Purpose
Chronic neuropathic ocular pain (NOP) can develop alongside chronic dry eye (DE) post–laser-assisted in-situ keratomileusis (LASIK), yet its specific characteristics remain poorly understood. This study aims to compare the clinical characteristics of patients who developed both DE and NOP after LASIK to those with only DE and to asymptomatic LASIK patients, to facilitate the diagnosis of NOP.
Methods
Prospective, cross-sectional “case-control” comparison study . An 89-subject post-LASIK study comprised 3 groups: 34 patients developing NOP and DE (NOP-DE group), 25 patients developing only DE (DE group), and 30 asymptomatic subjects (control group). Assessments included clinical history and symptom questionnaires (OSDI, mSIDEQ, NRS, WFPRS), anxiety and depression evaluation (HADS), tear film stability (osmolarity and TBUT) and production (Schirmer), and ocular surface integrity. Corneal mechanical and thermal sensitivity thresholds were measured using Belmonte’s noncontact esthesiometer, whereas tactile sensitivity threshold was assessed pre-/post-topical anesthesia using the Cochet-Bonnet esthesiometer. In vivo confocal microscopy (IVCM) was used to evaluate the sub-basal nerve plexus characteristics and dendritic cell density in the central cornea. Group comparisons and correlations were conducted.
Results
Compared with DE group, patients in the NOP-DE group exhibited significantly more DE symptoms with mSIDEQ ( P = .019) higher level of pain with NRS and WFPRS, increased use of ocular lubrication ( P = .003), greater frequency of patients with pathological results on anxiety and depression questionnaires ( P < .001), and a higher prevalence of central sensitization syndromes ( P < .001). Additionally, NOP-DE patients demonstrated higher tactile corneal sensitivity post-topical anesthesia ( P = .002). IVCM revealed lower nerve density ( P = .049) and higher microneuroma density ( P = .008) in the sub-basal nerve plexus of NOP-DE patients compared to DE patients without NOP ( P = .008). Most nerve metrics correlated moderately to strongly with clinical parameters.
Conclusions
Persistent high corneal tactile sensitivity postanesthesia, reduced nerve density, and increased microneuroma density in the central cornea may serve as diagnostic indicators for confirming NOP in patients experiencing chronic DE post-LASIK. These findings underscore the potential utility of incorporating these measures into clinical assessments to improve diagnostic accuracy and guide management strategies in this patient population.
INTRODUCTION
Laser in-situ keratomileusis (LASIK) is one of the most common corneal refractive surgeries (RS) performed. Proper patient selection usually achieves efficient, predictable, and safe outcomes in more than 90% of cases.
The potential side effects of LASIK include dry eye (DE)-related symptoms such as dryness, stinging, burning, photophobia, redness, and visual fatigue. The intensity and duration of these symptoms are highly variable, being more bothersome during the first month, and usually disappearing in the 6-12 months postsurgery. However, persistent symptomatic DE after LASIK has been reported in up to 20% of patients who were photoablated with older laser platforms.
Another potential complication after RS is pain, which often overlaps with DE. It usually starts 2 hours after surgery as acute mild-to-moderate and can last up to 4 days. This pain is nociceptive, meaning that it is the consequence of nociceptors or free nerve endings that respond to surgical intervention, and it is usually associated with tear film abnormalities (eg, tear instability) and corneal epithelial disruption. LASIK surgery also induces corneal nerve damage whose reinnervation does not return to the preoperative state. This may result in the development of chronic neuropathic ocular pain (NOP). In recent years, the literature reporting NOP after LASIK and other surgeries has increased considerably. Damaged corneal nerve plexus has a high relevance to the dysfunction of the integrated lacrimal functional unit, leading to DE. However, patients with NOP have more intense symptomatology and are discordant with typical signs of DE. We recently reported that among post-RS patients with persistent DE, 78.8% of them also suffered chronic ocular pain, which was neuropathic (NOP) in origin in 63.5% of cases.
The International Association for the Study of Pain defined neuropathic pain as pain that arises as a direct consequence of a lesion or diseases affecting the somatosensory system. , The DEWS II report classified NOP as another entity differentiated from DE, although it can often be associated. More recently, we published the criteria that chronic ocular pain had to meet to be considered neuropathic in nature (NOP). However, NOP can still be difficult to properly diagnose due to the absence of evident clinical signs and also challenging to treat due to its resistance to conventional analgesic treatments.
The present study aimed to define objective signs that can help diagnose NOP in patients suffering from chronic DE after LASIK, focusing on corneal esthesiometry and the morphologic changes of the sub-basal corneal innervation.
METHODS
This study was designed as a case-control, observational, single-visit, single-center investigation approved by the Ethics Committee of the Valladolid University Clinic Hospital, adhering to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants after they had been fully informed, and the privacy rights of human subjects were consistently observed.
PATIENTS AND STUDY DESIGN
Patients with persistent symptoms after undergoing LASIK at external centers were enrolled during their scheduled first visit to the Ocular Pain Unit. A standardized evaluation was performed, and only those with microkeratome-assisted LASIK were included and classified into 3 groups:
- 1.
NOP-DE group : Patients with chronic dry eye (DE)-related persistent symptoms and chronic neuropathic ocular pain (NOP) post-LASIK.
- 2.
DE group : Patients with chronic DE symptoms post-LASIK but no pain.
- 3.
Control group : Asymptomatic patients post-LASIK.
Inclusion criteria:
For all groups:
- •
Age ≥18 years.
- •
LASIK performed in both eyes as the only type of ocular surgery, at least 3 months prior to recruitment.
- •
Absence of ocular symptoms before LASIK (no use of ocular lubricants or a maximum of 2 drops daily for contact lens [CL]-related discomfort.
Additional inclusion criteria for specific groups:
- •
NOP-DE group: Diagnosis of chronic NOP and chronic DE.
- •
DE group: Diagnosis of chronic DE.
- •
Control group: Absence of ocular symptoms.
Exclusion criteria:
Exclusion criteria applied to all groups:
- 1.
Presence of any ocular surface disease other than the one under study (DE or NOP).
- 2.
Concomitant inflammatory ophthalmic diseases.
- 3.
Previous ocular, periocular, or orbital surgeries (except LASIK).
- 4.
Noncompliance with the following study requirements:
- a.
Discontinuation of CL use at least 15 days before the study.
- b.
Avoidance of topical medications within 7 days before the study (or 4 weeks for special medications such as cyclosporine, tacrolimus, or steroids).
- c.
No use of artificial tears within the 12 hours before the study.
- a.
The presence of ocular pain was considered when both the Numerical Rating Scale (NRS) and the Wong-Baker Faces Pain Rating Scale (WFPRS) scores were ≥ 2.19 Both, DE and NOP were considered chronic when the duration was at least 3 months.
We considered chronic ocular pain was “neuropathic” (NOP) when at least 3 of the following 5 requirements were present. (1) evidence of damage or injury to the somatosensory nervous system; (2) minimum corneal damage (fluorescein corneal staining ≤ 1 with the Oxford scale); (3) the presence of at least 2 typical descriptors (tingling, pins or needles, stabbing, shooting or electric shock-like pains); (4) abnormal corneal sensitivity including allodynia, hyperalgesia, and/or radiating pain; and (5) persistence of symptoms after topical anesthesia. Additionally, the definite diagnosis of NOP for our patients was corroborated by a medical doctor specializing in oculofacial pain (coauthor EO).
To minimize the variation of a changing external environment, all participants were evaluated under the so-called “simulated normal environment conditions” (23°C and 50% relative humidity), in our Controlled Environment Laboratory (CELab) ( www.visionrd.com/celab/ ) between 9.00 and 13.00 hours. The same investigator performed the clinical assessment to avoid interobserver variability. ,
First, a brief medical history was recorded, including the previous spherical equivalent, the number of surgeries per eye, the onset and duration of symptoms, the comorbidities present, and the treatments used previously and at the time of the study visit.
CLINICAL QUESTIONNAIRES
We used 5 different questionnaires. The Ocular Surface Disease Index (OSDI) questionnaire defined the severity of DE-related symptoms according to the following scoring: asymptomatic (score ≤12); mild (score 13-22), moderate (score 23-32), and severe (score 33-100). , The Modified Single-Item Dry Eye Questionnaire (mSIDEQ) assessed the frequency of dryness, foreign body sensation, burning, pain, itching, photophobia, and blurred vision from 0 to 4 scale (0, absence of symptom; 1, rarely felt; 2, sometimes felt; 3, always felt but without affecting daily activities; 4, always felt with affected daily activities) (range, 0-28). The NRS scored the intensity of pain on a 0-10 scale: 0-1=no pain, 2-4=mild, 5-7=moderate, 8-10=severe. The WFPRS , scored the intensity of pain using 6 different faces, with a numerical equivalence, horizontally lined up to express an increasing level of pain intensity from left to right (0 = no pain; 2 = discomfort; 4 = light pain; 6 = moderate pain; 8 = intense pain; 10 = unbearable pain). The level of anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS) which consists of a 14-item self-reported scale (range, 0-42), whose overall score is obtained from the sum of its two 7-item subscales (range, 0-21 for each), to assess the existence of anxiety and depression. The subscale cut-off points were 0-7=normal; 8-10=borderline; and >10=existence of a clinical problem. The total HADS score was obtained by summing each subscale. ,
VISUAL ASSESSMENT
The uncorrected and corrected high (100%) and low (10%) contrast visual acuity (VA) was evaluated. The logarithm of the minimum angle of resolution (logMAR) was assessed using a liquid crystal display screen 22” (Topcon CO LDT, Tokyo, Japan) at a distance of 4 m.
CLINICAL TESTS
We performed the tests in both eyes. The starting eye was randomly selected, and the mean was calculated (unless otherwise specified) in the following order:
Tear osmolarity was evaluated using an osmometer (TearLab Corporation, San Diego, CA, USA), and values >308 mOsm/L were considered abnormal.
Bulbar conjunctival hyperemia and Meibomian gland dysfunction (MGD) were assessed using a slit-lamp (SL-D7, Topcon Corporation, Tokyo, Japan) following the Efron scale (range, 0-4).
Tear film stability was evaluated using the fluorescein tear break-up time (TBUT) test (the mean of 3 consecutive measurements), and values ≤ 7 s (s) were considered abnormal. ,
Ocular surface integrity was evaluated at the slit-lamp with fluorescein corneal staining using the Oxford scale (range, 0-5) and the Cornea and Contact Lens Research Unit (CCLRU) grading scale (range, 0-4) ; immediately after, conjunctival staining was assessed using Lissamine green strips (I-DEW green, Entod Research Cell UK Ltd, London, UK) with Oxford scale; for both scales, staining ≥ 1 was considered abnormal.
Corneal sensitivity was determined using both noncontact and contact esthesiometry. First, mechanical and thermal (hot and cold) thresholds were registered using a prototype of Belmonte’s noncontact gas esthesiometer. Briefly, the device was placed 5 mm from the central cornea and following standard protocols of our research group and the level method, , the mechanical threshold was first determined by triggering 3-seconds with variable airflow (range, 0 to 200 mL/min) pulses at neutral corneal temperature (34 °C). Subsequently, heat or cold thresholds were randomly determined by varying the temperature (range, −4 to 3.6 °C) and flow rate 10 mL/min below the mechanical threshold to avoid mechanical stimulation. Second, after a 30-minute interval to prevent overstimulation, a Cochet-Bonnet esthesiometer (Luneau Ophthalmology, Chartres, Paris, France) was used to estimate tactile sensitivity in the central cornea pre- and post-topical anesthesia following standard protocols (range, 60-0 mm). The longest length detected was recorded as the corneal threshold. After topical anesthetic instillation (1 drop of 0.1% tetracaine and 0.4% oxibuprocaine) (Anestésico Doble Colirio; Alcon Cusí, El Masnou, Spain), the assessment was repeated. ,
The anesthetic challenge test was answered between pre and postanesthesia Cochet-Bonnet esthesiometry postanesthesia. Each patient rated the change in intensity of their current ocular symptoms postanesthesia using the Global Rating of Change (GRC) scale. It measures enhancement or weakening of symptoms ranging from −5 (completely recovered), through 0 (unchanged) to +5 (very much worse). Nociceptive pain was associated with great improvement (range, −3 to −5), NOP with unchanged or worsening symptoms (range, 0 to +5), and mixed pain with slight enhancement (range, −2 to −1).
Basal tear production was determined using the Schirmer test with topical anesthesia. Values ≤ 5 mm after 5 minutes were considered abnormal.
In vivo confocal microscopy (IVCM) was performed on the central cornea of one randomly selected eye of each patient. Heidelberg Retina Tomograph III (HRT3) and a corneal module (Rostock Cornea Module, Heidelberg Engineering GmbH, Heidelberg, Germany https://www.heidelbergengineering.com/ ) were used to study the morphology of the sub-basal corneal nerve plexus and the density of inflammatory cells. Previously, 1 drop of the aforementioned anesthetic eye drops was instilled into the inferior conjunctival fornix and a blepharostat was placed to keep the eye open. Viscotears gel (Carbomer 980, 0.2%; Novartis Farmacéutica S.A., Barcelona, Spain) was applied on the outside and inside of a sterile disposable cap (TomoCap) placed over the objective lens. Good quality, nonoverlapping images of the sub-basal nerve plexus in the central cornea were obtained using the Heyex Eye Explorer (HeyexTM) platform, always by the same examiner (AV).
Following previous protocols , 3 high-quality images of the central cornea from each patient were analyzed by 2 investigators in a masked fashion and the mean value between the 2 observers for each parameter was computed for statistical analysis. Each captured image contained 384 × 384 pixels, covering an area of 400 × 400 µm (0.16 mm 2 ). For statistical analysis, the mean of each parameter evaluated in the 3 images was calculated, followed by the mean delivered by 2 masked examiners for each parameter evaluated. The Figure 1 shows some examples of images and the parameters analyzed, which are the following:
- 1.
Nerve characteristics: a) number of nerves (n/mm 2 and n/frame): sum of the nerves appearing in the image b) nerve density (mm/mm 2 ): total length of nerves existing in the image in the determined area; c) nerve length (mm/mm 2 ): the mean length of the nerves in the image; d) density of nerve branches (n/mm 2 ) in the image; and e) nerve tortuosity: assessed according to the scale described by Oliveira-Soto and Efron (0 = minimum tortuosity to 4 = maximum tortuosity).
- 2.
Density of microneuromas (n/mm 2 ): these are terminal enlargements of subbasal corneal nerves, characterized by irregularly-shaped, hyperreflective structures that form at sites of nerve damage or injury ( Figure 1 ).
- 3.
Dendritic cell density (n/mm2): these cells are visualized by their distinctive characteristics as bright cell bodies with dendritic structures. Among the different corneal immune cells, only dendritic cells were analyzed; inactive and activated keratocytes were not considered for this study
- 4.
Reflectivity: the histogram of each image was obtained using ImageJ software and used to obtain the mean reflectivity of each image or optical densitometry as an index of corneal transparency.
Nerve number, density and length were measured using the NeuronJ plugin A of the ImageJ B software. Nerve branching, microneuromas and dendritic were counted manually using the multipoint tool of the ImageJ software, and density was calculated as described in previous studies. , Two investigators (coautors AV, MB) evaluated the previously masked images and the mean of the values reported by them was calculated.
STATISTICAL ANALYSIS
Data were statistically analyzed using the SPSS software statistical package version 22.0 (SPSS Inc., Chicago, IL, USA) for Mac.
Kolmogorov-Smirnov test was used to check the normality assumption. Qualitative variables presented as frequencies and proportions were compared using the equality of proportions hypothesis or chi-squared test. Quantitative continuous variables were summarized as mean ± standard deviation (SD). Analysis of variance (ANOVA) test was used to compare the 3 groups and Student’s t-test for pairs of groups. Levene’s test was used to check homogeneity of variance and Welch’s test was used when this assumption was not valid.
Variables not following a normal distribution were described using the median [interquartile range (IQR)], unless otherwise specified in the text. In this case, Kruskall-Wallis was used to compare data among groups and Mann-Whitney U test, was performed between pairs or groups.
The Bonferroni correction was applied to adjust the experiment-wise error rate in all group comparisons.
Correlations between quantitative variables was quantified by Pearson or Spearman’s correlation coefficient (rho), depending on the normality assumption. The rho correlation coefficient can be interpreted according to the following ranges: from 0.80 to 1.00, very strong; from 0.60 to 0.79, strong; from 0.40 to 0.59, medium; from 0.20 to 0.39, low; and from 0.00 to 0.19, very low.
For the variables obtained with the corneal IVCM, the agreement between the 2 observers was measured using the intraclass correlation coefficient (ICC) (< 0.30 null; 0.31-0.5 mild; 0.51-0.70 moderate; 0.71-0.90 good; and > 0.90 very good).
P -values ≤.05 were considered statistically significant.
RESULTS
A total of 178 eyes of 89 RS LASIK patients were examined, of whom 57 (64.0%) were female; all of them had both eyes operated on. Of these, 34 patients were included in the NOP-DE group, 25 patients in the DE group, and 30 subjects were included in the control (asymptomatic) group. Table 1 summarizes their demographic characteristics, VA, and the main comorbidities. Of note is that the age and sex distribution in the 3 groups was not significantly different, ensuring that these 2 variables are not confounding factors. No significant differences were observed among the groups in either the spherical equivalent or the uncorrected and corrected distance high contrast VA. However, the NOP-DE group exhibited significantly poorer uncorrected and corrected low contrast VA than the control group.
| NOP-DE (Group 1) ( n = 34) | DE (Group 2) ( n = 25) | Control (Group 3) ( n = 30) | P Value | |||
|---|---|---|---|---|---|---|
| 1 vs 2 | 1 vs 3 | 2 vs 3 | ||||
| Age (years)—mean ± SD | 39.1 ± 6.5 | 40.2 ± 8.6 | 42.2 ± 7.0 | .098 a | .583 a | .266 a |
| Sex: women / men—n (%) | 26 (76.5) / 8 (23.5) | 16(64.0) / 9 (36.0) | 15 (50.0) / 15 (50.0) | .296 | .065 | .297 |
| Preoperative spherical equivalent refractive error (diopters)—mean±SD | −4.2 ± 3.5 | −1.9 ± 3.7 | −3.6 ± 2.9 | .084 | .288 | .124 |
| Visual acuity (LogMar)—mean±SD | ||||||
| High contrast (100%)—without correction | 0.2 ± 0.3 | 0.1 ± 0.2 | 0.1 ± 0.2 | .206 | .488 | .526 |
| High contrast (100%)—with correction | 0.1 ± 0.2 | 0.0 ± 0.1 | 0.0 ± 0.1 | .094 | .671 | .114 |
| Low contrast (10%)—without correction | 0.6 ± 0.3 | 0.5 ± 0.3 | 0.4 ± 0.2 | .083 | .036 | .606 |
| Low contrast (10%)—with correction | 0.6 ± 0.3 | 0.4 ± 0.2 | 0.4 ± 0.2 | .065 | .036 | .800 |
| Number of surgeries per eye—mean±SD | 2.4 ± 0.9 | 2.7 ± 1.2 | 2.2 ± 0.5 | .188 | .401 | .071 |
| Months from surgery to visit—mean±SD | 100.5 ± 70.7 | 114.6 ± 58.4 | 138.0 ± 42.5 | .276 | .087 | .150 |
| Onset of symptoms (months post-LASIK)—mean±SD | 24.5 ± 49.0 | 33.5 ± 60.1 | NA | .773 | NA | NA |
| Months with symptoms—mean±SD | 67.7 ± 61.1 | 75.8 ± 55.6 | NA | .407 | NA | NA |
| Comorbidities | ||||||
| Migraines—n (%) | 16 (47.1) | 10 (40.0) | 0 (0) | .589 | <.001 | <.001 |
| Autoimmune hypothyroidism | 2 | 2 | 0 | .749 | .177 | .115 |
| Psychiatric disorders—n (%) | 5 (14.7) | 2 (8) | 1 (3.3) | .431 | .119 | .448 |
| Central sensitization-related syndromes—n (%) | 12 (35.2) | 0 (0) | 0 (0) | <.001 | <.001 | 1 |
| Arthralgias | 2 | 1 | 0 | .745 | .177 | .269 |
| Temporomandibular disorders | 1 | 0 | 0 | .387 | .344 | – |
| Chemical sensitization syndrome | 2 | 0 | 0 | .217 | .177 | – |
| Irritable bowel syndrome | 2 | 0 | 0 | .217 | .177 | – |
| Chronic fatigue syndrome | 2 | 0 | 0 | .217 | .177 | – |
| Fibromyalgia / Cervical dystonia | 2 / 1 | 0 / 0 | 0 / 0 | .217/.387 | .177/.344 | – |
| Sensitivity alterations | 1 | 0 | 0 | .240 | .344 | – |
| Other chronic pain | 1 | 0 | 0 | .387 | .344 | – |
| Contact hypersensitivity (drug, metals…) | 5 | 3 | 0 | .764 | .029 | .051 |
| Rosacea | 1 | 1 | 0 | .824 | .344 | .269 |
| Topical agents used—n (%) | ||||||
| Lubricants | 34 (100) | 19 (76.0) | 0 (0.0) | .003 | <.001 | .002 |
| Topical cyclosporine (>3 months) | 8 (23.5) | 3 (12.0) | 0 (0.0) | .261 | .005 | .050 |
| Blood derivates | 5 (14.7) | 3 (12.0) | 0 (0.0) | .747 | .005 | .050 |
| Lid hygiene (home-based) | 8 (23.5) | 5 (20.0) | 0 (0.0) | .764 | .029 | .050 |
| Analgesics (only those for ocular pain)—n (%) | 7 (20.6) | 2 (8.0) | 0 (0.0) | .431 | .029 | .115 |
Migraines were diagnosed more frequently in the NOP-DE and DE groups than in the control group. Interestingly, central sensitization-related syndromes were more frequently diagnosed in patients who had the neuropathic type of pain (NOP-DE group) than those without it (DE and control groups). Additionally, the use of artificial tears was significantly higher in the NOP-DE group (100%) than in the DE-group (76%).
Symptomatology and clinical test results are shown in Table 2 . The scores of DE- and pain-related questionnaires, as well as the frequency of abnormal values of anxiety and depression were significantly different among the 3 groups, showing more abnormal values in the NOP-DE group than in the DE group.
| NOP-DE (Group 1) ( n = 34) | DE (Group 2) ( n = 25) | Control (Group 3) ( n = 30) | P Value | |||
|---|---|---|---|---|---|---|
| 1 vs 2 | 1 vs 3 | 2 vs 3 | ||||
| OSDI (0-100)—mean±SD | 64.2 ± 20.7 | 51.8 ± 24.7 | 8.0 ± 3.0 | .065 | <.001 | <.001 |
| mSIDEQ (0-28)—mean±SD | 19.7 ± 3.7 | 16.5 ± 5.9 | 5.3 ± 3.0 | .019 | <.001 | <.001 |
| Level of pain, (NRS scale, 0-10)—mean±SD | 6.7 ± 2.0 | 2.2 ± 2.6 | 0.1 ± 0.3 | <.001 | <.001 | <.001 |
| No pain (0-1)—n (%) | NA | 15 (60.0) | 30 (100.0) | <.001 | <.001 | <.001 |
| Mild pain (2-4)—n (%) | 8 (23.5) | 4 (16.0) | NA | .02 | .004 | .007 |
| Moderate pain (5-7)—n (%) | 10 (29.4) | 4 (16.0) | NA | .006 | <.001 | .001 |
| Severe pain (8-10)—n (%) | 16 (47.1) | 2 (8.0) | NA | <.001 | <.001 | <.001 |
| Level of pain, (WFPRS scale, 0-10)—mean±SD | 6.7 ± 2.0 | 2.6 ± 2.7 | 0.0 ± 0.0 | <.001 | <.001 | <.001 |
| No pain (0)—n (%) | NA | 9 (36.0) | 30 (100.0) | <.001 | <.001 | <.001 |
| Discomfort (2)—n (%) | 1 (2.9) | 8 (32.0) | NA | .002 | .003 | .572 |
| Light pain (4)—n (%) | 6 (17.6) | 3 (12.0) | NA | .061 | .016 | .021 |
| Moderate pain (6)—n (%) | 11 (32.4) | 2 (8.0) | NA | <.001 | <.001 | <.001 |
| Intense pain (8)—n (%) | 12 (35.3) | 3 (12.0) | NA | <.001 | <.001 | <.001 |
| Unbearable pain (10)—n (%) | 4 (11.8) | NA | NA | .034 | .018 | .022 |
| HADS questionnaire (0-42)—mean±SD | 18.9 ± 8.0 | 18.2 ± 11.8 | 6.1 ± 5.5 | .645 | <.001 | <.001 |
| Anxiety subscale (0-21)—mean±SD | 10.9 ± 4.1 | 9.8 ± 5.8 | 4.2 ± 3.2 | .419 | <.001 | <.001 |
| Anxiety subscale (≥8)—n (%) | 25 (73.5) | 15 (60.0) | 3 (10.0) | <.001 | <.001 | <.001 |
| Depression subscale (0-21)—mean±SD | 8.0 ± 4.3 | 8.5 ± 6.4 | 1.9 ± 2.4 | .92 | <.001 | <.001 |
| Depression subscale (≥8)—n (%) | 18 (52.9) | 13 (52.0) | 1 (3.3) | <.001 | <.001 | <.001 |
| Tear osmolarity (mOsm/L)—mean±SD | 316.2 ± 17.0 | 314.2 ± 14.1 | 310.6 ± 13.4 | .820 | .063 | .247 |
| Ocular surface integrity—mean±SD | ||||||
| Corneal staining (Oxford scale, 0-5) | 1.0 ± 0.8 | 1.5 ± 0.7 | 0.9 ± 0.8 | .036 | .549 | .018 |
| Corneal staining (CCLRU, 0-4) | 0.9 ± 0.7 | 1.1 ± 0.6 | 1.0 ± 0.6 | .181 | .262 | .799 |
| Conjunctival staining (Oxford scale, 0-5) | 0.8 ± 0.8 | 0.8 ± 0.8 | 0.2 ± 0.4 | .981 | .001 | <.001 |
| Conjuntival hyperemia (Efron scale, 0-4) | 1.4 ± 0.6 | 1.6 ± 0.7 | 1.8 ± 0.8 | .958 | .121 | .351 |
| MGD (Efron scale, 0-4) | 1.1 ± 0.5 | 1.2 ± 0.6 | 0.8 ± 0.6 | .56 | .008 | .005 |
| Tear stability and production | ||||||
| TBUT (s)—mean±SD | 3.7 ± 2.1 | 4.1 ± 2.1 | 5.8 ± 3.7 | .334 | .007 | .112 |
| TBUT ≤ 7 s—n (%) | 33 (97.1) | 21 (84.0) | 20 (66.7) | .029 | .024 | .009 |
| Schirmer test (mm)—mean±SD | 6.9 ± 7.4 | 7.0 ± 4.7 | 13.9 ± 5.8 | .318 | <.001 | <.001 |
| Schirmer test ≤ 5 mm—n (%) | 19 (55.8) | 10 (40.0) | 0 (0.0) | <.001 | <.001 | <.001 |
CORNEAL SENSITIVITY
Corneal sensitivity data are presented in Table 3 . Noncontact corneal sensitivity assessed with Belmonte’s esthesiometer showed similar results in mechanical threshold for the 3 groups. However, the thermal (both heat and cold) thresholds were significantly lower (sensitivity was higher) in the NOP-DE and DE groups than in the control group.
| Characteristics | NOP-DE (Group 1) ( n = 34) | DE (Group 2) ( n = 25) | Control (Group 3) ( n = 30) | P Value | ||
|---|---|---|---|---|---|---|
| 1 vs 2 | 1 vs 3 | 2 vs 3 | ||||
| Corneal esthesiometry (noncontact, Belmonte)—mean±SD | ||||||
| Mechanical threshold—(mL/min) | 119.4 ± 38.2 | 112.9 ± 28.6 | 110.2 ± 36.9 | .673 | .419 | .554 |
| Heat threshold (°C) | 0.8 ± 0.6 | 1.1 ± 0.8 | 1.4 ± 0.7 | .243 | <.001 | .076 |
| Cold threshold (°C) | −1.3 ± 1.0 | −1.7 ± 1.1 | −2.0 ± 0.6 | .735 a | .048 a | .776 a |
| Corneal esthesiometry (contact, Cochet Bonnet)—mean±SD | ||||||
| Without topical anesthesia (mm) | 54.8 ± 7.0 | 57.0 ± 4.6 | 57.3 ± 2.9 | .131 | .196 | .718 |
| With topical anesthesia (mm) | 11.9 ± 15.0 | 1.5 ± 2.6 | 1.5 ± 2.8 | .002 | <.001 | .792 |
| Patients With topical anesthesia ≥ 10 mm—n (%) | 17 (50.0) | 6 (24.0) | 4 (13.3) | .043 | .003 | .307 |
| Anesthetic challenge test- GRC scale (−5 to 5) | −0.7 ± 2.0 | −0.8 ± 2.6 | 0.9 ± 2.2 | .852 | .017 | <.001 |
Tactile corneal sensitivity threshold measured using the Cochet-Bonnet esthesiometer was similar in the 3 groups. However, when it was measured after topical anesthesia, it remained significantly elevated only in the NOP-DE group. The Cochet-Bonnet pain threshold after anesthesia was ≥ 10 mm in significantly more patients with NOP than in the DE and control groups.
The GRC scale was significantly higher in the control group. In the NOP-DE group, only 8 (23.5%) patients reported relief of symptoms after topical anesthesia with GRC (−3 to −5) whereas the remaining 26 (76.5%) patients: reported slight improvement (9, 26.4%), no improvement 10 (29.4%) or even increased symptoms (7, 20.6%).
IN VIVO CONFOCAL MICROSCOPY
The data collected using IVCM are shown in Table 4 . The agreement between the 2 independent observers when assessing IVCM parameters was very good, except for the analysis of nerve tortuosity, which was moderate. Figure 1 shows representative images of each group.
| Characteristics | Agreement Between Observers ICC [95%CI] | NOP-DE (Group 1) ( n = 34) | DE (Group 2) ( n = 25) | Control (Group 3) ( n = 30) | P Value | ||
|---|---|---|---|---|---|---|---|
| 1 vs 2 | 1 vs 3 | 2 vs 3 | |||||
| Number of nerves (n/mm 2 ) | 0.97 [0.95-0.98] | 30.3 ± 13.7 | 36.7 ± 18.8 | 68.1 ± 21.1 | .239 | <.001 | <.001 |
| Number of nerves (n/frame) | 0.97 [0.95-0.98] | 4.9 ± 2.3 | 6.0 ± 2.9 | 11.2 ± 3.6 | .239 | <.001 | <.001 |
| Nerve density (mm/mm 2 ) | 0.99 [0.98-0.99] | 7.2 ± 3.2 | 9.6 ± 4.0 | 15.7 ± 475.7 | .049 a | <.001 a | <.001 a |
| Nerve length (mm/mm 2 ) | 0.95 [0.92-0.97] | 1.5 ± 3.3 | 1.6 ± 3.1 | 1.5 ± 2.0 | .550 a | .791 a | .056 a |
| Density of nerve branch points (n/mm 2 ) | 0.97 [0.96-0.98] | 11.2 ± 12.4 | 18.1 ± 15.9 | 43.4 ± 25.5 | .132 | <.001 | <.001 |
| Nerve tortuosity (0-4) | 0.63 [0.43-0.76] | 2.5 ± 0.9 | 2.6 ± 0.8 | 2.3 ± 0.6 | .958 a | .958 a | .282 a |
| Density of microneuromas (n/mm 2 ) | 0.97 [0.95-0.98] | 1.8 ± 4.6 | 0.2 ± 0.4 | 0.1 ± 0.3 | .008 | .001 | .510 |
| Density of dendritic cells (n/mm 2 ) | 0.98 [0.97-0.99] | 73.3 ± 99.1 | 54.3 ± 57.7 | 30.1 ± 40.8 | .766 | .043 | .132 |
| Reflectivity | 1.0 [1.0-1.0] | 99.3 ± 14.4 | 103.3 ± 21.8 | 101.0 ± 17.2 | 1 a | 1 a | 1 a |
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