diurnal changes. The study results show the occurrence of time-of-day–related variations in neural activity of brain regions linked to the orienting attentional system (left parietal lobe—BA40, left and right FEFs), simultaneously providing arguments for temporal stability of the executive system and default mode network. These results also seem to suggest that the involuntary, exogenous (bottom-up) mechanism of attention is more vulnerable to circadian and fatigue factors than the voluntary (top-down) mechanism, which appear to be maintained at the same functional level during the day. The above phenomena were observed at the neural level. (Author correspondence: marek@uj.edu.pl)     

Interocular Retinal Nerve Fiber Layer Thickness Difference in Normal Adults

PurposeTo determine the interocular retinal nerve fiber layer (RNFL) thickness difference of normal subjects.MethodsBoth eyes of 230 normal adults received peripapillary RNFL thickness measurements using OCT. The effect of ocular cyclotorsion on the RNFL thickness profile was mathematically corrected. The fractional and absolute interocular RNFL thickness differences at 256 points of peripapillary area were calculated. We divided the subjects into 3 groups according to the locations of superior and inferior peak thickness, respectively, and compared the interocular RNFL thickness differences between the subgroups.ResultsThe fractional interocular RNFL thickness difference exhibited smaller regional variations than the absolute interocular difference. The means of fractional interocular differences were 0.100 ± 0.077 in the temporal half area and 0.146 ± 0.105 in the nasal half area, and the tolerance limits for the 95th and 99th distributions were about 0.246 and 0.344 in the temporal half area and 0.293 and 0.408 in the nasal half area, respectively. The fractional interocular differences of subgroups classified by the locations of superior and inferior peak RNFL thickness showed difference at smaller areas than the absolute interocular differences (19 and 8 points versus 49 and 23 points, respectively).ConclusionGlaucoma can be strongly suspected, if interocular fractional RNFL thickness difference is over 25% at 5 consecutive points or over 35% at 3 consecutive points in the temporal half area. The fractional interocular comparison is a better diagnostic approach because the fractional interocular RNFL thickness difference is less influenced by the locations of peak RNFL thickness.     

Optic Neuritis Is Associated with Inner Nuclear Layer Thickening and Microcystic Macular Edema Independently of Multiple Sclerosis

Background

Microcystic macular edema (MME) and inner nuclear layer thickening (INL) were described in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients using optical coherence tomography (OCT). The cause of these findings is currently unknown and a relation to inflammatory or degenerative processes in the optic nerve is discussed.

Objective

The aim of our study was to investigate whether INL thickening and MME are related to optic neuritis (ON) in various neuro-inflammatory disorders causingON: MS, NMO and chronic inflammatory optic neuropathy.

Methods

We retrospectively analyzed data from 216 MS patients, 39 patients with a clinically isolated syndrome, 20 NMO spectrum disorder patients, 9 patients with chronic inflammatory optic neuropathy and 121 healthy subjects. Intra-retinal layer segmentation was performed for the eyes of patients with unilateral ON. Scanning laser ophthalmoscopy (SLO) images were reviewed for characteristic ocular fundus changes.

Results

Intra-retinal layer segmentation showed that eyes with a history of ON displayed MME independent INL thickening compared to contralateral eyes without previous ON. MME was detected in 22 eyes from 15 patients (5.3% of all screened patients), including 7 patients with bilateral edema. Of these, 21 had a prior history of ON (95%). The SLO images of all 22 MME-affected eyes showed crescent-shaped texture changes which were visible in the perifoveal region. A second grader who was blinded to the results of the OCT classified all SLO images for the presence of these characteristic fundus changes. All MME eyes were correctly classified (sensitivity = 100%) with high specificity (95.2%).

Conclusion

This study shows that both MME and INL thickening occur in various neuro-inflammatory disorders associated with ON. We also demonstrate that detection and analysis of MME by OCT is not limited to B-scans, but also possible using SLO images.     

Macular Microcysts in Mitochondrial Optic Neuropathies: Prevalence and Retinal Layer Thickness Measurements

Purpose

To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON).

Methods

All patients with molecularly confirmed MON, i.e. Leber’s Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections.

Results

MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1±7μm vs 122.3±9μm in MM patients (p<0.01) and 128.5±8μm vs. 122.3±9μm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4±1mμ) compared to patients without MM [77.5±8mμ (p<0.001)] and controls [78.4±7mμ (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls.

Conclusion

The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces.     

Postnatal Changes in Enzyme Activities in Synaptosomes Isolated from Hamster Optic Nerve Endings

Subsynaptosomal fractions isolated from optic terminal nuclei of adult and neonatal hamsters exhibited developmental changes in specific density, mitochondrial activity, and K+-stimulated, ouabain-inhibited p-nitrophenylphosphatase (K-pNPPase) activity around the time of eye opening. The specific activity of K-pNPPase was six- to sevenfold higher after eye opening (14-16 days postnatal). A significant proportion of high-specific- activity K-pNPPase was recovered from the lightest subsynaptosomal fraction at all ages. This fraction contained very little external membrane by galactose oxidase - NaB3H4 labeling, suggesting that it may represent an internal pool, possibly the axonally transported form of the enzyme. Synaptic mitochondrial cytochrome c. oxidase activity also approximately doubled in the period between 12 and 16 days. The specific density of the external membrane increased very slowly, banding at 1.0 M sucrose at 12 and 16 days, and at 1.2 M in adults. These maturational events may reflect increased energetic needs for optic nerve endings following eye opening.     

Retinal Nerve Fiber Layer Thickness Changes in Parkinson Disease: A Meta-Analysis

Background

Parkinson disease (PD) is a neurodegenerative process that leads to a selective loss of dopaminergic neurons, mainly in the basal ganglia of the brain. Numerous studies have analyzed the ability of optical coherence tomography (OCT) to detect retinal nerve fiber layer (RNFL) thickness abnormalities and changes in PD, but the results have not always been consistent. Therefore, we carried out a meta-analysis to evaluate the RNFL thickness measured with OCT in PD.

Methods and Findings

Case-control studies were selected through an electronic search of the Cochrane Controlled Trials Register, PUBMED and EMBASE. For the continuous outcomes, we calculated the weighted mean difference (WMD) and 95% confidence interval (CI). The statistical analysis was performed by RevMan 5.0 software. Thirteen case-control studies were included in the present meta-analysis, containing a total of 644 eyes in PD patients and 604 eyes in healthy controls. The results of our study showed that there was a significant reduction in average RNFL thickness in patients with PD compared to healthy controls (WMD = −5.76, 95% CI: −8.99 to −2.53, P = 0.0005). Additionally, differences of RNFL thickness in superior quadrant (WMD = −4.44, 95% CI: −6.93 to −1.94, P = 0.0005), inferior quadrant (WMD = −7.56, 95% CI: −11.33 to −3.78, P<0.0001), nasal quadrant (WMD = −3.12, 95% CI: −5.63 to −0.61, P = 0.01) and temporal quadrant (WMD = −4.63, 95% CI: −7.20 to −2.06, P = 0.0004) were all significant between the two groups.

Conclusion

In view of these results and the noninvasive nature of OCT technology, we surmise that OCT could be a useful tool for evaluating the progression of the Parkinson disease.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01928212","term_id":"NCT01928212"}}NCT01928212     

Does Optic Nerve Head Surface Topography Change Prior to Loss of Retinal Nerve Fiber Layer Thickness: A Test of the Site of Injury Hypothesis in Experimental Glaucoma

Purpose

To test the hypothesis that optic nerve head (ONH) deformation manifesting as changes in its mean surface height precedes thinning of the peripapillary retinal nerve fiber layer (RNFL) in experimental glaucoma (EG).

Methods

68 rhesus macaque monkeys each had three or more baseline imaging sessions under manometric intraocular pressure (IOP) control to obtain average RNFL thickness (RNFLT) and the ONH surface topography parameter mean position of the disc (MPD). Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic, mild-to-moderate IOP elevation and bi-weekly imaging continued. Event analysis was applied to determine for each parameter when an ‘endpoint’ occurred (signficant change from baseline) for eight different endpoint criteria. Specificity was assessed in the group of 68 fellow control eyes. Classical signal detection theory and survival analysis were used to compare MPD with RNFLT.

Results

Regardless of the endpoint criterion, endpoints were always more frequent for MPD than for RNFLT. The discriminability index (d’) was 2.7 ± 0.2 for MPD and 1.9 ± 0.2 for RNFLT (p<0.0001). Endpoints were reached by MPD an average of 1-2 months earlier than by RNFLT (p<0.01). At the onset of the first specific, detectable MPD change in EG eyes, there was still no significant change in RNFLT on average (p=0.29) and only 25% of individual eyes exhibited signficant reduction. In contrast, at onset of signficant RNFLT change, MPD had already changed an average of 101 µm from baseline (p<0.0001) and 71% of the individual eyes had exhibited significant change. The magnitude of MPD change was more than could be explained on the basis of axon loss alone.

Conclusions

This study demonstrates that the average surface height of the ONH changes prior to any detectable loss of average peripapillary RNFL thickness in non-human primate eyes with experimental glaucoma.     

Central Retinal Venous Pressure in Eyes of Normal-Tension Glaucoma Patients with Optic Disc Hemorrhage

ObjectiveTo compare central retinal venous pressure (CRVP) among eyes with and without optic disc hemorrhage (ODH) in bilateral normal-tension glaucoma (NTG) patients and NTG eyes without an episode of ODH.MethodsIn this prospective study, 22 bilateral NTG patients showing a unilateral ODH and 29 bilateral NTG patients without an episode of ODH were included. Eyes were categorized into group A (n = 22, eyes with ODH), group B (n = 22, fellow eyes without ODH), and group C (n = 29, NTG eyes without an episode of ODH). A contact lens ophthalmodynamometer was used to measure CRVP and central retinal arterial pressure (CRAP).ResultsIntraocular pressure (IOP) measured on the day of contact lens ophthalmodynamometry showed no difference among groups. However, the mean baseline IOP in group A was significantly lower than that in group C (P = .008). The CRVP in group A (29.1 ± 10.8 mmHg) was significantly lower than that in group C (40.1 ± 8.8 mmHg, P = .001), but similar to that in group B (30.5 ± 8.7 mmHg, P = .409). A similar relationship was noted for CRAP. No significant eye-associated variable for ODH was found in group A and B by conditional logistic regression analysis (all P > 0.05). However, multivariate logistic regression analysis in groups A and C revealed that low mean baseline IOP (odds ratio [OR] = 0.69, 95% confidence interval [CI] 0.49-0.98, P = 0.043) and low CRVP (OR = 0.88, 95% CI 0.80-0.95, P = 0.003) were associated with ODH.ConclusionsCRVP was lower in NTG eyes with ODH than in eyes without an episode of ODH, but similar to that of fellow eyes without ODH. These imply less likelihood of association between increased central retinal venous resistance and ODH.     

Target-Dependent Regulation of Retinal Nicotinic Acetylcholine Receptor and Tubulin RNAs During Optic Nerve Regeneration in Goldfish

A fundamental issue in central nervous system development regards the effect of target tissue on the differentiation of innervating neurons. We address this issue by characterizing the role the retinal ganglion cell target, i.e., the optic tectum, plays in regulating expression of tubulin and nicotinic acetylcholine receptor genes in regenerating retinal ganglion cells. Tubulins are involved in axonal growth, whereas nicotinic acetylcholine receptors mediate communication across synapses. Retinal ganglion cell axons were induced to regenerate by crushing the optic nerve. Following crush, there was a rapid increase in alpha-tubulin RNAs (3 days), which preceded the increase in nicotinic acetylcholine receptor RNAs (10-15 days). Both classes of RNAs approached control levels by the time retinotectal synapses and functional recovery were restored (4-6 weeks). If the optic nerve was repeatedly crushed or its target ablated, tubulin RNAs remained elevated, and the increase in receptor RNAs that would otherwise be seen 2 weeks after a single nerve crush did not occur. The interaction of retinal ganglion cell axons with their targets in the optic tectum appears, then, to exert a suppressive effect on the RNA encoding a cytoskeletal protein, tubulin, and an inductive effect on RNAs encoding nicotinic acetylcholine receptors involved in synaptic communication.     

Peripapillary Retinal Nerve Fiber Layer Changes in Preclinical Diabetic Retinopathy: A Meta-Analysis

BackgroundDiabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent.ObjectiveTo assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy.MethodsA literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software.ResultsThirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88μm, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21μm, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79μm, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99μm, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88μm, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22μm, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients.ConclusionPeripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention.     

Protection of Pattern Electroretinogram and Retinal Ganglion Cells by Oncostatin M after Optic Nerve Injury

Injury to retinal ganglion cell (RGC) axons leads to selective loss of RGCs and vision. Previous studies have shown that exogenous neurotrophic factors promote RGC survival. We investigated the neuroprotective effects of oncostatin M (OSM), a member of the IL-6 family of cytokines, on pattern electroretinogram (PERG) and RGC survival after optic nerve crush (ON-crush) in the mouse. BALB/C mice received ON-crush in the left eyes for either 4-second or 1-second duration (4-s or 1-s). Fluoro-gold retrograde labeling was used to identify RGCs. RGC function was assessed by PERG measurement. OSM or CNTF protein was injected intravitreally immediately after ON-crush. OSM responsive cells were identified by localization of increased STAT3 phosphorylation. Significant higher RGC survival (46% of untreated control) was seen in OSM-treated eyes when assessed 2 weeks after 4-s ON-crush as compared to that (14% of untreated control) of the PBS-treated eyes (P<0.001). In addition, PERG amplitude was significantly higher in eyes treated with OSM or CNTF 1 week after 1-s ON-crush (36% of baseline) as compared with the amplitude of PBS-treated eyes (19% of the baseline, P = 0.003). An increase in STAT3 phosphorylation was localized in Müller layer after OSM treatment, suggesting that Müller cells mediate the effect of OSM. Our results demonstrate that one single injection of either OSM or CNTF after ON-crush improves RGC survival together with their electrophysiological activity. These data provide proof-of-concept for using neurotrophic factors OSM and CNTF for RGC degenerative diseases, including glaucoma and acute optic nerve trauma.     

Dynamic Visual Tests to Identify and Quantify Visual Damage and Repair Following Demyelination in Optic Neuritis Patients

In order to follow optic neuritis patients and evaluate the effectiveness of their treatment, a handy, accurate and quantifiable tool is required to assess changes in myelination at the central nervous system (CNS). However, standard measurements, including routine visual tests and MRI scans, are not sensitive enough for this purpose. We present two visual tests addressing dynamic monocular and binocular functions which may closely associate with the extent of myelination along visual pathways. These include Object From Motion (OFM) extraction and Time-constrained stereo protocols. In the OFM test, an array of dots compose an object, by moving the dots within the image rightward while moving the dots outside the image leftward or vice versa. The dot pattern generates a camouflaged object that cannot be detected when the dots are stationary or moving as a whole. Importantly, object recognition is critically dependent on motion perception. In the Time-constrained Stereo protocol, spatially disparate images are presented for a limited length of time, challenging binocular 3-dimensional integration in time. Both tests are appropriate for clinical usage and provide a simple, yet powerful, way to identify and quantify processes of demyelination and remyelination along visual pathways. These protocols may be efficient to diagnose and follow optic neuritis and multiple sclerosis patients.In the diagnostic process, these protocols may reveal visual deficits that cannot be identified via current standard visual measurements. Moreover, these protocols sensitively identify the basis of the currently unexplained continued visual complaints of patients following recovery of visual acuity. In the longitudinal follow up course, the protocols can be used as a sensitive marker of demyelinating and remyelinating processes along time. These protocols may therefore be used to evaluate the efficacy of current and evolving therapeutic strategies, targeting myelination of the CNS.