Neuroenhancement and neuroprotection by oral solution citicoline in non-arteritic ischemic optic neuropathy as a model of neurodegeneration: A randomized pilot study

Vincenzo Parisi, Lucilla Barbano, Antonio Di Renzo, Gianluca Coppola, Lucia Ziccardi, Vincenzo Parisi, Lucilla Barbano, Antonio Di Renzo, Gianluca Coppola, Lucia Ziccardi

Abstract

Purpose: To evaluate whether treatment with Citicoline in oral solution (OS-Citicoline) would increase visual function, retinal ganglion cells (RGCs) function, and neural conduction along visual pathways (neuroenhancement), and/or induce preservation of RGCs fibers' loss (neuroprotection) in non-arteritic ischemic optic neuropathy (NAION), a human model of neurodegeneration.

Methods: Thirty-six patients with NAION and 20 age-matched controls were enrolled. Nineteen NAION patients received 500 mg/day of OS-Citicoline for a 6-month period followed by 3-month of wash-out (NC Group); 17 NAION patients were not treated (NN Group) from baseline to 9 months. In all subjects at baseline, and in NC and NN eyes at 6 and 9 months of follow-up, we assessed Visual Acuity (VA), Pattern Electroretinogram (PERG), Visual Evoked Potentials (VEP), retinal nerve fiber layer thickness (RNFL-T), and Humphrey 24-2 visual field mean deviation (HFA MD). Mean differences were statistically evaluated with ANOVA between Groups, and linear correlations were analysed with Pearson's test.

Results: At 6 months, significant differences between groups for all parameters were observed (ANOVA, p<0.01). In NC eyes, VA increased, PERG responses increased, VEP recordings improved and were significantly correlated with increases in HFA MD (p<0.01), and RNFL-T was unmodified or improved. In contrast, in NN eyes, VA, PERG, VEP responses, RNFL-T, and HFA MD were further worsened. Significant differences were still present at 9-month follow-up in the NN Group and after 3 months of OS-Citicoline wash-out in NC eyes.

Conclusions: OS-Citicoline treatment induced neuroenhancement (improvement in RGCs function and neural conduction along visual pathways related to improvement of visual field defects) and neuroprotection (unmodified or improved RNFL morphological condition) in a human model of NAION involving fast RGCs degeneration.

Trial registration: ClinicalTrials.gov NCT03758118.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT participant flow diagram.
Fig 1. CONSORT participant flow diagram.
Fig 2. Examples of simultaneous Visual Evoked…
Fig 2. Examples of simultaneous Visual Evoked Potentials (VEP) and Pattern Electroretinogram (PERG) recordings, Humphrey Field Analyzer (HFA 24–2) and Retinal Nerve Fiber Layer Thickness (RNFL-T) by optical coherence tomography (OCT) from two patients with non-arteritic ischemic optic neuropathy (NAION).
Fig 3. Pattern and visual evoked potentials…
Fig 3. Pattern and visual evoked potentials (VEP) P100 implicit time recorded in response to 15’ checks (15’) results.
(A) Mean of absolute PERG P50-N95 Amplitude values observed in NC and NN Groups. * = ANOVA, p<0.01 in NN and NC Groups with respect to baseline. Vertical lines: one mean standard deviation. The statistical evaluation is reported in S2 Table. (B) Individual PERG P50-N95 Amplitude values observed in NC eyes at baseline plotted as a function of the values of the corresponding differences at the end of treatment (6 months minus baseline). Pearson’s test was used for regression analysis and linear correlation. (C) Mean of absolute VEP P100 implicit time values observed in NC and NN Groups. * = ANOVA, p<0.01 in NN and NC Groups with respect to baseline. Vertical lines: one mean standard deviation. Statistical evaluation is reported in “S2 Table”. (D) Individual VEP P100 implicit time values observed in NC eyes at baseline plotted as a function of the values of the corresponding differences at the end of treatment (6 months minus baseline). Pearson’s test was used for regression analysis and linear correlation.
Fig 4. Retinal Nerve Fiber Layer Thickness…
Fig 4. Retinal Nerve Fiber Layer Thickness average from all quadrants (RNFL-T Overall) results.
(A) Individual changes detected in patients with Non-Arteritic Ischemic Optic Neuropathy (NAION) treated with Citicoline in oral solution (NC Group, N = 19 eyes) and in untreated NAION patients (NN Group, N = 17 eyes). The percentage of unmodified eyes (within the 95% confidence test-retest limit), eyes with improvement (values over the 95% confidence test-retest limit, dashed line), and eyes with worsening (values under the 95% confidence test-retest limit, solid line) are reported in “S1 Table”. (B) Mean of individual differences observed in NC and NN Groups. * = ANOVA, p<0.01 between NN and NC Groups. Vertical lines: one mean standard deviation. Statistical evaluation is reported in Table 2. (C) Mean of absolute values observed in NC and NN Groups. * = ANOVA, p<0.01 in NN and NC Groups with respect to baseline. Vertical lines: one mean standard deviation. The statistical evaluation is reported in “S3 Table”. (D) Individual values observed in NC eyes at baseline condition plotted as a function of the values of the corresponding differences at the end of treatment (6 months minus baseline). Pearson’s test was used for regression analysis and linear correlation.

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