Clinical StudyAutologous Platelet-Rich Plasma Eye Drops for the Treatment ofPost-LASIK Chronic Ocular Surface Syndrome

Jorge L. Alio,1,2 Alejandra E. Rodriguez,3 Ahmed A. Abdelghany,4,5 and Renan F. Oliveira6

1Division of Ophthalmology, School of Medicine, Universidad Miguel Hernández, Alicante, Spain2Refractive Surgery Department, VISSUM, Alicante, Spain3Research & Development Department and Cornea and Ocular Surface Department, VISSUM, Alicante, Spain4Division of Ophthalmology, Universidad Miguel Hernández, Alicante, Spain5Ophthalmology Department, Faculty of Medicine, Minia University, Minia, Egypt6Research & Development Department, VISSUM, Alicante, Spain

Correspondence should be addressed to Jorge L. Alio; jlalio@vissum.com

Received 19 June 2017; Revised 5 September 2017; Accepted 16 October 2017; Published 12 December 2017

Academic Editor: David P. Piñero

Copyright © 2017 Jorge L. Alio et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Purpose. To evaluate the efficacy of autologous platelet-rich plasma (E-PRP) eye drops for the treatment of chronic ocularsurface syndrome (OSS) following laser in situ keratomileusis (LASIK). Methods. This prospective interventionalconsecutive clinical study include 156 eyes of 80 patients affected by post-LASIK chronic OSS who were treated withautologous E-PRP 6 times a day as monotherapy for 6 weeks. Results. Dry eye symptoms improved in 85% of the cases. Adecrease in at least one quadrant to total disappearance on CFS was observed in 89.6% of the patients who had positiveCFS before treatment. Three eyes presented severe punctate keratitis (1.9%) at baseline, all of which healed completely.Conjunctival hyperemia improved in 93.3% of the patients with previous signs of ocular surface inflammation. There wasa significant improvement in logMAR CDVA from 0.14± 0.19 to 0.06± 0.12 (p = 0 000), and 74 (71.4%) eyes improved atleast 1 line in CDVA. Conclusion. Monotherapy with autologous E-PRP is a well-tolerated, safe, and effective treatment forthe management of post-LASIK ocular surface syndrome. Precis. Monotherapy with autologous platelet-rich plasma eyedrops has been shown to be an adequate option for the treatment of post-LASIK chronic ocular surface syndrome. Thistrial is registered with NCT03322917.

1. Introduction

Laser in situ keratomileusis (LASIK) surgery is the mostcommonly performed refractive surgical procedure. Postop-erative complications are rare, and patient satisfaction isgenerally excellent, with 95.4% of the patients indicatingsatisfaction when a survey is conducted 7 or more monthsafter LASIK [1].

Although usually transitory, signs and symptoms of teardysfunction after LASIK occur in nearly all patients, withspontaneous resolution in the vast majority of cases. How-ever, some patients may develop chronic ocular surface dys-function that lasts for 6 months or longer. Post-LASIK ocularsurface syndrome (OSS) is a term used to describe a spectrum

of dry eye disease (DED) characterized by symptoms of dryeye, persistent neurotrophic epitheliopathy, tear film insta-bility, true aqueous tear deficiency, decreased correcteddistance visual acuity (CDVA) and visual quality, and neu-ropathic pain states [2–13]. This clinical condition has alsoreceived different names, being the term LASIK-inducedneurotrophic epitheliopathy (LINE) as one of the most fre-quently used [4, 5]. Signs or symptoms of DED after LASIKhave been found to be present in 50% of the patients at 1week postoperatively, 40% at 1 month, and 20–40% at 6months [6].

These changes in the ocular surface are caused by multi-ple factors inherent to the LASIK technique. The transectionof large numbers of afferent sensory nerve fibers during the

HindawiJournal of OphthalmologyVolume 2017, Article ID 2457620, 6 pageshttps://doi.org/10.1155/2017/2457620

lamellar cut results in early postoperative corneal hypoesthe-sia, which decreases neurotrophic influence on epithelial cellsand disrupts the ocular surface-lacrimal gland functionalunit, leading to decreased reflex and basal tear productionas well as blinking rate, with consequent tear film hyperos-molarity and ocular surface inflammation [2, 4, 5, 10, 11].Additional causes for post-LASIK OSS include a reductionin goblet cell density and mucin production, leading to tearfilm instability [12, 13], and altered tear film distributiondue to changes in the corneal shape [2, 4, 5].

Most cases of early postoperative dry eye symptoms wereresolved with appropriate management, which may includenonpreserved lubricant eye drops, punctal plugs, soft contactlenses, oral supplementation with omega-3 essential fattyacids, and/or topical anti-inflammatory agents such as0.05% cyclosporine A [2, 4, 5, 7]. However, 0.8% to 20% ofthe patients may present signs and symptoms of chronicLASIK-associated dry eye, persisting after 6 months [8, 9],in which case traditional treatment modalities are usuallyineffective, thus requiring special management [2]. A betterapproach should aim to limit morbidity in these chroniccases by directing management towards the optimization ofepithelial healing and possibly the neural mechanisms under-lying LASIK-induced ocular surface changes and associateddry eye symptoms [10].

Blood derivatives such as autologous serum or a specialpreparation for topical eye application of platelet-rich plasma(E-PRP) have been shown to be powerful therapeutic tools inaccelerating the healing response of the ocular surface andother different tissues [14–18]. This enhancing effect isattributed to growth factors and bioactive proteins that aresynthesized and present in blood, especially in activatedplatelets’ alpha-granules. Some articles published by ourgroup have demonstrated the benefits of PRP in promotingoptimal healing of dormant corneal ulcers of different etiolo-gies and reducing symptoms and punctate keratopathy inmoderate-to-severe DED and even neurotrophic keratopathyafter LASIK [3, 17–22].

The present study aims to assess the efficacy of autolo-gous platelet-rich plasma eye drop (E-PRP) monotherapyin the management of post-LASIK chronic OSS in a largeprospective series of consecutive cases.

2. Materials and Methods

2.1. Study Design. This is a prospective interventional non-comparative consecutive clinical study. The ethical commit-tee approval was obtained for the purpose of this prospectiveinvestigation. Adequate informed consent was signed byeach one of the patients of the study. The investigation wascarried out in accordance with the Declaration of Helsinki.

2.2. Patients. Adult patients suffering from moderate-to-severe dry eye syndrome for 6 months or more after conven-tional treatments with artificial tears following LASIK wereincluded in the study. Surgical procedures were not standard-ized since up to 40% of the patients were referred from otherservices and therefore had undergone different methods ofLASIK flap creation (i.e., mechanical microkeratome and

femtosecond laser), different excimer laser platforms, andvariable and often unknown amounts of ablated cornealstroma. Thus, this study did not intend to investigate thepathogenesis or assess the potential causes for the develop-ment of post-LASIK OSS but intended to evaluate the effec-tiveness of E-PRP monotherapy for the improvement ofsigns and symptoms in patients developing this condition.

Patients were classified according to the dry eye severitygrading scheme proposed by the Dry EyeWorkShop (DEWS)[23], which takes into account the following parameters: ocu-lar discomfort, visual symptoms, conjunctival injection, con-junctival and corneal fluorescein staining (CFS), corneal/tearsigns, lid/meibomian glands, tear film break-up time (TBUT),and Schirmer II test score. All patients presented a tear break-up time (TBUT) between 4 and 9 seconds. Patients weretreated with autologous PRP eye drops 6 times a day for 6consecutive weeks. All previous forms of treatment werestopped 48 hours prior to receiving the autologous PRP.

Symptoms were evaluated based on the Ocular SurfaceDisease Index (OSDI) self-administered questionnaire,which was completed once at the time of enrollment in thestudy (baseline) and again after 6 weeks of treatment withE-PRP. Patients were also directly asked to report any changein their perception of ocular hyperemia, foreign body sensa-tion, itching, photophobia, dryness, and pain.

Corrected distance visual acuity (CDVA) was measuredin decimal notation with Snellen charts on a conventionalprojection screen, without using any eye drops for at least 1hour before assessment. Conversion to logMAR units andlines of vision was posteriorly done to allow for assessmentof visual improvement and statistical analysis.

Corneal fluorescein staining (CFS) was used to evaluatecorneal superficial punctate epithelial keratitis. The modifiedOxford scale, ranging from 0 (no staining dots) to 5 (worststaining condition), was used for this purpose. A decreasein CFS scores in at least one quadrant to total disappearancefrom baseline indicated improvement.

2.3. Autologous Platelet-Rich Plasma Preparation. The pro-cess to obtain PRP from autologous blood has been reportedby our group previously [3]. PRP was prepared in optimalsterile conditions under a vented sterile fume hood. Blooddrawn from patients was collected in 10mL sterile tubes con-taining 1mL sodium citrate acting as an anticoagulant.Enrichment of platelets in the plasma fraction (upper frac-tion) was achieved by the centrifugation of total blood atoptimal conditions. Platelets were enriched by 2 to 2.5 times,according to quantitation performed through a coulterdevice. Under these conditions of centrifugation, leukocyteswere dragged to the bottom of the tube and proteins andplatelets remained in the upper fraction, enriching theplasma. Depending on the patient’s hematocrit, the plasmafraction could vary from25% to 50% of the total blood. Ninetypercent of the plasma obtained after centrifugation wascollected. Generally, 24 to 40mL of platelet-rich plasma wasobtained from 100mL of the total blood. Mean values ofblood cell count are shown in Table 1. The eye drop containerwas kept at 4°C for a maximum of 7 days, and the remainingvials were stored at −20°C for a maximum of 3 months.

2 Journal of Ophthalmology

2.4. The Main Outcome Measures. The main outcomemeasures were assessed at the end of the 6th week of unin-terrupted treatment with E-PRP and included change incorrected distance visual acuity (CDVA), improvement ofsymptoms based on OSDI scores and/or patients’ testimo-nial, decreased conjunctival hyperemia, and improvementin corneal fluorescein staining (CFS). All tests were per-formed at least 4 hours after the last topical instillationof PRP.

3. Results and Discussion

3.1. Results. One hundred and fifty-six eyes of 80 myopicpatients were included in the study. Sixty-two patients werefemale (77.5%), and 18 patients were male (22.5%), with agesranging from 22 to 82 years (mean 43.7± 12.3). All eyesunderwent femtosecond laser-assisted myopic LASIK, withprogrammed spherical equivalent (SE) correction rangingfrom −2.00 to −7.50 diopters (D), being affected postopera-tively by severe-to-moderate dry eye syndrome for 6 monthsor more.

The main outcomes are summarized in Table 2. Regard-ing symptoms after 6 weeks of uninterrupted treatment withE-PRP, 68 patients (85%) reported an improvement withrespect to its previous condition, showing reduction orabsence of symptoms, while 12 patients (15%) did not expe-rience any change in symptoms. No patients reported wors-ening of symptoms.

Positive corneal fluorescein staining (CFS) was present in116 out of 156 eyes (74.3%) at baseline, with modified Oxfordscale scores ranging from grades I to IV. Improvement indi-cated by a decrease of at least 1 point in the modified Oxfordscale or improvement in at least one quadrant to total disap-pearance in CFS (as shown in Figure 1) was observed in 104eyes (89.6%), while 10 eyes (8.6%) showed no change and 2eyes (1.7%) presented slight worsening in superficial punc-tate keratitis. Three eyes (1.9%) presented severe punctatekeratitis (grade IV) at baseline, all of which healed completelyafter 6 weeks of monotherapy with E-PRP.

Conjunctival hyperemia, present in 29 eyes (18.7%) atbaseline, improved in 27 eyes (93.3%), while two eyes(6.7%) showed no change. No eyes had worsening in ocularsurface inflammation, and none of the patients reportedintolerance to the use of PRP eye drops, indicated by extremediscomfort or stinging sensation at the time of instillation.

Mean decimal CDVA improved from 0.77± 0.25 (range0.1 to 1.0) at baseline to 0.89± 0.17 (range 0.2 to 1.0) aftertreatment with PRP, which represents a statistically signifi-cant improvement in logMAR CDVA from 0.14± 0.19 to0.06± 0.12 (p = 0 000). The number of eyes presenting deci-mal CDVA≥ 0.8 increased from 101 (64.8%) to 124 (79.7%)before and after treatment, respectively. When consideringeyes with decimal CDVA≤ 0.9 before treatment (and there-fore with some potential for visual improvement), 74(71.4%) eyes improved at least 1 line of vision, 25 (24.5%)had no change, and 4 eyes (4.1%) lost 1 line of vision(Figure 2). All 53 eyes who had decimal CDVA=1.0 at base-line maintained the same visual acuity. Visual improvementwas significantly higher in eyes with worse CDVA at baseline(p = 0 000, R = −0 78) and was also directly correlated withimprovement in the CFS score (p = 0 04, R = +0 60).

3.2. Discussion. Post-LASIK OSS is a complex, multifactorial,and nonuniform condition that affects patients in differentlevels of intensity and duration in the postoperative follow-

Table 1: Blood cell count before (whole blood) and after centrifugation (PRP).

Platelets× 103/μL RBC× 106/μL WBC× 103/μLWhole blood (mean± SD) 193.77± 51.86 4.12± 0.40 4.91± 1.92PRP (mean± SD) 342.07± 89.04 0.03± 0.04 1.09± 0.75Concentration index (mean) 1.85 — —

Reduction (%) — −99.3 −77.8μL: microliter; RBC: red blood cells; WBC: white blood cells; SD: standard deviation; PRP: platelet-rich plasma.

Table 2: Signs and symptoms of post-LASIK ocular surface syndrome before and after monotherapy with autologous platelet-rich plasma eyedrops.

Number of cases before treatmentn (%)

Worsening No change Improvement

Dry eye symptoms (patients) 80 (100%) 0 (0%) 12 (15%) 68 (85%)

Fluorescein staining (eyes) 116 (74.3%) 2 (1.7%) 10 (8.6%) 104 (89.6%)

Conjunctival hyperemia (eyes) 29 (18.7%) 0 (0%) 2 (6.7%) 27 (93.3%)

(a) (b)

Figure 1: Patient with post-LASIK chronic OSS. (a) Before treatment,positive corneal fluorescein staining showing paracentral diffuse andcoalescent areas of punctate keratitis in the inferior quadrant. (b)Transparent cornea, with complete resolution of previous punctatekeratitis after treatment with E-PRP.

3Journal of Ophthalmology

up. There are many potential causes of tear dysfunctionfollowing LASIK, including corneal denervation, changesin corneal shape and tear distribution, and damage to gobletcells [4, 5]. Corneal denervation, secondary to LASIK flapcreation and excimer laser stromal ablation, impairs the ocu-lar surface-lacrimal gland functional unit, causing a spec-trum of ocular surface conditions including reduced tearproduction, tear film instability, corneal and conjunctivalepitheliopathy, symptoms of DED, and neuropathic painstates [2, 4, 5, 10].

While classification of the severity of DED in nonoper-ated eyes has already been shown to be quite difficult due topoor and even conflicting correlation between signs andsymptoms in up to 40% of the patients [24, 25], this can beeven more challenging in cases of post-LASIK OSS, mainlydue to its primarily neuropathic etiology. For example, onepatient with profound hypoesthesia and severe neuropathicepitheliopathy may not report any symptom of pain or dis-comfort, whereas another patient without any sign of dryeye (i.e., no CFS and normal TFBUT) may present intenseneuropathic discomfort and even pain due to abnormalnerve fiber regeneration [26]. This apparent incompatibilitybetween symptoms and objective findings has led to differ-ent definitions of post-LASIK “dry eye,” as well as varyingmethodologies in its assessment in both clinical practiceand the literature, resulting in inconsistent results betweenpublished reports.

According to the 2007 International Dry Eye Workshop(DEWS), the prevalence of LASIK-induced dry eye inpatients without dry eye history ranged between 0.25% and48% [27]. Approximately half of all LASIK patients reportdry eye symptoms up to 6 months after surgery, and tearfilm function and corneal sensitivity return to preoperativelevels by 6 months after LASIK in most patients [1, 2, 10].However, the occurrence of chronic OSS, indicated with aduration of at least 6 months, increases by 18–41% afterLASIK [10] and has been reported in 0.8% to 20% of thepatients [8, 9].

LASIK-induced neurotrophic epitheliopathy (LINE) isseen in about 4–14% of the LASIK patients. It usually reachesa severity peak between the first week and the third monthafter LASIK and then returns to preoperative levels by thesixth month [4, 5, 10]. Corneal nerve damage caused byLASIK has been shown to be persistent, with corneal nervefiber density between 6 months and 2 years following LASIKbeing significantly lower than preoperative levels. Alteredtear concentrations of nerve growth factor (NGF) and otherneuropeptides, such as substance P (SP) and calcitoningene-related peptide (CGRP), may also be key factors inLINE’s pathophysiology [10]. Altered corneal nerve mor-phology parameters—lower nerve density, thinner width,fewer interconnections, and higher tortuosity—have beenshown by in vivo laser scanning confocal microscopy at 6to 12 months after LASIK, along with higher dry eye symp-toms, CGRP levels, and conjunctival sensitivity with respectto nonoperated healthy eyes [28].

LASIK has also been associated with loss of goblet cellsdue to the pressure applied over the perilimbal conjunctivaby the suction ring to create the flap either with femtosecondlaser or with microkeratome [13], which leads to decreasedproduction of goblet cell mucin and, hence, tear film instabil-ity. It may take up to 6 months for goblet cell density toreturn to baseline values after LASIK [13]. Studies suggestthat tear film break-up time (BUT) is decreased after LASIK[29–31] and Schirmer II scores range from no change tomoderate decrease [8, 32].

Bower et al. [8] found a significant decrease in TBUT andan increase in rose bengal corneal staining up until 12months after LASIK when compared to preoperative findingsbut did not find a significant decrease in Schirmer II test atany time point along the follow-up, suggesting that chronictear film changes after LASIK are rather qualitative, such asdecreased levels of goblet cell mucin and neurotrophic fac-tors, reduced blink rate, and changes in corneal shape andtear film distribution. Therefore, patients who develop post-LASIK chronic OSS should be better treated with therapeutictools that not only promote ocular surface lubrication butalso produce trophic changes for an effective and sustainedhealing process.

Autologous PRP is a preservative-free biological productfrom the patient’s own blood, and its effectiveness is deter-mined by the presence of a high concentration of platelets,whose alpha-granules contain storage pools of growth fac-tors, including platelet-derived growth factors, transforminggrowth factor β (TGF-β), epithelial growth factors, fibroblastgrowth factors, insulin-like growth factor I, and vascularendothelial growth factors, as well as cytokines (such as PF4and CD40L), chemokines, and newly synthesized activemetabolites [19]. These products are involved in prolifera-tion, migration, and differentiation of corneal epithelial cells,thus helping to heal and maintain the proper condition of theocular surface. Autologous PRP has been used successfully inother ocular surface disorders such as moderate-to-severeDED (both evaporative and aqueous deficiency), persistentepithelial defects, alkali burn, dormant ulcers, and cornealsurface reconstructions in corneal perforations [3, 15–22].E-PRP can be stored at −20°C for up to 3 months

−1

4.1

40.0

35.0

30.0

25.0

20.0

15.0

10.0

5.0

0.0

24.5

32.7

22.4

8.2 8.2

0 1Gain of lines (CDVA)

Eyes

(%)

2 3 4

Figure 2: Visual change after treatment with autologous PRP eyedrops in eyes presenting post-LASIK ocular surface syndrome andCDVA≤ 0.9.

4 Journal of Ophthalmology

maintaining constant or slight variations in the concentra-tion of the most important growth factors.

In a prospective controlled randomized study by ourgroup [21], we have found that the use of E-PRP eye dropsfor standard postoperative treatment following LASIK hadbeneficial effects for promoting epithelial healing after LASIKbut had no objective “extra” positive effect on the recovery ofcorneal sensitivity or regeneration of the corneal subbasalnerve layer as shown in confocal microscopy. Although pos-itive results have been demonstrated in both experimentaland clinical investigations regarding the speed of the periph-eral nerve regeneration when using PRP for more severeepitheliopathies such as neurotrophic ulcers, we believe thesame effect was not obtained in our previous study due tothe limited bioavailability of growth factors in corneal stromawhen the substance is topically administered [21]. Growthfactors present in PRP are large molecules (i.e., 30,000 kilo-daltons for platelet-derived growth factor) and are composedin part of hydrophilic units, which limit its penetration acrossthe fully or relatively intact corneal epithelium after LASIK.The epithelial status after LASIK is much distinct from thatin other more severe epitheliopathies such as neurotrophiculcers, in which a lack of epithelial integrity would facilitatethe penetration and action of PRP on the damaged nerves.Indeed, in another study conducted by our group to assessthe effects of autologous PRP in the treatment of dormantcorneal ulcers [19], we have shown that topical E-PRP pro-moted complete healing in 13 cases (50%), while 11 (42%)improved significantly and only 2 (8%) showed no changein biomicroscopy examination. Moreover, PRP has beenshown to reduce pain, inflammation, and photophobia andto improve vision in the majority of the patients withdormant corneal ulcers included in that study [19].

We have found that 15% of the patients did not showimprovement in symptoms after treatment. Nettune andPflugfelder [2] have advocated that corneal nerves that regen-erate 6 months to 2 years after LASIK surgery are differentfrom preexisting nerves, and this abnormal nerve regenera-tion may be responsible for much of the irritation sensationreported after LASIK. This neurally mediated spectrum ofpost-LASIK OSSmay vary frommild but persistent sensationcharacteristic of tear dysfunction to severe and disablingchronic pain states. Confocal microscopy suggests that thesepatients may have abnormal regeneration of the subbasalnerve plexus. Thus, ocular surface symptoms experiencedby some after LASIK may be misattributed to tear dysfunc-tion, when in fact they are due to the altered sensitivity andectopic firing of peripheral nerves. Tuisku et al. found thateven 2 to 5 years after LASIK for high myopia, most patientsexperienced ocular surface discomfort consistent with dryeye syndrome despite the absence of clinical signs of ocularsurface disease and with normal sensitivity when measuredwith noncontact esthesiometry [23]. This would explainwhy some patients in our study did not show improvementsin symptoms despite a better status of the ocular surface aftertreatment with E-PRP.

In the present study, we show evidence that supports thebeneficial effects of monotherapy with autologous E-PRP onpatients with post-LASIK chronic OSS. Of the 113 (74.3%)

eyes presenting chronic punctate keratitis 6 months afterLASIK (baseline), 101 (89.4%) showed significant improve-ment after treatment with E-PRP. There was a significantimprovement in CDVA, which correlated positively withthe recovery of the epithelial status, and 71.4% of the eyesimproved at least 1 line in CDVA. E-PRP had a remarkableeffect on the relief of symptoms of DES and improvementof conjunctival hyperemia and inflammation. AutologousPRP was well tolerated, and no adverse effects were observedduring the clinical study.

4. Conclusions

In conclusion, monotherapy with autologous PRP eye dropshas been shown to be a very good option for the treatmentof post-LASIK chronic OSS. Significant advantages are easeof preparation, absence of preservatives, its autologous ori-gin, safety, and minimal or no intolerance, with no observedside effects.

Conflicts of Interest

The authors declare that there is no conflict of interestregarding the publication of this paper.

Acknowledgments

This study has been supported in part by a grant from theSpanishMinistry ofHealth, Instituto Carlos III, Red Temáticade Investigación Cooperativa en Salud “Patología ocular delenvejecimiento, calidad visual y calidad de vida,” Subproyectode Calidad Visual (RD07/0062) and a grant from the SpanishMinistry of Economy and Competitiveness, Instituto CarlosIII, Red Temática de Investigación Cooperativa en Salud(RETICS) “Prevención, detección precoz y tratamiento dela patología ocular prevalente, degenerativa y crónica,” Sub-programa “dioptrio ocular y patologías frecuentes” (RD12/0034/0007).

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