Macular ganglion cell-inner plexiform layer defect patterns in multiple sclerosis patients without optic neuritis: A Spectral-Domain-Optical Coherence Tomography Cross-Sectional, Case-Control, Pilot Study.

PURPOSE: Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate, in patients with multiple sclerosis without a history of optic neuritis (MSNON), the proportion of the different macular ganglion cell-inner plexiform layer complex (mGCIP) defect patterns. The results were compared with those of healthy controls (HCs). METHODS: In this cross-sectional case-control study, 34 eyes of 34 individuals, 17 with MSNON and 17 HCs, were evaluated. All participants underwent mGCIP thickness measurement using SD-OCT (Zeiss Cirrus HD-OCT 4000, macular cube protocol). The mGCIP defect patterns were classified in nine types (minimal, inner, outer, diffuse mild, diffuse severe inferior confined, inferior dominant, superior confined, and superior dominant), according to the shape derived by the deviation map of the instrument, and the proportion of each type was assessed. RESULTS: A mGCIP defect pattern was detected in 70.5% of MSNON eyes, with an inner type as the most frequent pattern (47%), followed by the outer type (11.7%) and the inferior confined type (11.7%). No defect was found in Hcs. CONCLUSIONS: A significant thinning of the mGCIP with the frequent presence of an inner defect was seen in MSNON patients. The presence of this defect may serve as a biomarker of subclinical optic nerve involvement in MS patients.

Retrograde Optic Nerve Degeneration in Pituitary Adenoma: A Study with RE-PERG.

Purpose: RE-PERG is altered in presence of primary neuronal degeneration of retinal ganglion cells, both in glaucoma and other diseases. A previous study showed that in a model of retrograde degeneration (vascular dementia) RE-PERG was normal. In this study, we enrolled patients with pituitary adenoma (PA) to evaluate RE-PERG findings in another model of retrograde degeneration compared with healthy controls (HC). Based on the outcome of the present and our previous studies with RE-PERG, and reviewing the literature, we discuss the physiopathology of glaucoma. Methods: Twelve PA patients and 14 age-matched HC were recruited. All participants performed visual field (VF) test, retinal nerve fiber layer (RNFL) and ganglion cells complex (GCC) thickness measurement by means of optical coherence tomography (OCT), visual evoked potentials (VEPs) and RE-PERG, a non-invasive, fast steady-state pattern electroretinogram (SS-PERG) sampled in five consecutive blocks of 130 events. Results: VEPs amplitude was significantly lower in PA with respect to HC (6.8±0.6 vs 7.4±0.6 µV; p=0.045). VEPs latency was higher in PA (123.2±5.8 vs 103.6±4.1 msec; p<0.01). As for VF, mean defect (MD) and pattern standard deviation (PSD) were higher in PA (-6.6±2.6 vs -0.01±1.02 dB; p<0.01 and 8.5±3.1 vs 1.5±0.3; p<0.01, respectively). RNFL thickness was lower in PA (88±8.1 vs 97±9.3 µ; p=0.01). There was no statistically significant difference between PA and HC for RE-PERG. There was a significant correlation among MD, PSD, VEPs amplitude, PERG amplitude and RNFL thickness in the PA group, whereas no correlation was found with SDPh, which remains as normal as in the HC group. Conclusion: Our findings confirm that RE-PERG is not altered in retrograde degeneration. Based on the outcome of the present and our previous studies about RE-PERG and glaucoma, we assume that in glaucoma a double mechanism of retinal ganglion cells degeneration, both retrograde and primary, can coexist.

Multicenter, Prospective, Randomized, Single Blind, Cross-Over Study on the Effect of a Fixed Combination of Citicoline 500 mg Plus Homotaurine 50 mg on Pattern Electroretinogram (PERG) in Patients With Open Angle Glaucoma on Well Controlled Intraocular Pressure.

Purpose: To evaluate the potential beneficial and synergistic effects of oral intake of a fixed combination of citicoline 500 mg plus homotaurine 50 mg (CIT/HOMO) on retinal ganglion cell (RGC) function in subjects with glaucoma using pattern electroretinogram (PERG) and to investigate the effects on visual field and quality of life. Methods: Consecutive patients with primary open-angle glaucoma with controlled IOP (<18 mmHg) receiving beta-blockers and prostaglandin analogs alone or as combination therapy (fixed or un-fixed); with stable disease (progression no more than -1 dB/year at the visual field MD); and an early to moderate visual field defect (MD < -12 dB) were randomized to: arm A. topical therapy + CIT/HOMO for 4 months, 2 months of wash out, 4 months of topical therapy alone; arm B. topical therapy alone for 4 months, topical therapy + CIT/HOMO for 4 months, 2 months of wash out. All patients underwent 4 visits: complete ocular examination, visual field, PERG and quality of life assessment (NEI-VFQ25) were performed at each visit. Results: Fifty-seven patients completed the study: 26 in group A and 31 in group B. At the end of the intake period, PERG's P50 and N95 waves recorded a greater amplitude. The increase was statistically significant in the inferior and superior P50 waves amplitude: 0.47 µV (95%CI, 0.02-0.93; p = 0.04) and 0.65 µV (95% CI, 0.16-1.13; p = 0.009), respectively, and in the inferior N95 wave amplitude 0.63 µV (95% CI, 0.22-1.04; p = 0.002). A significantly shorter peak time of 3.3 µV (95% CI, -6.01- -0.54; p = 0.01) was observed for the superior P50 wave only. Conclusions: Daily oral intake of the fixed combination CIT/HOMO for 4 months improved the function of inner retinal cells recorded by PERG in the inferior and in the superior quadrants, independently from IOP reduction. This interesting association could represent a valid option for practicing neuromodulation in patients with glaucoma to prevent disease progression.

The Spectrum of Ocular Manifestations in Patients with Waldenström's Macroglobulinemia.

PURPOSE: To investigate the ocular manifestations in 91 Waldenström's macroglobulinemia (WM) patients. METHODS: Retrospective, cross-sectional, observational analysis. RESULTS: Ocular impairments, detected in 19 patients, included flame-shaped hemorrhages, venous sausaging, papilledema, macular detachments, or central retinal vein occlusion in 16 patients; paraproteinemic keratopathy in 2; and a CANOMAD syndrome in 1. Best-corrected visual acuity was ≥0.5 logMAR units in 11 of 38 eyes. Intraocular pressure was increased in seven eyes. Genetic analysis in seven patients showed a mutation in the MYD88 gene in six patients and a nonsense mutation in the CXCR4 gene in five patients. Plasmapheresis followed by chemotherapy with or without the addition of rituximab resulted in improvement or normalization of the ophthalmological findings in 15 patients. CONCLUSION: The ocular manifestations of WM are protean and potentially sight threatening. Recent advances in genomic profiling and chemotherapy have remarkably improved the hematological and ophthalmological outcomes of these patients.

RE-PERG in early-onset Alzheimer's disease: A double-blind, electrophysiological pilot study.

PURPOSE: To evaluate the ability of re-test pattern electroretinogram (RE-PERG), a non-invasive and fast steady-state PERG, to detect inner retinal bioelectric function anomalies in patients with early-onset Alzheimer's disease (AD). METHODS: The study population consisted of 17 patients with AD-related mild cognitive impairment (MCI), 16 patients with vascular dementia (VD)-related MCI, both assessed using the neuropsychological Mini-Mental State Examination (MMSE) and by structural magnetic resonance imaging, and 19 healthy, age-matched normal controls (NC). All participants were visually asymptomatic, had normal or near-normal general cognitive functioning and no or minimal impairments in daily life activities. Visual field (VF) test, optical coherence tomography (OCT) and RE-PERG, sampled in five consecutive blocks of 130 events, were performed. RESULTS: There was no statistically significant difference among the three groups with respect to age, VF parameters (mean and pattern standard deviations) and OCT parameters (ganglion cell complex thickness and retinal nerve fiber layer thickness). The mean amplitude in the RE-PERG was significantly lower, but only weakly in the AD group than in NC (p = 0.1) whereas the intrinsic variability of the 2nd harmonic phase was significantly higher in the AD group than in either the VD or NC group (p<0.001). CONCLUSIONS: RE-PERG is altered in early-stage AD, showing a reduced amplitude with high intrinsic phase variability. It also allows the discrimination of AD from VD. A high intrinsic variability in the PERG signal, determined using RE-PERG, may thus be a new promising test for neurodegenerative diseases.

Ocular sarcoidosis: clinical experience and recent pathogenetic and therapeutic advancements.

PURPOSE: To describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed. METHODS: Data from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available. RESULTS: Ocular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Löfgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon's injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-α is a central mediator of granuloma formation, adalimumab, targeting TNF-α, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis. CONCLUSION: Uveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.

RE-PERG, a new paradigm for glaucoma diagnosis, in myopic eyes.

PURPOSE: To evaluate reliability of steady-state pattern electroretinogram (ssPERG) phase variability in re-test (procedure called RE-PERG) in the presence of myopia, which is known to affect ssPERG amplitude, in glaucomatous patients (GP), normal controls (NC), and myopic patients (MY). METHODS: The procedure was performed on 50 GP, 35 NC, and 19 MY. All subjects were examined with RE-PERG, spectral-domain coherence tomography (SD-OCT), and standard automated perimetry (SAP). Standard deviation of phase (ssPERG SDph) and mean amplitude value (ssPERG Amp) of second harmonic (2ndH) were correlated, by means of one-way ANOVA and Pearson correlation, with mean deviation (MD) and pattern standard deviation (PSD) assessed by SAP and retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness assessed by SD-OCT. Receiving operating characteristics were calculated in cohort populations with and without myopia. RESULTS: GP showed significant differences from the control group for MD, PSD, RNFL, GCC, ssPERG Amp, and ssPERG SDph; GP also showed significant differences from the MY group for all the parameters except for ssPERG Amp, which is reduced in both groups. In GP group, ssPERG Amp showed a specificity of 82.1% (95% confidence interval [CI]I: 66.5-92.5). In MY group, ssPERG Amp was reduced in 58% of the patients. As a consequence of this, in GP and MY groups, considered as a whole, total specificity dropped to 70.69% (95% CI: 57.3-81.9). In the GP group, ssPERG SDph showed a specificity of 84.6% (95% CI: 69.5-91.1). In both GP and MY groups, considered as a whole, ssPERG SDph total specificity increased from 84.6% to 93.1% (95% CI: 83.3-98.1). CONCLUSION: Intrinsic phase variability of ssPERG is not influenced by myopia, even in the presence of fundus alterations.

RE-PERG, a new procedure for electrophysiologic diagnosis of glaucoma that may improve PERG specificity.

PURPOSE: A significant variability of the second harmonic (2ndH) phase of steady-state pattern electroretinogram (SS-PERG) in intrasession retest has been recently described in glaucoma patients (GP), which has not been found in healthy subjects. To evaluate the reliability of phase variability in retest (a procedure called RE-PERG or REPERG) in the presence of cataract, which is known to affect standard PERG, we tested this procedure in GP, normal controls (NC), and cataract patients (CP). METHODS: The procedure was performed on 50 GP, 35 NC, and 27 CP. All subjects were examined with RE-PERG and SS-PERG and also with spectral domain optical coherence tomography and standard automated perimetry. Standard deviation of phase and amplitude value of 2ndH were correlated by means of one-way analysis of variance and Pearson correlation, with the mean deviation and pattern standard deviation assessed by standard automated perimetry and retinal nerve fiber layer and the ganglion cell complex thickness assessed by spectral domain optical coherence tomography. Receiver operating characteristics were calculated in cohort populations with and without cataract. RESULTS: Standard deviation of phase of 2ndH was significantly higher in GP with respect to NC (P<0.001) and CP (P<0.001), and it correlated with retinal nerve fiber layer (r=-0.5, P<0.001) and ganglion cell complex (r=-0.6, P<0.001) defects in GP. Receiver operating characteristic evaluation showed higher specificity of RE-PERG (86.4%; area under the curve 0.93) with respect to SS-PERG (54.5%; area under the curve 0.68) in CP. CONCLUSION: RE-PERG may improve the specificity of SS-PERG in clinical practice in the discrimination of GP.

Can Variability of Pattern ERG Signal Help to Detect Retinal Ganglion Cells Dysfunction in Glaucomatous Eyes?

OBJECTIVE: To evaluate variability of steady-state pattern electroretinogram (SS-PERG) signal in normal, suspected, and glaucomatous eyes. METHODS: Twenty-one subjects with suspected glaucoma due to disc abnormalities (GS), 37 patients with early glaucoma (EG), and 24 normal control (NC) were tested with spectral-domain optical coherence tomography (SD-OCT), standard automated perimetry (SAP), and SS-PERG. Mean deviation (MD), pattern standard deviation (PSD), retinal nerve fiber layer (RNFL), and ganglionar complex cells (GCC) were evaluated. The SS-PERG was recorded five consecutive times and the amplitude and phase of second harmonic were measured. PERG amplitude and coefficient of variation of phase (CVphase) were recorded, and correlation with structural and functional parameters of disease, by means of one-way ANOVA and Pearson's correlation, was analysed. RESULTS: PERG amplitude was reduced, as expression of retinal ganglion cells (RGCs) dysfunction, in EG patients and GS subjects compared to NC patients (P < 0.0001). CVphase was significantly increased in EG patients and GS subjects, compared to healthy (P < 0.0001), and it was also correlated with PSD (P = 0.0009), GCC (P = 0.028), and RNFL (P = 0.0078) only in EG patients. CONCLUSIONS: Increased intrasession variability of phase in suspected glaucomatous eyes may be a sign of RGCs dysfunction.