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Clinical science
Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain
  1. Anat Galor1,2,
  2. Leonid Zlotcavitch2,
  3. Scott D Walter1,2,
  4. Elizabeth R Felix1,3,
  5. William Feuer2,
  6. Eden R Martin4,5,
  7. Todd P Margolis6,
  8. Konstantinos D Sarantopoulos1,7,
  9. Roy C Levitt1,4,5,7
  1. 1Miami Veterans Administration Medical Center, Miami, Florida, USA
  2. 2Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
  3. 3Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida, USA
  4. 4John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
  5. 5John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
  6. 6Departement of Ophthalmology, Washington University School of Medicine, St Louis, Missouri, USA
  7. 7Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, USA
  1. Correspondence to Dr Anat Galor, Department of Ophthalmology, Miami VA Medical Center, 1201 NW 16th Street, Miami, FL 33125, USA; agalor{at}med.miami.edu

Abstract

Objective Studies of patients with non-ocular pain suggest that it is therapeutically useful to identify those with features of neuropathic pain. No data is available, however, on whether this approach has similar utility in dry eye. The purpose of this study was to determine whether severity and persistence of dry eye symptoms associate with self-reported symptoms of neuropathic ocular pain (NOP).

Methods Design: Cohort study. Participants/setting: 102 men seen in the Miami Veterans Affairs eye clinic. A baseline evaluation was performed consisting of the dry eye questionnaire 5 (DEQ5) and ocular surface evaluation. Patients were contacted ≥2 years later to repeat the DEQ5 and complete questionnaires that further characterised their eye pain. Main outcome measure: The relationship between dry eye symptom severity and persistence (DEQ5) and additional measures of ocular pain (NOP).

Results Of 102 patients with variable dry eye symptoms, 70 reported at least mild symptoms on both encounters (DEQ5≥6). Fifty-four of 70 (77%) reported ≥1 NOP feature, and the number of NOP features correlated moderately with dry eye symptoms at both encounters (r=0.31–0.46, p<0.01). Patients with any symptom of NOP had higher dry eye symptom scores at both encounters (p<0.05), but similar ocular surface parameters. Hypersensitivity to wind and photoallodynia were associated with having mild or greater symptoms on both encounters (OR 3.4, 95% CI 1.2 to 10.0, p=0.02; OR 15.6, 95% CI 2.0 to 123, p=0.009, respectively).

Conclusions NOP features are common in patients with symptomatic dry eye and these features correlate with symptom severity and persistence.

  • Epidemiology
  • Ocular surface

https://doi.org/10.1136/bjophthalmol-2014-306057

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    Introduction

    Dry eye affects the quality of life of millions of Americans.1 One challenge to effectively managing dry eye is that patients given the diagnosis have a heterogeneous group of disorders. We believe that an important first step in individualising the treatment of dry eye is to classify patients with dry eye by clinical signs, and by symptoms, an approach largely not taken by eye care providers. In fact, the most commonly used dry eye questionnaires arrive at a symptom score by combining a variety of different types of symptoms, including visual disturbances, tearing and pain, rather than using these symptoms to categorise patients.2 ,3

    Data from other chronic pain conditions may shed light on improved ways to classify symptoms of patients with dry eye.4 ,5 As defined by the International Association for the Study of Pain, pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”6 Based on this broadly accepted definition, some dry eye symptoms (eg, burning, aching) should be classified as pain.

    Pain disorders are broadly classified into two categories: nociceptive pain, which is the normal physiological response to a noxious stimulus and which typically stops when the noxious stimulus terminates; and neuropathic pain, which is pain that persists in the absence of the initiating insult. Neuropathic pain is caused by a wide array of disorders of the somatosensory nervous system and includes conditions such as postherpetic neuralgia, diabetic neuropathy and phantom limb pain.7 Neuropathic pain is frequently chronic in nature.7

    There is a growing understanding that many patients diagnosed with dry eye describe features of neuropathic pain, including spontaneous pain, dysaesthesias (unpleasant, abnormal sensation), hyperalgesia (exaggerated pain response to suprathreshold noxious stimuli) and allodynia (pain response to normally non-noxious stimuli).7 ,8 Furthermore, some patients diagnosed with dry eye have abnormal corneal nerve morphology and sensitivity.8–10 It is not known, however, what proportion of patients with dry eye symptoms report features of neuropathic pain, and whether these symptoms associate with disease severity. The goal of this study was to evaluate whether severity and persistence of dry eye as assayed by the dry eye questionnaire 5 (DEQ5) associated with self-reported symptoms of neuropathic ocular pain (NOP).

    Methods

    Study population

    The study population built on a cohort of male patients previously recruited from the Miami Veterans Affairs Medical Center for a study on the relationship between dry eye symptoms and systemic androgen levels.11 This cohort consisted of 263 patients with grossly normal eyelid, conjunctival and corneal anatomy. Exclusion criteria included age under 50 years, contact lens use, recent ocular surgery (<3 months), active anterior segment ocular disease other than dry eye (eg, keratitis) or a diagnosis of HIV, sarcoidosis, graft-versus host disease or any collagen vascular disease.12 Of the original 263 patients, we were able to recontact 102 members to re-evaluate their dry eye symptoms, as part of a quality improvement project. Of the 161 that were not recontacted, 13 had died, 14 had incorrect contact information, 109 could not be reached and 25 were not interested in participating. No differences in demographic information (age, race, ethnicity) were found between participants and non-participants. Miami VA Institution Review Board approval was obtained to perform a chart review and link patient data to the questionnaires. The study was conducted in accordance with the principles of the Declaration of Helsinki.

    Data collection

    For each individual, we collected demographic information, pertinent history and medication information from the medical record. At the initial visit, all patients completed the DEQ53 and underwent an ocular surface examination. The ocular surface examination included measurement of tear osmolarity (TearLAB, San Diego, California, USA), tear break-up time, corneal staining (Oxford (Bron)), basal tear secretion test (Schirmer's strips with anaesthesia), and morphological and qualitative characterisation of the eyelid margin and meibomian glands.12 The DEQ5 was selected because its score combines patient responses regarding discomfort, dryness and tearing without considering visual function. The more commonly used Ocular Surface Disease Index, on the other hand, considers visual function and includes questions related to difficulty with reading, driving at night, working with a computer, and watching TV. Many of our patients seek eye care treatment for visual dysfunction, and on pilot testing, many had high Ocular Surface Disease Index scores for reasons other than dry eye.

    The 102 patients that we could contact were again asked to complete the DEQ5 2–3 years later, along with the short-form McGill Pain Questionnaire13 (SF-MPQ) as it pertained to their ocular symptoms. The SF-MPQ is commonly used by pain specialists to characterise features of pain.5 The questionnaire consists of 15 words which include the sensory descriptors: throbbing, shooting, stabbing, sharp, cramping, gnawing, hot burning, aching, heavy, tender, splitting; and the affective descriptors: tiring exhausting, sickening, fearful and punishing cruel quantitatively scored from 0 (none) to 3 (severe). Patients were asked to apply these descriptors to their eye pain. The SF-MPQ was scored in three ways: an overall score, generated by summing responses to all 15 descriptors; a sensory score, calculated by summing responses to the sensory descriptors (1–11); and an affective score, calculated by summing responses to the affective descriptors (12–15). In addition, each descriptor of the SF-MPQ can be examined individually. Of note, hot burning is a classic descriptor of dysaesthesia and is the SF-MPQ descriptor most closely related to neuropathic pain.5 Patients were also asked about NOP symptoms of allodynia (eye pain caused or worsened by light (photoallodynia) and/or a change in temperature) and hyperalgesia (eye pain caused or worsened by wind).

    Main outcome measures

    The main outcome measure was the relationship between dry eye symptom severity and persistence (DEQ5) and additional measures of ocular pain (eg, SF-MPQ scores, NOP). Features of NOP were considered present if the patient (1) characterised the eye pain as hot burning, (2) reported symptoms of allodynia to light and/or change in temperature and/or (3) reported symptoms of hyperalgesia to wind.

    Statistical analysis

    All statistical analyses were performed using SPSS V.21.0 (SPSS, Chicago, Illinois, USA) statistical package. Frequencies and descriptive statistics were applied to the data, as appropriate. χ2 and Student's t tests (for normally distributed variables), and Mann-Whitney tests (for non-normally distributed variables) were applied (as appropriate) to compare categorical and continuous variables between subjects. Multivariable logistic regression analysis was used to determine factors that correlated with persistent dry eye symptoms over 2–3 years.This sample size was deemed appropriate to detect factors with moderate effect size, such as on symptom persistence (with a sample size of 102 patients and response probability of 15% and α=0.05, the power was greater than 90% to demonstrate effects of factors with OR ≥2.0 in a multiple logistic regression model for a variety of types of variables (ie, normally distributed continuous, dichotomous, ordinal)).

    Results

    Study population

    The mean age of the 102 study patients was 68 years (SD 8.2) (table 1). At the first study visit 81 patients (79%) reported at least mild dry eye symptoms (DEQ5≥6). At the second encounter, a mean of 2.8 years later (SD 0.34), 70 of these 81 patients (86%) reported persistence of at least mild dry eye symptoms.

    View this table:
    Table 1

    Demographics and comorbidities of the study population

    Patients with persistent dry eye symptoms frequently report ocular pain

    Of the 70 patients with persistent dry eye symptoms (DEQ5≥6 on both encounters), 52 (74%) complained of 1 or more eye pain descriptors on the SF-MPQ. Of those 52, mean total SF-MPQ scores were 4.0 (SD 5.5), with a mean sensory score of 3.64 (SD 3.9) and a mean affective score of 2.8 (SD 2.9). SF-MPQ scores correlated moderately with dry eye symptoms as assayed by the DEQ5 on the second encounter: r=0.35 (total), 0.39 (sensory) and 0.26 (affective), p value <0.05 for all.

    Patients with persistent dry eye symptoms frequently report clinical features of NOP

    Of the 70 patients with persistent dry eye symptoms, 54 (77%) complained of one or more features of NOP; 26 (37%) of burning, 33 (47%) of hypersensitivity to wind, 26 (37%) of sensitivity to light and 17 (24%) of sensitivity to temperature. Twenty-one patients (30%) described one NOP feature, 20 (29%) described two NOP features, 8 (11%) described three NOP features and 4 (6%) described all four NOP features. The presence of any NOP feature was associated with significantly higher dry eye symptom scores at either encounter. However, signs of dry eye (tear break-up time, Schirmer scores) were similar between those with and those without symptoms of NOP (assessed at first visit) (table 2).

    View this table:
    Table 2

    Relationship between neuropathic ocular pain (NOP) and symptoms and signs of dry eye in a population of patients with persistent dry eye symptoms

    NOP features correlate with persistent dry eye symptoms

    We next used univariable logistic regression analyses to determine whether there was any association between each symptom of NOP (ocular pain described as hot burning, hyperalgesia to wind, and allodynia to light or change in temperature) and symptoms of persistent dry eye (defined by DEQ5≥6 on both encounters) in our study group. As noted in table 3, there was a statistically significant correlation between persistent dry eye and each of the four symptoms of NOP. We next evaluated this same data using a multivariable forward stepwise logistic regression model that included patient demographics, comorbidities, clinical descriptors of NOP and ocular surface examination findings. Using this model we found a statistically significant association between persistent dry eye symptoms and hypersensitivity to wind (OR 3.4, 95% CI 1.2 to 10.0, p=0.02) and photoallodynia (OR 15.6, 95% CI 2.0 to 123, p=0.009).

    View this table:
    Table 3

    Neuropathic ocular pain (NOP) features correlate with persistent dry eye symptoms (DEQ5≥ 6 on both encounters)

    Discussion

    This study aimed to determine whether pain and NOP, measured by metrics standardly used by pain specialists, are present in patients with persistent dry eye. First, we found that a significant proportion of patients with dry eye symptoms had ocular pain as assessed by the SF-MPQ, a well-established assay of pain. Second, a significant proportion of patients complained of features of NOP (dysaesthesia, allodynia and hyperalgesia). Furthermore, the presence of these features associated with dry eye symptom severity and persistence. These findings are important since in non-ocular sites the treatment of neuropathic pain frequently does not respond to local therapies.14

    Previous studies have summarised potential insults and anatomical locations where the generation of NOP might occur.8 ,15 The rich density and superficial location of the corneal nociceptors, integrated between superficial epithelial cells, makes them vulnerable to damage and injury in the setting of even minor insults.16 Recurrent damage to these exposed nerve endings may result in altered neuronal healing, maladaptive neuroplasticity, and prolonged hypersensitivity to normally non-noxious stimuli. Confocal microscopy studies have demonstrated abnormal corneal nerve morphology (nerve sprouts, increased nerve thickness, beadlike formations, and tortuosity) in a subset of patients diagnosed with dry eye.9 ,17–21 Furthermore, corneal polymodal neurons easily sensitise after injury, displaying spontaneous firing, lower thresholds and increased responses to stimuli.22 However, neuroplasticity associated with dry eye is likely to occur not solely at the corneal surface.8 Corneal nociceptors have their cell bodies in the trigeminal ganglion and synapse in the brainstem trigeminal nuclei, specifically the trigeminal subnucleus interpolaris/subnucleus caudalis (Vi/Vc) transition zone and the subnucleus caudalis/upper cervical transition zone (Vc/C1–2).23 ,24 Dry-responsive second order neurons have been identified in the Vi/Vc zone, and a subset of these neurons also receive input from corneal afferents sensitive to acidity, heat and chemicals.24 Therefore, neurons in the transition zone appear to integrate innocuous as well as noxious sensory information from the eye, and may constitute the neurophysiological substrate of central sensitisation.25

    Despite evidence that neuropathic pain may be driving dry eye symptoms in some patients with dry eye, limited data are available to support the use of neuropathic pain medication in the management of dry eye. For example, diclofenac, in addition to its antiprostaglandin effects, attenuates excitatory neurotransmitter release, resulting in an antiallodynic and antihyperalgesic effect.16 ,26–28 In one study, treatment of healthy volunteers with diclofenac drops (Voltaren, Novartis) attenuated ocular discomfort to mechanical, chemical and thermal stimuli.29 On the other hand, treatment with topical flurbiprofen, a non-steroidal anti-inflammatory agent without similar effects on neurotransmitter release, did not attenuate discomfort in the same study.

    As with all studies, the current work has limitations that need to be considered. First, we recognise that patients’ self-reported responses to any questionnaire, including the SF-MPQ, cannot definitely diagnose the presence of neuropathic pain, which requires direct assays of nerve conduction. But the questionnaires that we used have been validated in non-ocular pain and direct studies of human corneal nerve conduction are not currently available. Second, results from our patient population, which consists of older male US veterans seeking eye care services, may not be generalisable to other dry eye populations, including female patients. Third, dry eye symptom persistence was defined by two time points in our study, and this definition may not adequately capture the distinction between patients with transient versus persistent symptoms. Finally, the SF-MPQ pain descriptors are general descriptors and as such, do not incorporate many of the specific complaints of patients with dry eye.

    Despite these limitations, these data are important because they suggest patient symptoms may affect treatment decisions. For example, in patients with ocular surface disruption but no features of NOP, optimising the ocular surface environment is a reasonable approach. In patients who display features of NOP, however, multimodal therapy may be more appropriate, with a focus on ocular surface protection and on modulating ocular sensory apparatus function. Further studies are needed to assess whether topical and/or centrally acting neuromodulators have a role in the treatment of patients with dry eye with features of NOP.

    Acknowledgments

    The authors thank Drs D A Lubarsky and K Candiotti for their generous input and support. The authors note that the contents of this study do not represent the views of the Department of Veterans Affairs or the US Government.

    References

    1. ↵
      The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:93–107.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      The ocular surface disease index (OSDI) questionnaire. http://www.dryeyezone.com/encyclopedia/documents/OSDI.pdf (accessed 15 Jul).
    3. ↵
      1. Chalmers RL,
      2. Begley CG,
      3. Caffery B
      . Validation of the 5-Item dry eye questionnaire (DEQ-5): discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses. Cont Lens Anterior Eye 2010;33:55–60.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Bouhassira D,
      2. Attal N,
      3. Fermanian J, et al
      . Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248–57.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Lovejoy TI,
      2. Turk DC,
      3. Morasco BJ
      . Evaluation of the psychometric properties of the revised short-form McGill Pain Questionnaire. J Pain 2012;13:1250–7.
      OpenUrlCrossRefPubMed
    6. ↵
      Definition of pain. International Assocation for the Study of Pain website. http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698#Pain. (accessed 15 Jul).
    7. ↵
      1. Costigan M,
      2. Scholz J,
      3. Woolf CJ
      . Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32:1–32.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Rosenthal P,
      2. Borsook D
      . The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf 2012;10:2–14.
      OpenUrlCrossRefPubMed
    9. ↵
      1. Benitez-Del-Castillo JM,
      2. Acosta MC,
      3. Wassfi MA, et al
      . Relation between corneal innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. Invest Ophthalmol Vis Sci 2007;48:173–81.
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Bourcier T,
      2. Acosta MC,
      3. Borderie V, et al
      . Decreased corneal sensitivity in patients with dry eye. Invest Ophthalmol Vis Sci 2005;46:2341–5.
      OpenUrlAbstract/FREE Full Text
    11. ↵
      1. Azcarate PM,
      2. Venincasa VD,
      3. Galor A, et al
      . Androgen deficiency and dry eye syndrome in the aging male. Invest Ophthalmol Vis Sci 2014;55:5046–53.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Galor A,
      2. Feuer W,
      3. Lee DJ, et al
      . Ocular surface parameters in older male veterans. Invest Ophthalmol Vis Sci 2013;54:1426–33.
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Melzack R
      . The short-form McGill pain questionnaire. Pain 1987;30:191–7.
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      1. Kulkantrakorn K,
      2. Lorsuwansiri C,
      3. Meesawatsom P
      . 0.025% capsaicin gel for the treatment of painful diabetic neuropathy: a randomized, double-blind, crossover, placebo-controlled trial. Pain Pract 2013;13:497–503.
      OpenUrlCrossRefPubMed
    15. ↵
      1. Belmonte C
      . Eye dryness sensations after refractive surgery: impaired tear secretion or "phantom" cornea? J Refract Surg 2007;23:598–602.
      OpenUrlPubMedWeb of Science
    16. ↵
      1. Guthoff RF,
      2. Wienss H,
      3. Hahnel C, et al
      . Epithelial innervation of human cornea: a three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea 2005;24:608–13.
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Tuominen IS,
      2. Konttinen YT,
      3. Vesaluoma MH, et al
      . Corneal innervation and morphology in primary Sjogren's syndrome. Invest Ophthalmol Vis Sci 2003;44:2545–9.
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Benitez del Castillo JM,
      2. Wasfy MA,
      3. Fernandez C, et al
      . An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci 2004;45:3030–5.
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Villani E,
      2. Galimberti D,
      3. Viola F, et al
      . The cornea in Sjogren's syndrome: an in vivo confocal study. Invest Ophthalmol Vis Sci 2007;48:2017–22.
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. Tuisku IS,
      2. Konttinen YT,
      3. Konttinen LM, et al
      . Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome. Exp Eye Res 2008;86:879–85.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Zhang M,
      2. Chen J,
      3. Luo L, et al
      . Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy. Cornea 2005;24:818–24.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Belmonte C,
      2. Giraldez F
      . Responses of cat corneal sensory receptors to mechanical and thermal stimulation. J Physiol 1981;321:355–68.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Okamoto K,
      2. Bereiter DF,
      3. Tashiro A, et al
      . Ocular surface-evoked Fos-like immunoreactivity is enhanced in trigeminal subnucleus caudalis by prior exposure to endotoxin. Neuroscience 2009;159:787–94.
      OpenUrlCrossRefPubMed
    24. ↵
      1. Kurose M,
      2. Meng ID
      . Corneal dry-responsive neurons in the spinal trigeminal nucleus respond to innocuous cooling in the rat. J Neurophysiol 2013;109:2517–22.
      OpenUrlAbstract/FREE Full Text
    25. ↵
      1. Sarantopoulos C
      . Burning mouth syndrome: a misunderstood, underinvestigated, and undertreated clinical challenge. Reg Anesth Pain Med 2013;38:378–9.
      OpenUrlCrossRefPubMed
    26. ↵
      1. Huang CW,
      2. Hung TY,
      3. Liao YK, et al
      . Underlying mechanism of regulatory actions of diclofenac, a nonsteroidal anti-inflammatory agent, on neuronal potassium channels and firing: an experimental and theorethical study. J Physiol Pharmacol 2013;64:269–80.
      OpenUrlPubMed
    27. ↵
      1. Kawano T,
      2. Zoga V,
      3. Gemes G, et al
      . Suppressed Ca2+/CaM/CaMKII-dependent K(ATP) channel activity in primary afferent neurons mediates hyperalgesia after axotomy. Proc Natl Acad Sci USA 2009;106:8725–30.
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Kawano T,
      2. Zoga V,
      3. McCallum JB, et al
      . ATP-sensitive potassium currents in rat primary afferent neurons: biophysical, pharmacological properties, and alterations by painful nerve injury. Neuroscience 2009;162:431–43.
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Acosta MC,
      2. Berenguer-Ruiz L,
      3. Garcia-Galvez A, et al
      . Changes in mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci 2005;46:282–6.
      OpenUrlAbstract/FREE Full Text

    Footnotes

    • Contributors All authors contributed to this manuscript: design and conduct of the study (AG, LZ, ERF, KDS and RCL) collection (AG) management (AG) analysis (AG and WF) Interpretation of the data (AG, ERF, WF, RCL and TPM) preparation (AG, SDW and RCL) review or approval of the manuscript (AG, LZ, SDW, ERF, WF, ERM, KDS, RCL and TPM).

    • Funding Supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development's Career Development Award CDA-2-024-10S (AG), NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Department of Defense (DOD- Grant# W81XWH-09-1-0675 and Grant# W81XWH-13-1-0048 ONOVA) (institutional); NIH NIDCR R01 DE022903 (RCL and ERM), and the Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida for funding.

    • Competing interests None.

    • Ethics approval Miami VAMC IRB.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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