Citicoline (cytidine-5-diphosphocholine), an intermediate product of phospholipid biosynthesis, is believed to be transformed to cytidine monophosphate and phosphocholine by phosphodiesterases in the cell wall and taken up into neuronal cells.1,2 In addition to the synthesis of acetylcholine, cells use choline as a precursor of certain phospholipids (eg, phosphocholine) that are major constituents of all biological membranes.2 Exogenous citicoline has been used as a therapeutic drug to treat central nervous system disorders including ischemic stroke and Parkinson's disease.3,4 Furthermore, there is growing evidence of the neuroprotective and neuromodulatory role of citicoline in clinical conditions with varying etiopathogenesis, such as Alzheimer's disease, cerebral hypoxic neuronal injury, and Parkinson's disease.4–6 Some clinical studies show that citicoline eye drops may have a therapeutic effect in patients with glaucoma and glaucomatous optic neuropathy.7,8
Refractive surgical procedures are popular operations that provide emmetropization. However, procedures such as epikeratophakia, radial keratotomy, laser photorefractive keratectomy, and laser in situ keratomileusis (LASIK) have been associated with reduced corneal sensitivity postoperatively.9–12 After LASIK, the corneal nerve tissue is altered by the flap incision and stromal ablation.13 Damage to the corneal neural structures results in reduced corneal sensitivity, tear production, and tear film stability, which lead to postoperative dry eye symptoms.14
To avoid corneal neural damage in LASIK, several surgical modifications have been recommended to spare the neural component of the functional lacrimal unit, such as changing hinge position, using a femtosecond laser instead of a microkeratome for flap creation, and making a thinner flap.15–18 Experimentally, the use of agents such as macrophage migration inhibitory factor, glial cell line-derived neurotrophic factor, opioid growth factor, and ciliary neurotrophic factor have also been investigated.19–22
In the current study, we used a Cochet–Bonnet esthesiometer to examine the effect of citicoline eye drops on corneal sensitivity in patients who underwent myopic LASIK. Although the neuroprotective and neuromodulatory properties of citicoline are supported by previous reports, to the best of our knowledge, this is the first study on the use of citicoline following femtosecond laser–assisted LASIK.
Patients and Methods
The study included 156 patients (78 women and 78 men) aged 18 to 43 years with low to moderate myopia (spherical refractive error between −1.50 and −6.25 diopters [D]; cylindrical refractive error between −1.00 and −2.00 D) who presented to the Ekol Eye Hospital outpatient clinic with the desire to stop using glasses or contact lenses. Patients who had any systemic disease (eg, diabetes mellitus or neurological disorders) that may cause neurodegeneration, ocular pathology other than refractive error detected during anterior or posterior segment examination, or history of ocular surgery or trauma were questioned in detail and were not included in the study. Patients who had a history of any chronic drugs interacting with peripheral nerves (eg, antidepressants or gabapentin) were also excluded. The washout period for contact lens users was at least 2 weeks.
Informed consent forms were obtained from all patients in accordance with the tenets of the Declaration of Helsinki. Approval for the study was obtained from the Alanya Alaaddin Keykubat University Ethics Committee (protocol no. 2-18/2018).
Preoperatively, all patients underwent a standard eye examination including uncorrected and corrected distance visual acuity assessment with Snellen chart (converted into logMAR units), slit-lamp anterior segment examination and dilated fundus examination, intraocular pressure measurement with Goldmann applanation tonometry, corneal topography, pachymetry, cornea sensitivity assessment using a Cochet– Bonnet esthesiometer, and Schirmer's and tear film break-up time (TBUT) tests.
For all patients, surgery was planned with a flap hinge in the superior position in both eyes. Surgeries were performed by the same surgeon (EC) using the same platform (flap lifting procedure: LenSx device, refractive correction: WaveLight EX500 excimer laser, both Alcon Laboratories, Inc., Fort Worth, TX). Flap diameter was set to 9 mm and flap thickness to 110 µm in all procedures. Laser energy was set to 1 µJ, tangential and radial spot separation to 7 µm, hinge angle to 45 degrees, flap side cut energy to 2.2 µJ, and flap side cut angle to 70 degrees. In all patients, the flap was created using a LenSx device following the docking procedure with a single-use Patient Interface (Alcon laboratories, Inc.) insert, which conforms to the surface and curvature of the cornea. Refractive errors were corrected using a WaveLight EX500 excimer laser. None of the patients were made to wear contact lenses after the surgery.
All surgeries were performed under topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine; Alcon, Geneva, Switzerland). Postoperatively, all patients were prescribed 0.3% tobramycin and 0.1% fluorometholone to use four times a day for 15 days.
A total of 38 female and 40 male patients (78 eyes) were randomly selected to use citicoline eye drops (OMK1; Omikron, Rome, Italy) three times a day for 1 month. The dosing schedule of every 8 hours for 1 month was chosen based on studies recommending citicoline for neuroprotection in glaucoma.7,8 Randomly selected 78 eyes of 78 patients from the refractive surgery patients consecutively comprised the control group. The control group was given 1.5% sodium hyaluronate eye drops three times a day for 1 month.
Corneal sensitivity was measured under the biomicroscope light using Cochet–Bonnet esthesiometry. A nylon filament 0.12 mm in diameter and 60 mm in length held perpendicularly to the eye was used to touch the central cornea and the filament length at which the patient blinked involuntarily was recorded. If the patient did not sense the contact with the cornea, the procedure was repeated by shortening the filament by 5 mm each time. Measurements were repeated for each patient preoperatively and at postoperative weeks 1, 2, 3, 4, 6, 8, and 12. All sensitivity measurements were performed by the same masked researcher (GE).
For Schirmer's test, 1% proparacaine was instilled in the lower fornix as a topical anesthetic; after 5 minutes, a standard Schirmer's test strip (Alcon Laboratories, Inc.) was placed in the lower fornix and held there for 5 minutes. The length of strip wetted in 5 minutes was recorded in millimeters.
To assess TBUT, 1% proparacaine was instilled in the lower fornix and after 2 minutes a sodium fluorescein strip was touched to the lower fornix to stain the ocular surface. The patient was instructed not to blink. The ocular surface was observed at the slit-lamp with a cobalt blue filter and the time elapsed before the appearance of the first dry spot on the ocular surface was recorded in seconds.
After data collection, mean and standard deviation values were calculated. Based on these values, parametric and non-parametric distributions were analyzed. Because the data conformed to normal parametric distribution in both groups, the Student's t test was used for comparisons between groups. The Spearman correlation test was used for correlation analysis. For all statistical analyses, SPSS software (version 17.0; SPSS, Inc., Chicago IL) was used. A P value of less than .05 was considered statistically significant.
The patients' age, gender, preoperative refraction values, amount of ablation, and pachymetry values are shown in detail in Table 1. There were no differences in preoperative demographic data between the citicoline and control groups (P > .05 for all).
Demographic Data of Study and Control Groups
Corneal sensitivity measurements were significantly better in the citicoline group at weeks 1, 2, 3, 4, and 6, but were not significantly different at weeks 8 or 12. Comparisons of central cornea esthesiometry measurements during follow-up are presented in Table 2. Figure 1 is a box plot and line chart showing the mean and standard deviation values of corneal sensitivity data from the citicoline and control groups at 1, 4, 8, and 12 weeks.
Clinical Parameters of Study and Control Groups
Box plot shows the mean and standard deviation values of corneal sensitivity data from the citicoline and control groups at 1, 4, 8, and 12 weeks.
Comparison of Schirmer's and TBUT results between the citicoline and control groups showed significantly better results in the citicoline group at weeks 1, 2, 3, 4, and 6, whereas no significant difference was detected between the groups at 8 or 12 weeks (Table 2). When compared with baseline values, Schirmer's and TBUT values in both groups were significantly lower at 1, 2, 3, 4, and 6 weeks but did not differ significantly from baseline at 8 or 12 weeks. Schirmer's and TBUT baseline and postoperative values of the citicoline and control groups are given in detail in Table 2. Line charts showing values of Schirmer's and TBUT results at 1, 4, 8, and 12 weeks for each group are shown in Figure A (available in the online version of this article).
Line charts show values of Schirmer's and tear break-up time (TBUT) test results at 1, 4, 8, and 12 weeks for each group.
Spearman correlation analysis was performed to evaluate the correlation between the corneal sensitivity and Schirmer's and TBUT tests at 1, 4, 6, 8, and 12 weeks. Corneal sensitivity was significantly correlated with Schirmer's and TBUT tests at 1 and 4 weeks, but not at 6, 8, and 12 weeks in the citicoline group. Correlations between the corneal sensitivity and Schirmer's test and corneal sensitivity and the TBUT test were significant at postoperative 1, 4, and 6 weeks, whereas there were no significant correlations at postoperative 8 and 12 weeks in the control group.
No local (eg, corneal epitheliopathy, opacity, corneal vascularization, or delayed corneal epithelial closure) or systemic side effects were observed in any of the patients during follow-up.
Based on the neuroprotective and neuromodulatory properties of citicoline, this study investigated the effect of the recently introduced ophthalmic drop form on corneal hypoesthesia after femtosecond laser–assisted LASIK. We observed significantly better corneal sensitivity in the citicoline group compared to the control group in the first postoperative 6 weeks. Sensitivity returned to preoperative levels at week 4 in the citicoline group (55.7 ± 4.4 mm, P = .265 compared to baseline) versus week 8 in the control group (55.4 ± 3.6 mm, P = .285 compared to baseline). These findings demonstrate that citicoline eye drops significantly improve after femtosecond laser–assisted LASIK corneal sensitivity earlier than with sodium hyaluronate drops. Another finding in our study is that improved corneal sensitivity was accompanied by improvements in TBUT and Schirmer's test results. There were significant differences in Schirmer's and TBUT test results between the citicoline and control groups starting in week 1 and continuing until week 6. There was no statistically significant difference between the groups in terms of Schirmer's and TBUT test results at 8 weeks. The results of this study indicate that the improvement in central corneal sensitivity due to citicoline also had a positive effect on the functional lacrimal unit.
LASIK is a predictable and effective procedure commonly performed throughout the world with highly satisfactory results. However, damage to corneal afferent sensory innervation during flap creation and stromal ablation results in dry eye at rates of 0.8% to 40%.23,24 Dry eye is an irritating multifactorial condition that can lead to tear film instability and subsequent ocular surface damage.25 The results of our study suggest that, due to the presumed neuroprotective or neuromodulatory activity of citicoline, supplementing after femtosecond laser–assisted LASIK treatment with citicoline eye drops has a favorable impact on the neural component of the functional lacrimal unit, thus contributing to earlier resolution of dry eye symptoms. Exactly how citicoline affects corneal innervation after femtosecond laser–assisted LASIK at a molecular level is beyond the scope of this study and there are no experimental or clinical studies on this subject. However, potential mechanisms after femtosecond laser–assisted LASIK can be speculated upon in light of findings from clinical and experimental studies of citicoline conducted in glaucoma, ischemic optic neuropathy, retinal ganglion cell cultures, and optic nerve injury.
Parisi et al.7 evaluated whether treatment with topical citicoline eye drops affected retinal function and the neural conduction along the visual pathways in open-angle glaucoma. Of 47 patients using topical beta-blocker eye drops, 24 also used citicoline eye drops three times a day for 2 months. After treatment, the citicoline group showed increased P50-N95 amplitude on pattern electroretinography and shortened P100 implicit time on visual evoked potential. Thus, their study showed that topical treatment with citicoline in eyes with open-angle glaucoma enhanced retinal bioelectrical responses (increase of pattern electroretinogram amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex. Roberti et al.8 clinically investigated the neuroprotective activity of citicoline eye drops and experimentally evaluated its vitreous penetration. In the clinical part of the same study, 16 of 34 patients with open-angle glaucoma were treated with citicoline eye drops three times a day for 2 months and demonstrated reduced P50 latency and increased N95-P50 amplitude after a 1-month washout period. According to the findings in that study, Roberti et al. reported that topical citicoline seems to have a neuroprotective effect. Cholinergic neurons use choline for the synthesis of the neurotransmitter acetylcholine, which plays a crucial role in synaptic transmission.26
Oshitari et al.27 evaluated the neuroprotective effect of citicoline on mice in their experimental studies and showed the results of quantitative analysis of TUNEL methods (TdT-dUTP terminal sequence) on damaged retinal ganglion cells in mouse retinal cultures. The proportion of TUNEL-positive ganglion cells was low in mouse retina treated with 0.1 to 10 mmol/L citicoline compared to the control group. The authors postulated an antiapoptotic effect of citicoline in mitochondria-dependent cell death mechanism and its ability to support axon regeneration. Parisi et al.28 measured visual function before and after treatment with oral citicoline for 60 days in patients with nonarteritic ischemic optic neuropathy and reported increases in pattern electroretinography, visual evoked potential parameters, and visual acuity compared to pretreatment values. Schuettauf et al.29 investigated the antiapoptotic effect of citicoline administered by intraperitoneal injection to rats with experimentally induced optic nerve injury and showed that citicoline increased levels of antiapoptotic Bcl-2 protein and prevented apoptosis. They also showed that the synaptic connection between superior colliculus and retinal ganglion cells was better in the citicoline group, thus providing significant evidence of its neuroprotective activity. Yen et al.30 showed that cells deprived of choline died via apoptosis, possibly as a result of cell cycle disruption due to reduced membrane phosphatdylcholine concentration.
In a controlled rat study of the neuromodulatory activity of citicoline, retinal damage was induced by intravitreal administration of the glutamate analog, kainic acid.31 After giving kainic acid, 500 mg/kg citicoline was administered intraperitoneally to rats and showed that the intraperitoneal citicoline-treated rats had less retinal damage. The authors suggested that citicoline may have exerted a neuroprotective effect that prevented glutamate-mediated cell death. Another study using citicoline eye drops in diabetic rat models showed that retinal nerve fiber thickness measured on optical coherence tomography and the ganglion cell complex were spared from glycemic damage, offering important evidence of the neuroprotective action of citicoline.32 The same study also showed that citicoline eye drops did not offer significant benefit in terms of choroidal tissue dysfunction in diabetic rats, highlighting the effect of citicoline activity in areas with dense neural tissue rather than vascular structures. Both clinical and experimental studies present a growing body of evidence of the neuroprotective and neuromodulatory action of citicoline. Our findings of earlier recovery of corneal sensitivity in the citicoline group compared to the control group after femtosecond laser–assisted LASIK surgery in patients with moderate myopia/astigmatism may offer clinical corroboration of the neuroprotective effect of citicoline.
During LASIK, the superficial stromal nerves are damaged by the flap incision and the deep stromal nerves are damaged by excimer laser photoablation to correct myopia. Morphologically, Linna et al.13 showed in a rabbit study that on day 3, the superficial stromal nerves outside the hinge area were severed, that a small number of new nerve fibers had started budding both at the flap margins and between the flap and ablative stroma, and some nerves had formed anastomoses with the new nerves. Some intact epithelial, subepithelial, and anterior stromal nerves remained in the hinge area, to which the authors attributed an important role in reinnervation toward the corneal apex. In their examination at 2 months, Linna et al. clearly demonstrated the presence of numerous new nerve fibers extending toward the central cornea, as well as regeneration from the severed roots of existing nerves. In addition, several neuronal survival pathways are regulated by neuronal growth factor signaling, and topical murine neuronal growth factor eye drops improved the rate of corneal epithelial healing and corneal sensitivity.33 The effects of citicoline at the morphological, cellular, or molecular level after femtosecond laser–assisted LASIK nerve regeneration have not been previously investigated. In the various clinical and experimental studies performed to date, proposed mechanisms of its neuroprotective and neuromodulatory effects include preventing glutamate-mediated damage, preventing neuronal damage caused by hyperglycemia, preventing apoptosis, affecting neurotransmitters in the synaptic junctions, inhibiting production of free fatty acids by stimulating phosphocholine synthesis, stabilizing cardiolipin (a mitochondrial membrane phospholipid), and increasing the amount of neurotransmitters such as dopamine, noradrenaline, and serotonin in the brain.29,31,32,34–36 Many authors have investigated the role of citicoline in Alzheimer's disease, Parkinson's disease, and amblyopia, postulating that stimulation of the dopaminergic system by citicoline is the basis of the improvement in neurological symptoms in Parkinson's disease, that citicoline may improve retinal and postretinal visual pathways in amblyopia, and that it may hinder the deposition of beta-amyloid, a pivotal neurotoxic protein in the pathophysiology of Alzheimer's disease.4,5,34
The role of citicoline in the recovery of hypoesthesia after femtosecond laser–assisted LASIK shown in our study may be related to various mechanisms of effect demonstrated in different clinical and experimental research models, such as protecting the cell membrane (membrane phospholipid stabilization), stimulating neurotransmitters, or preventing apoptosis. We believe that the neuroprotective activity of citicoline in neural tissue damage induced by various factors such as glutamate, hyperglycemia, hypoxia, trauma, and injury suggests that citicoline may treat neural damage via membrane phospholipids or neurotransmitters, independently of the factor that caused the damage. Similarly, our study demonstrated that citicoline may heal corneal nerve damage created by photoablation in femtosecond laser–assisted LASIK surgeries more rapidly than occurs with spontaneous healing, even though the damage was caused by a different mechanism. We are planning future studies to investigate how citicoline affects femtosecond laser–assisted LASIK corneal damage and its potential mechanisms with experimental models.
Citicoline is an endogenous mononucleotide comprising cytosine, ribose, pyrophosphate, and choline. It occurs naturally as an intermediate molecule during the synthesis of membrane phospholipids such as phosphatidylcholine.1,2 Choline is made in the body through the conversion of exogenous precursor molecules. Cytidine and choline combine to form citicoline in the central nervous system after crossing the blood–brain barrier from the systemic circulation. There, citicoline acts in several ways. It stimulates the biosynthesis of phospholipids, exerting a structural action by replenishing the cardiolipin component of the inner mitochondrial membrane.35 It also has functional activity, increasing the levels of certain neurotransmitters (dopamine, noradrenaline, and serotonin) and serving as a choline donor in the biosynthesis of acetylcholine.36 Citicoline is considered a non-toxic molecule. In preclinical animal studies, the maximum oral dose did not cause mortality, and there were no effects on blood chemistry, organ histology, or neurological and urinary parameters. In a study to determine the safety profile of citicoline, only 5% of 2,817 patients reported adverse effects related to citicoline therapy and none discontinued treatment.37
Our study has certain limitations. Morphological analysis of nerves (eg, nerve density, distribution, tortuosity, and branching patterns) using confocal microscopy in the citicoline and control groups could have provided clues regarding the potential mechanisms. The relatively short follow-up time and no evaluation of ocular surface disease index outcomes are other limitations of our study.
We studied the action of citicoline on corneal hypoesthesia after femtosecond laser–assisted LASIK in human eyes. Our results showed that treatment with citicoline eye drops significantly increased corneal sensitivity and tear volume within the first 6 postoperative weeks. These findings suggest that citicoline eye drops, which have neuroprotective, antioxidative, neurotrophic, and anti-inflammatory properties, can be considered as a therapeutic option for the treatment of corneal hypoesthesia after femtosecond laser–assisted LASIK.
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- Cacabelos R, Caamaño J, Gómez MJ, Fernández-Novoa L, Franco-Maside A, Alvarez XA. Therapeutic effects of CDP-choline in Alzheimer's disease: cognition, brain mapping, cerebrovascular hemodynamics, and immune factors. Ann N Y Acad Sci. 1996;777(1):399–403. doi:10.1111/j.1749-6632.1996.tb34452.x [CrossRef]8624120
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- Roberti G, Tanga L, Parisi V, Sampalmieri M, Centofanti M, Manni G. A preliminary study of the neuroprotective role of citicoline eye drops in glaucomatous optic neuropathy. Indian J Ophthalmol. 2014;62(5):549–553. doi:10.4103/0301-4738.133484 [CrossRef]24881599
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- Campos M, Hertzog L, Garbus JJ, McDonnell PJ. Corneal sensitivity after photorefractive keratectomy. Am J Ophthalmol. 1992;114(1):51–54. doi:10.1016/S0002-9394(14)77412-4 [CrossRef]1621785
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- Donnenfeld ED, Solomon K, Perry HD, et al. The effect of hinge position on corneal sensation and dry eye after LASIK. Ophthalmology. 2003;110(5):1023–1029. doi:10.1016/S0161-6420(03)00100-3 [CrossRef]12750107
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Demographic Data of Study and Control Groups
|Parameter||Study Group (n = 78)||Control Group (n = 78)||P|
|Age (y)||26.8 ± 7.6||26.1 ± 7.4||.982|
|CDVA (logMAR)||0.101 ± 0.01||0.104 ± 0.01||.918|
|Preoperative refraction (D)||−3.20 ± 2.70||−3.40 ± 2.50||.844|
|Ablation depth (µm)||52.2 ± 19.5||54.2 ± 18.2||.765|
|Corneal sensitivity||60 ± 0||60 ± 0||–|
|Pachymetry (µm)||524 ± 55||527 ± 53||.812|
Clinical Parameters of Study and Control Groups
|Time||Corneal Sensitivity (mm)||Schirmer (mm)||TBUT (sn)|
|Study Group||Control Group||P||Study Group||Control Group||P||Study Group||Control Group||P|
|Preoperative||60.0 ± 0||60.0 ± 0||1.00||13.4 ± 2.2||13.1 ± 2.4||.847||13.9 ± 3.1||14.1 ± 2.5||.847|
|1 week||22.5 ± 5.9||8.3 ± 4.2||.012a||5.2 ± 1.5||4.5 ± 1.2||.002a||5.8 ± 1.3||5.06 ± 1.2||.001a|
|2 week||37.5 ± 6.5||14.1 ± 4.2||.001a||7.1 ± 1.8||6.1 ± 1.2||.001a||7.9 ± 1.7||7.0 ± 1.5||.001a|
|3 week||48.1 ± 6.2||24.6 ± 4.9||.015a||10.0 ± 2.1||9.0 ± 2.1||.009a||10.1 ± 1.9||9.3 ± 1.7||.008a|
|4 week||55.7 ± 4.4||40.4 ± 5.4||.015a||11.4 ± 2.4||10.4 ± 1.9||.014a||11.7 ± 2.1||11.0 ± 1.9||.040a|
|6 week||56.7 ± 2.7||55.7 ± 3.6||.037a||12.7 ± 2.4||11.2 ± 2.1||.042a||12.6 ± 2.1||11.7 ± 2.0||.044a|
|8 week||57.3 ± 3.7||56.0 ± 3.9||.952||13.4 ± 2.2||13.2 ± 2.0||.320||13.5 ± 2.1||13.1 ± 2.1||.655|
|12 week||59.8 ± 0.3||59.3 ± 1.6||.950||13.8 ± 2.1||13.3 ± 1.9||.940||14.2 ± 2.0||14.0 ± 2.0||.791|