Publications by authors named "Roy C Levitt"

71 Publications

Reversion mutation of cDNA CA8-204 minigene construct produces a truncated functional peptide that regulates calcium release in vitro and produces profound analgesia in vivo.

Mamm Genome 2020 12 28;31(9-12):287-294. Epub 2020 Nov 28.

Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, USA.

Intracellular calcium is critical in orchestrating neuronal excitability and analgesia. Carbonic anhydrase-8 (CA8) regulates intracellular calcium signaling through allosteric inhibition of neuronal inositol trisphosphate receptor 1 (ITPR1) to produce profound analgesia. Recently, we reported the "G" allele at rs6471859 represents cis-eQTL regulating alternative splicing of a 1697 bp transcript (CA8-204) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3. In this study we show the reversion mutation (G to C) at rs6471859 within the CA8-204 expression vector also produced a stable 1697 bp transcript (CA8-204) coding for a smaller peptide (~ 22 kDa) containing only the first three CA8 exons. Surprisingly, this peptide inhibited ITPR1 (pITPR1) activation, ITPR1-mediated calcium release in vitro; and produced profound analgesia in vivo. This is the first report showing CA8-204 codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia.
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http://dx.doi.org/10.1007/s00335-020-09848-yDOI Listing
December 2020

Corneal Nerve Pathway Function in Individuals with Dry Eye Symptoms.

Ophthalmology 2021 Apr 8;128(4):619-621. Epub 2020 Aug 8.

Department of Anesthesia, University of Miami, Miami, Florida.

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http://dx.doi.org/10.1016/j.ophtha.2020.07.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868519PMC
April 2021

Periorbital botulinum toxin A improves photophobia and sensations of dryness in patients without migraine: Case series of four patients.

Am J Ophthalmol Case Rep 2020 Sep 4;19:100809. Epub 2020 Jul 4.

Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, 900 NW 17th Street, Miami, FL, USA.

Purpose: Individuals receiving botulinum toxin A (BoNT-A) injections in the head and neck for migraine treatment have reported decreases in photophobia and sensations of dryness, independent of ocular surface parameters. We hypothesized that patients without migraine but with similar ocular neuropathic-like symptoms would also experience symptomatic improvement with periocular BoNT-A injections, independent of ocular surface changes.

Observations: We identified four individuals without a history of migraine but with neuropathic ocular pain (symptoms of dryness, burning, and photophobia that were out of proportion to ocular surface findings and unresponsive to ongoing dry eye (DE) therapies). Individuals underwent 1 session of periocular BoNT-A injections. Validated questionnaires (Visual Light Sensitivity Questionnaire-8, Dry Eye Questionnaire-5) assessed photophobia and DE symptoms pre- and 1-month post-injections. All four reported improvements in frequency and severity of photophobia and eye discomfort following BoNT-A injections. Tear film parameters (phenol red thread test, tear break-up time, corneal staining, and Schirmer test) and eyelid (palpebral fissure height and levator palpebrae superioris function) and eyebrow (position) anatomy were also evaluated before and after injections. Despite a unanimous improvement in symptoms, there were no consistent changes in ocular surface parameters with BoNT-A injections across individuals.

Conclusions: Periocular BoNT-A shows promise in reducing photophobia and sensations of dryness in individuals with neuropathic-like DE symptoms without a history of migraine, independent of tear film, eyelid, or eyebrow parameters.
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http://dx.doi.org/10.1016/j.ajoc.2020.100809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350146PMC
September 2020

Effect of non-invasive intranasal neurostimulation on tear volume, dryness and ocular pain.

Br J Ophthalmol 2020 09 12;104(9):1310-1316. Epub 2019 Dec 12.

Ophthalmology, Miami VA Medical Center, Miami, Florida, USA

Purpose: To evaluate the effect of one TrueTear session on change in tear volume and symptoms of dryness and ocular pain.

Methods: Retrospective interventional case series of patients seen in a dry eye clinic. Seventy-five individuals underwent an ocular surface examination and one session of neurostimulation. Outcome measures included objective change in tear volume measured via phenol red test, and subjective change in sensations of dryness and ocular pain measured on a 0-10 Numerical Rating Scale.

Results: The mean age of the 75 individuals was 59±13 years, and the majority were male (73%). Intranasal neurostimulation increased tear volume (mean 13.40±8.00 mm, p<0.0005) and reduced intensities of dryness (mean -2.85±2.79, p<0.0005) and ocular pain (mean -1.48±2.41, p<0.0005 for both). However, these effects were independent of one another as change in symptom report did not correlate with change in tear volume (r=-0.13, p=0.25 for dryness; r=0.07, p=0.56 for pain). In a multivariable model, the strongest predictors for increased tear volume were lower baseline tear volume (standardised beta (β)=-0.50, p<0.0005) and absence of an autoimmune disease (β=-0.36, p=0.001) (R=0.30). The strongest predictors for reduced dryness and pain scores were lower baseline dryness and ocular pain scores. No complications related to neurostimulation were noted.

Conclusion: Intranasal neurostimulation increased tear volume and reduced intensities of dryness and ocular pain, independently of one another.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315065DOI Listing
September 2020

The Genetics of Neuropathic Pain from Model Organisms to Clinical Application.

Neuron 2019 11;104(4):637-653

Neural Injury Group, Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK. Electronic address:

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic.
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http://dx.doi.org/10.1016/j.neuron.2019.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868508PMC
November 2019

Pregabalin Failed to Prevent Dry Eye Symptoms after Laser-Assisted in Situ Keratomileusis (LASIK) in a Randomized Pilot Study.

J Clin Med 2019 Sep 1;8(9). Epub 2019 Sep 1.

Department of Physical Medicine and Rehabilitation, University of Miami, Miami, FL 33136, USA.

Purpose: Perioperative pregabalin administration has been found to reduce the risk of persistent pain after a variety of surgical procedures. However, this approach has not been tested in relation to eye surgery. As such, the purpose of this study was to evaluate whether perioperative pregabalin can reduce the presence of dry eye (DE) symptoms, including eye pain, six months after laser-assisted in situ keratomileusis (LASIK).

Methods: Prospective, masked, randomized single-center pilot study. Patients were treated with either pregabalin (oral solution of pregabalin 150 mg twice daily, first dose prior to surgery, continued for a total of 28 doses over 14 days) or placebo solution. The primary outcome was dry eye symptoms as measured by the Dry Eye Questionnaire 5 (DEQ-5). Secondary outcome measures included pain-related eye symptoms.

Results: In total, 43 individuals were enrolled in the study and randomized to pregabalin ( = 21) or placebo ( = 22). Of those, 42 individuals completed the final visit after six months of follow-up. Some differences were noted between the two groups at baseline, including a higher frequency of females in the pregabalin group. At 6-months, there were no significant differences in the percentage of patients with DE symptoms (DEQ5 ≥ 6, 57% vs. 33%, = 0.14), DE symptom severity (DEQ5, 6.6 ± 5.0 vs. 4.5 ± 4.2, = 0.14), ocular pain intensity (numerical rating scale, 1.10 ± 1.48 vs. 0.38 ± 0.97, = 0.08), or neuropathic pain complaints (Neuropathic Pain Symptom Inventory-Eye, 2.81 ± 4.07 vs. 3.14 ± 5.85, = 0.83) between the pregabalin and control groups. Ocular signs were likewise similar between the groups, and of note, did not correlate with DE symptoms. The strongest predictor of DE symptoms six months post-surgery was the presence of DE symptoms prior to surgery.

Conclusions: Perioperative pregabalin did not reduce the frequency or severity of DE symptoms at a six month follow-up after LASIK in this small pilot study.
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http://dx.doi.org/10.3390/jcm8091355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780750PMC
September 2019

Dysfunctional Coping Mechanisms Contribute to Dry Eye Symptoms.

J Clin Med 2019 Jun 24;8(6). Epub 2019 Jun 24.

Ophthalmology and Research Services, Miami Veterans Affairs (VA) Medical Center, Miami, FL 33125, USA.

Dysfunctional coping behaviors, such as catastrophizing, have been implicated in pain severity and chronicity across several pain disorders. However, the impact of dysfunctional coping has not been examined under the context of dry eye (DE). This study evaluates relationships between catastrophizing and measures of DE, including pain severity and pain-related daily interference. The population consisted of patients seen at Miami Veterans Affairs eye clinic between April 2016 and October 2017. Patients filled out standardized questionnaires assessing symptoms of DE and eye pain, non-ocular pain, mental health, coping behaviors (Pain Catastrophizing Scale, PCS), and pain-related daily interference as a perceived impact on quality of life (Multidimensional Pain Inventory, Interference Subscale, MPI-Interference), and all patients underwent an ocular surface examination. In total, 194 patients participated, with a mean age of 58.8 ± 9.6 years, the majority being male, non-Hispanic, and black. PCS (catastrophizing) was correlated with DE symptom severity, including Dry-Eye Questionnaire 5 (DEQ5; r = 0.41, < 0.0005), Ocular Surface Disease Index (OSDI; r = 0.40, < 0.0005), and neuropathic-like eye pain (Neuropathic Pain Symptom Inventory-Eye (NPSI-Eye; r = 0.48, < 0.0005). Most tear metrics, on the other hand, did not correlate with PCS. Linear regressions showed that PCS, non-ocular pain intensity, and number of pain conditions were significant predictors of DEQ5 (overall DE symptoms), while PCS and non-ocular pain intensity were predictors of NPSI-Eye scores, as were insomnia scores and analgesic use. In a separate analysis, PCS and DE symptoms (OSDI) associated with pain-related interference (MPI-Interference) along with non-ocular pain intensity, post-traumatic stress disorder (PTSD), number of pain conditions, and non-Hispanic ethnicity. These findings suggest that catastrophizing is not significantly related to signs of DE, but is strongly associated to pain-related symptoms of DE and daily interference due to pain.
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http://dx.doi.org/10.3390/jcm8060901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617174PMC
June 2019

Oral Gabapentinoids and Nerve Blocks for the Treatment of Chronic Ocular Pain.

Eye Contact Lens 2020 May;46(3):174-181

Department of Ophthalmology (L.R.S., A.G., E.R.F., R.C.L., C.D.S.), Bascom Palmer Eye Institute, University of Miami, Miami, FL; Ophthalmology, Miami Veterans Administration Medical Center (A.G.), Miami, FL; Physical Medicine and Rehabilitation (E.R.F.), University of Miami, Miami, FL; Department of Anesthesiology, Perioperative Medicine and Pain Management (D.B.H., R.C.L., C.D.S.), University of Miami Miller School of Medicine, Miami, FL; John P. Hussman Institute for Human Genomics (R.C.L.), University of Miami Miller School of Medicine, Miami, FL; and John T Macdonald Foundation Department of Human Genetics (R.C.L.), University of Miami Miller School of Medicine, Miami, FL.

Purpose: There is a recognition that nerve dysfunction can contribute to chronic ocular pain in some individuals. However, limited data are available on how to treat individuals with a presumed neuropathic component to their ocular pain. As such, the purpose of this study was to examine the efficacy of our treatment approaches to this entity.

Methods: A retrospective review of treatments and outcomes in individuals with chronic ocular pain that failed traditional therapies.

Results: We started eight patients on an oral gabapentinoid (gabapentin and/or pregabalin) as part of their pain regimen (mean age 46 years, 50% women). Two individuals reported complete ocular pain relief with a gabapentinoid, in conjunction with their topical and oral medication regimen. Three individuals noted significant improvements, one slight improvement, and two others no improvement in ocular pain with gabapentin or pregabalin. We performed periocular nerve blocks (4 mL of 0.5% bupivacaine mixed with 1 mL of 80 mg/mL methylprednisolone acetate) targeting the periocular nerves (supraorbital, supratrochlear, infratrochlear, and infraorbital) in 11 individuals (mean age 54 years, 36% women), 10 of whom had previously used a gabapentinoid without ocular pain improvement. Seven individuals experienced pain relief after nerve blocks that lasted from hours to months and four failed to benefit. Five of the individuals who experienced pain relief underwent repeat nerve blocks, weeks to months later.

Conclusions: Approaches used to treat chronic pain outside the eye can be applied to ocular pain that is not responsive to traditional therapies.
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http://dx.doi.org/10.1097/ICL.0000000000000630DOI Listing
May 2020

Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL.

PLoS Genet 2019 06 14;15(6):e1008226. Epub 2019 Jun 14.

Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.g., CA8-204). Our functional genomic studies show the "G" allele at rs6471859 produces a cryptic 3'UTR splice site regulating expression of CA8-204. We developed constructs to study the expression and function of the naturally occurring CA8-204G transcript (G allele at rs6471859), CA8-204C (C allele at rs6471859 reversion mutation) and CA8-201 (full length transcript). CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells. We also show CA8-204 produces a stable peptide that inhibits pITPR1 and Ca++ release in HEK293 cells. These results imply homozygous G/G individuals at rs6471859, which are common in the general population, produce exclusively CA8-204G that is barely detectable in neuronal cells. CA8 null mutations that greatly impact neuronal functions are associated with severe forms of spinal cerebellar ataxia, and our data suggest G/G homozygotes should display a similar phenotype. To address this question, we show in vivo using AAV8-FLAG-CA8-204G and AAV8-V5-CA8-201 gene transfer delivered via intra-neural sciatic nerve injection (SN), that these viral constructs are able to transduce DRG cells and produce similar analgesic and anti-hyperalgesic responses to inflammatory pain. Immunohistochemistry (IHC) examinations of DRG tissues further show CA8-204G peptide is expressed in advillin expressing neuronal cells, but to a lesser extent compared to glial cells. These findings explain why G/G homozygotes that exclusively produce this truncated functional peptide in DRG evade a severe phenotype. These genomic studies significantly advance the literature regarding structure-function studies on CA8-ITPR1 critical to calcium signaling pathways, synaptic functioning, neuronal excitability and analgesic responses.
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http://dx.doi.org/10.1371/journal.pgen.1008226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615631PMC
June 2019

Individuals with migraine have a different dry eye symptom profile than individuals without migraine.

Br J Ophthalmol 2020 02 30;104(2):260-264. Epub 2019 Apr 30.

Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA

Background: Many individuals with migraine report symptoms of dry eye (DE). However, it is not known whether DE profiles are similar between individuals with and without migraine. To bridge this gap, we evaluated symptoms and signs of DE, including symptoms suggestive of nerve dysfunction, in a large group of individuals with DE symptoms, and compared profiles between individuals with migraine and those without migraine or headache.

Methods: Prospective cross-sectional study of individuals with DE symptoms seen at the Miami VA.

Results: Of 250 individuals, 31 met International Classification of Headache Disorders criteria for migraine based on a validated screen. Individuals with migraine were significantly younger (57 vs 62 years) and more likely to be female (26% vs 6%) than controls. Individuals with migraine had more severe DE symptoms and ocular pain compared with controls (mean Ocular Surface Disease Index 53.93 ± 21.76 vs 36.30 ± 22.90, p=0.0001; mean Neuropathic Pain Symptom Inventory modified for the Eye 39.39 ± 23.33 vs 21.86 ± 20.17, p=0.0001). The difference in symptom profile occurred despite similar ocular surface parameters between the groups.

Conclusions: Individuals with migraine had a different DE symptom yet a similar DE sign profile when compared with controls without migraine. This suggests that DE symptoms in individuals with migraine may be driven by nerve dysfunction as opposed to ocular surface abnormalities.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313471DOI Listing
February 2020

Modification of the Neuropathic Pain Symptom Inventory for use in eye pain (NPSI-Eye).

Pain 2019 07;160(7):1541-1550

Miami Veterans Administration Medical Center, Miami, FL, United States.

Chronic eye pain, which has previously been assumed to be due to ocular surface abnormalities (ie, "dry eye [DE] disease"), has recently garnered attention as a potential indicator of neuropathic ocular pain in some patients. The purpose of this study was to evaluate the psychometric properties of a modified version of the Neuropathic Pain Symptom Inventory in individuals with eye pain (NPSI-Eye). Enrolled participants (n = 397) completed the NPSI-Eye, general pain severity questionnaires, DE symptom report, and psychological health indices. Participants also underwent mechanical pain sensitivity testing of the cornea, tear film assessment, and evaluation of the efficacy of anesthetic eye drops to relieve pain. Short-term test-retest reliability of the NPSI-Eye was excellent (intraclass correlation coefficient = 0.98, P < 0.001). Correlations between the NPSI-Eye and indicators of general eye pain were ≥0.65 (P < 0.001), whereas correlations between the NPSI-Eye and DE symptom severity and psychological health indices were lower (rho = 0.56, 0.32, 0.37; all P < 0.001). Individuals who reported little or no decrease in pain after anesthetic eye drops (hypothesized to indicate eye pain with at least partial central involvement) had significantly higher NPSI-Eye scores than participants whose eye pain was completely relieved by anesthetic (P < 0.05). Overall, our results support preliminary validation of the NPSI-Eye, yielding similar metrics to those reported in Bouhassira et al.'s original NPSI publication (2004). However, additional evaluation and refinement of some questions may be desirable, including the potential elimination of items that were not highly endorsed.
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http://dx.doi.org/10.1097/j.pain.0000000000001552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586475PMC
July 2019

Resolution of pain with periocular injections in a patient with a 7-year history of chronic ocular pain.

Am J Ophthalmol Case Rep 2019 Jun 12;14:35-38. Epub 2019 Feb 12.

Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, 900 NW 17th Street, Miami, FL, 33136, USA.

Purpose: We report a case of a male patient with chronic ocular pain that resolved completely following peripheral nerve blocks.

Observations: A 66-year-old male presented with a seven-year history of severe left eye pain and photophobia. The pain began after retinal detachment repair with scleral buckle placement. Previous treatments included topical (autologous serum tears, corticosteroids, diclofenac, cyclosporine) and oral (gabapentin, diclofenac) therapies with no pain relief. The patient's pain was so severe that he requested enucleation. After discussion, the decision was made to perform periocular nerve blocks. Prior to the procedure, the patient reported an average pain intensity of 8 out of 10 and photophobia daily. Following left supraorbital, supratrochlear, infraorbital and infratrochlear injections with bupivacaine and methylprednisolone, pain intensity and photophobia improved to 1-2 out of 10. One week later, repeat infraorbital and infratrochlear nerve blocks were given, after which time the patient reported complete resolution of symptoms that lasted for 7 months. Repeat nerve blocks were administered with repeat resolution of pain. There were no complications associated with the procedures.

Conclusions And Importance: Chronic ocular pain can be a debilitating condition. Periorbital nerve blocks can provide pain relief and should be considered as a potential treatment option after medical management has failed.
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http://dx.doi.org/10.1016/j.ajoc.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378870PMC
June 2019

Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections.

Br J Ophthalmol 2019 08 29;103(8):1024-1029. Epub 2018 Sep 29.

Miami Veterans Administration Medical Center, Miami, Florida, USA

Background: To evaluate the efficacy of botulinum toxin A (BoNT-A) in reducing photophobia and dry eye symptoms in individuals with chronic migraine. Additionally, we aimed to evaluate tear film volume as a potential contributor to symptoms in these patients.

Methods: Retrospective review of 76 patients who received BoNT-A for chronic migraine between 23 August 2017 and 13 December 2017 at the Miami Veterans Affairs Medical Center Neurotoxin Clinic. Demographic data and all comorbidities were queried via chart review. Standardised validated surveys were administered to assess symptoms prior to and after BoNT-A injection. Preinjection tear volumes were obtained using the phenol red thread (PRT) test.

Results: Preinjection migraine, photophobia and dry eye symptom scores were all significantly correlated, p<0.05, and none were associated with preinjection PRT results. After BoNT-A, improvements in migraine, photophobia and dry eye symptoms were also significantly correlated, p<0.05 and similarly did not associate with preinjection PRT results. Photophobia scores significantly improved following BoNT-A, while dry eye symptoms significantly improved in those with severe symptoms at baseline (DEQ-5 score ≥12), p=0.027. In logistic regression analysis of all individuals with dry eye symptoms (DEQ-5 ≥6), individuals with more severe dry eye symptoms were more likely improve, OR 1.27, 95% CI 1.06 to 1.51, p<0.01.

Conclusions: BoNT-A significantly improved photophobia in patients being treated for migraine and also improved dry eye symptoms in patients with severe symptoms at baseline, independent of baseline tear film volume. These improvements may be due to modulation of shared trigeminal neural pathways.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440864PMC
August 2019

Epidemiology of Persistent Postsurgical Pain Manifesting as Dry Eye-Like Symptoms After Cataract Surgery.

Cornea 2018 Dec;37(12):1535-1541

Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL.

Purpose: To evaluate the epidemiology of persistent postsurgical pain (PPP) manifesting as dry eye (DE)-like symptoms 6 months after surgery.

Methods: This single-center study included 119 individuals whose cataract surgeries were performed by a single surgeon at the Bascom Palmer Eye Institute and who agreed to participate in a phone survey 6 months after surgery. Patients were divided into 2 groups: the PPP group was defined as those with a Dry Eye Questionnaire-5 score ≥6 and without PPP as those with a Dry Eye Questionnaire-5 score <6 at 6 months after cataract surgery.

Results: Mean age of the study population was 73 ± 8.0 years; 55% (n = 66) were female. PPP was present in 34% (n = 41) of individuals 6 months after surgery. Factors associated with an increased risk of PPP were female sex [odds ratio (OR) = 2.68, 95% confidence interval (CI) = 1.20-6.00, P = 0.01], autoimmune disorder (OR = 13.2, CI = 1.53-114, P = 0.007), nonocular chronic pain disorder (OR = 4.29, CI = 1.01-18.1, P = 0.06), antihistamine use (OR = 6.22, CI = 2.17-17.8, P = 0.0003), antireflux medication use (OR = 2.42, CI = 1.04-5.66, P = 0.04), antidepressant use (OR = 3.17, CI = 1.31-7.68, P = 0.01), anxiolytic use (OR = 3.38, CI = 1.11-10.3, P = 0.03), and antiinsomnia medication use (OR = 5.28, CI = 0.98-28.5, P = 0.047). PPP patients also reported more frequent use of artificial tears (P < 0.0001), higher ocular pain levels (P < 0.0001), and greater neuropathic ocular pain symptoms, including burning (P = 0.001), wind sensitivity (P = 0.001), and light sensitivity (P < 0.0001).

Conclusions: PPP in the form of persistent DE-like symptoms is present in approximately 34% of individuals 6 months after cataract surgery. The frequency of PPP after cataract surgery is comparable to that of other surgeries including laser refractive surgery, dental implants, and genitourinary procedures.
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http://dx.doi.org/10.1097/ICO.0000000000001741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218275PMC
December 2018

Human carbonic anhydrase-8 AAV8 gene therapy inhibits nerve growth factor signaling producing prolonged analgesia and anti-hyperalgesia in mice.

Gene Ther 2018 07 24;25(4):297-311. Epub 2018 Apr 24.

Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, USA.

Carbonic anhydrase-8 (Car8; murine gene symbol) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates neuronal intracellular calcium release. We previously reported that wild-type Car8 overexpression corrects the baseline allodynia and hyperalgesia associated with calcium dysregulation in the waddle (wdl) mouse due to a 19 bp deletion in exon 8 of the Car8 gene. In this report, we provide preliminary evidence that overexpression of the human wild-type ortholog of Car8 (CA8), but not the reported CA8 S100P loss-of-function mutation (CA8), inhibits nerve growth factor (NGF)-induced phosphorylation of ITPR1, TrkA (NGF high-affinity receptor), and ITPR1-mediated cytoplasmic free calcium release in vitro. In addition, we show that gene transfer using AAV8-V5-CA8 viral particles via sciatic nerve injection demonstrates retrograde transport to dorsal root ganglia (DRG) producing prolonged V5-CA8 expression, pITPR1 and pTrkA inhibition, and profound analgesia and anti-hyperalgesia in male C57BL/6J mice. AAV8-V5-CA8-mediated overexpression prevented and treated allodynia and hyperalgesia associated with chronic neuropathic pain produced by the spinal nerve ligation (SNL) model. These AAV8-V5-CA8 data provide a proof-of-concept for precision medicine through targeted gene therapy of NGF-responsive somatosensory neurons as a long-acting local analgesic able to prevent and treat chronic neuropathic pain through regulating TrkA signaling, ITPR1 activation, and intracellular free calcium release by ITPR1.
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http://dx.doi.org/10.1038/s41434-018-0018-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063772PMC
July 2018

Epidemiology of Persistent Dry Eye-Like Symptoms After Cataract Surgery.

Cornea 2018 Jul;37(7):893-898

Miami Veterans Affairs Medical Center, Miami, FL.

Purpose: To evaluate the frequency and risk factors for persistent postsurgical pain (PPP) after cataract surgery, defined as mild or greater dry eye (DE)-like symptoms 6 months after surgery.

Methods: This single-center study included 86 individuals who underwent cataract surgery between June and October 2016 and had DE symptom information available 6 months after surgery. Patients were divided into 2 groups: controls were defined as those without DE symptoms 6 months after surgery (defined by a Dry Eye Questionnaire 5 (DEQ5) score <6), cases were defined as those with mild or greater DE-like symptoms 6 months after surgery (DEQ5 ≥6).

Results: Mean age of the study population was 71 ± 8.6 years; 95% (n = 82) were men. DE-like symptoms were reported in 32% (n = 27) of individuals 6 months after cataract surgery; 10% (n = 8) reported severe symptoms (DEQ5 ≥12). Patients with DE-like symptoms after cataract extraction also had higher ocular pain scores and specific ocular complaints (ocular burning, sensitivity to wind and light) compared with controls with no symptoms. A diagnosis of nonocular pain increased the risk of DE-like symptoms after cataract surgery (odds ratio 4.4, 95% confidence interval 1.58-12.1, P = 0.005).

Conclusions: Mild or greater PPP occurred in approximately 1/3 of individuals after cataract surgery. Prevalence of severe PPP is in line with that of refractive surgery, dental implants, and genitourinary procedures.
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http://dx.doi.org/10.1097/ICO.0000000000001491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991988PMC
July 2018

Evidence that dry eye is a comorbid pain condition in a U.S. veteran population.

Pain Rep 2017 Nov 20;2(6):e629. Epub 2017 Nov 20.

Miami Veterans Administration Medical Center, Miami, FL, USA.

Introduction: Recent evidence suggests that dry eye (DE) may be comorbid with other chronic pain conditions.

Objectives: To evaluate DE as a comorbid condition in the U.S. veteran population.

Methods: Retrospective review of veterans seen in the Veterans Administration Healthcare System (Veteran Affairs) between January 1, 2010, and December 31, 2014. Dry eye and nonocular pain disorders were ascertained by codes. Dry eye was further separated into codes representing tear film dysfunction or ocular pain. χ and logistic regression analyses were used to examine frequency and risk of DE, ocular pain, and tear film dysfunction by pain disorders.

Results: Of 3,265,894 veterans, 959,881 had a DE diagnosis (29.4%). Dry eye frequency increased with the number of pain conditions reported ( < 0.0005). Ocular pain was most strongly associated with headache (odds ratio [OR] 2.98; 95% confidence interval [CI] 2.95-3.01), tension headache (OR 2.64; 95% CI 2.58-2.71), migraine (OR 2.58; 95% CI 2.54-2.61), temporomandibular joint dysfunction (OR 2.39; 95% CI 2.34-2.44), pelvic pain (OR 2.30; 95% CI 2.24-2.37), central pain syndrome (OR 2.24; 95% CI 1.94-2.60), and fibromyalgia/muscle pain (OR 2.23; 95% CI 2.20-2.26), all < 0.0005. Tear film dysfunction was most closely associated with osteoarthritis (OR 1.97; 95% CI 1.96-1.98) and postherpetic neuralgia (OR 1.95; 95% CI 1.90-2.00), both < 0.0005.

Conclusions: Dry eye, including both ocular pain and tear film dysfunction, is comorbid with pain conditions in this nationwide population, implying common mechanisms.
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http://dx.doi.org/10.1097/PR9.0000000000000629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741329PMC
November 2017

The Relationship Between Ocular Itch, Ocular Pain, and Dry Eye Symptoms (An American Ophthalmological Society Thesis).

Trans Am Ophthalmol Soc 2017 Aug 17;115:T5. Epub 2018 Jan 17.

Miami Veterans Administration Medical Center, Miami, Florida (Dr Galor); Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miami, Florida (Dr Galor, Dr Small, Mr Feuer); and Department of Anesthesiology, Perioperative Medicine and Pain Management (Dr Levitt, Dr Sarantopoulos), John P. Hussman Institute for Human Genomics (Dr Levitt), John T. Macdonald Foundation Department of Human Genetics (Dr Levitt), and Department of Dermatology and Miami Itch Center (Dr Yosipovitch), University of Miami Miller School of Medicine, Miami, Florida.

Purpose: To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs.

Methods: A cross-sectional study of 324 patients seen in the Miami Veterans Affairs eye clinic was performed. The evaluation consisted of questionnaires regarding ocular itch, DE symptoms, descriptors of neuropathic-like ocular pain (NOP), and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Analyses were performed to examine for differences between those with and without subjective complaints of ocular itch.

Results: The mean age was 62 years with 92% being male. Symptoms of DE and NOP were more frequent in patients with moderate-severe ocular itch compared to those with no or mild ocular itch symptoms. With the exception of ocular surface inflammation (abnormal matrix metalloproteinase 9 testing) which was less common in those with moderate-severe ocular itch symptoms, DE signs were not related to ocular itch. Individuals with moderate-severe ocular itch also demonstrated greater sensitivity to evoked pain on the forearm and had higher non-ocular pain, depression, and post-traumatic stress disorders scores, compared to those with no or mild itch symptoms.

Conclusions: Subjects with moderate-severe ocular itch symptoms have more severe symptoms of DE, NOP, non-ocular pain and demonstrate abnormal somatosensory testing in the form of increased sensitivity to evoked pain at a site remote from the eye, consistent with generalized hypersensitivity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774848PMC
August 2017

Noninvasive Electrical Stimulation for the Treatment of Chronic Ocular Pain and Photophobia.

Neuromodulation 2018 Dec 28;21(8):727-734. Epub 2017 Dec 28.

Miami Veterans Administration Medical Center, Miami, FL, USA.

Introduction: "Dry eye" or "keratoconjunctivitis sicca" is a multifactorial disease estimated to have a worldwide prevalence of 5-33%. Conventional therapies targeting the ocular surface with artificial tears, anti-inflammatories, punctal closure, eyelid hygiene, and antibiotics do not provide relief in all patients, especially those with neuropathic-like ocular complaints (wind hyperalgesia and photophobia). We anticipated that ocular transcutaneous electrical nerve stimulation (TENS) would alleviate symptoms of ocular pain, photophobia, and dryness in these latter individuals.

Methods: All individuals who received electrical stimulation between May 10, 2016 and April 6, 2017 for the treatment of chronic ocular pain at the oculofacial pain clinic of the Miami Veterans Administration Hospital were included in this retrospective review. All patients had symptoms of dryness along with other neuropathic-like symptoms (e.g., photophobia) and minimal signs of tear dysfunction. Ocular pain intensity, symptoms of dryness, and light sensitivity were compared pre-treatment and five min post-treatment via a two-tailed paired Student's t-test.

Results: The use of TENS significantly reduced the mean pain intensity in both the right and left eyes five min after treatment compared to prior to treatment (p < 0.05, paired t-test). The use of TENS significantly decreased light sensitivity in both eyes (p < 0.05). The findings for symptoms of dryness, however, were equivocal with a significant decrease in the left eye but not the right (p < 0.05, paired t-test).

Discussion: Our data indicate that TENS may similarly provide analgesia in patients with dry eye symptoms as it does for many other chronic pain conditions. Furthermore, the noted effect on symptoms of photophobia and dryness suggest that all may be linked by similar trigeminal-thalamic-cortical pathways. Prospective studies with electrical stimulation of dry eye are needed to further elucidate its benefit and mechanism of action.
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http://dx.doi.org/10.1111/ner.12742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023783PMC
December 2018

Neuropathic-Like Ocular Pain and Nonocular Comorbidities Correlate With Dry Eye Symptoms.

Eye Contact Lens 2018 Nov;44 Suppl 2:S307-S313

Department of Ophthalmology (V.S.C., T.P.R., C.L.K., A.G.), Bascom Palmer Eye Institute, University of Miami, Miami, FL; Department of Ophthalmology (R.C.L., A.G.), Miami Veteran Affairs Medical Center; Department of Anesthesiology, Perioperative Medicine and Pain Management (R.C.L., C.S.), Miller School of Medicine, University of Miami, Miami, FL; John P. Hussman Institute for Human Genomics (R.C.L.), Miller School of Medicine, University of Miami, Miami, FL; and John T. Macdonald Foundation Department of Human Genetics (R.C.L.), Miller School of Medicine, University of Miami, Miami, FL.

Objective: To evaluate the association between dry eye (DE) symptoms and neuropathic-like ocular pain (NOP) features, chronic pain conditions, depression, and anxiety in patients presenting for routine ophthalmic examinations.

Methods: Two hundred thirty-three consecutive patients ≥18 years of age presenting to a comprehensive eye clinic between January and August 2016 were included in this study. Information on demographics, chronic pain conditions, medication use, DE symptoms (dry eye questionnaire, DEQ5), NOP complaints (burning; wind, light, and temperature sensitivity), depression, and anxiety indices (patient health questionnaire 9, PHQ-9 and symptom checklist 90-revised, SCL-90-R) were collected for each individual. Pearson correlation was used to evaluate strengths of association. Logistic regression analysis examined risk factors for any (DEQ5≥6) and severe (DEQ5≥12) DE symptoms.

Results: The mean age of the population was 46.3 years (±13.0); 67.8% (n=158) were female. Per the DEQ5, 40.3% (n=94) had mild or greater DE symptoms and 12% (n=24) had severe symptoms. Severity of DE symptoms correlated with NOP complaints: burning (Pearson r=0.37, P<0.001); sensitivity to wind (r=0.37, P<0.001), sensitivity to light (r=0.34, P<0.001), and sensitivity to temperature (r=0.30, P<0.001). Sex, race, and ethnicity were not significant risk factors for DE symptoms. Risk factors for mild or greater DE symptoms included a greater number of chronic nonocular pain conditions (odds ratio [OR]=1.38, P<0.001), arthritic pain (OR=6.34, P<0.001), back pain (OR=2.47, P=0.004), headaches (OR=2.14, P=0.02), depression (OR=1.17, P<0.001), and anxiety (OR=1.13, P=0.02).

Conclusion: Dry eye severity positively associated with NOP complaints, comorbid chronic pain conditions, and symptoms of depression and anxiety.
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http://dx.doi.org/10.1097/ICL.0000000000000463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991979PMC
November 2018

Botulinum Toxin A for the Treatment of Photophobia and Dry Eye.

Ophthalmology 2018 01 27;125(1):139-140. Epub 2017 Oct 27.

Miami Veterans Administration Medical Center, Miami, Florida; Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miami, Florida. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2017.09.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741464PMC
January 2018

Neuropathic pain and dry eye.

Ocul Surf 2018 01 12;16(1):31-44. Epub 2017 Oct 12.

Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, USA; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.

Dry eye is a common, multifactorial disease currently diagnosed by a combination of symptoms and signs. Its epidemiology and clinical presentation have many similarities with neuropathic pain outside the eye. This review highlights the similarities between dry eye and neuropathic pain, focusing on clinical features, somatosensory function, and underlying pathophysiology. Implications of these similarities on the diagnosis and treatment of dry eye are discussed.
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http://dx.doi.org/10.1016/j.jtos.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756672PMC
January 2018

Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice.

Neuroreport 2017 Dec;28(18):1215-1220

aDepartment of Anesthesiology, Perioperative Medicine and Pain Management bJohn P. Hussman Institute for Human Genomics cJohn T. Macdonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida dCenter for Pharmacogenetics and Individualized Therapy, University of North Caroline, Eshelman School of Pharmacy, Chapel Hill eDepartment of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA.

Recently, we showed that murine dorsal root ganglion (DRG) Car8 expression is a cis-regulated eQTL that determines analgesic responses. In this report, we show that transduction through sciatic nerve injection of DRG with human wild-type carbonic anhydrase-8 using adeno-associated virus viral particles (AAV8-V5-CA8WT) produces analgesia in naive male C57BL/6J mice and antihyperalgesia after carrageenan treatment. A peak mean increase of about 4 s in thermal hindpaw withdrawal latency equaled increases in thermal withdrawal latency produced by 10 mg/kg intraperitoneal morphine in these mice. Allometric conversion of this intraperitoneal morphine dose in mice equals an oral morphine dose of about 146 mg in a 60-kg adult. Our work quantifies for the first time analgesia and antihyperalgesia in an inflammatory pain model after DRG transduction by CA8 gene therapy.
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http://dx.doi.org/10.1097/WNR.0000000000000872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685868PMC
December 2017

Traumatic brain injury, dry eye and comorbid pain diagnoses in US veterans.

Br J Ophthalmol 2018 05 26;102(5):667-673. Epub 2017 Aug 26.

Department of Ophthalmology, Miami VA Medical Center, Miami, Florida, USA.

Aims: The purpose of the study is to evaluate the relationship between dry eye (DE) and pain diagnoses in US veterans with and without traumatic brain injury (TBI).

Methods: Retrospective cohort study of veterans who were seen in the Veterans Administration Hospital (VA) between 1 January 2010 and 31 December 2014. Veterans were separated into two groups by the presence or absence of an International Classification of Diseases, Ninth Revision diagnosis of TBI and assessed for DE and other comorbidities. A dendrogram was used to investigate the linkage between TBI, DE, chronic pain and other comorbid conditions.

Results: Of the 3 265 894 veterans seen during the 5-year period, 3.97% carried a diagnosis of TBI. Veterans with TBI were more likely to have a diagnosis of DE compared with their counterparts without TBI (37.2% vs 29.1%, p<0.0005). The association was stronger between TBI and ocular pain (OR 3.08; 95% CI 3.03 to 3.13) compared with tear film dysfunction (OR 1.09; 95% CI 1.07 to 1.10). Those with TBI were also about twice as likely to have a diagnosis of chronic pain, headache, depression or post-traumatic stress disorder compared with their counterparts without TBI. Cluster analysis of TBI, DE and pain diagnoses of interest revealed that central pain syndrome, cluster headache, sicca syndrome, keratoconjunctivitis sicca and late effect of injury to the nervous system (as can be seen after TBI) were all closely clustered together.

Conclusions: DE and pain disorders occur at higher frequencies in patients with a diagnosis of TBI, suggesting a common underlying pathophysiology.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310509DOI Listing
May 2018

Epidemiology of discordance between symptoms and signs of dry eye.

Br J Ophthalmol 2018 05 18;102(5):674-679. Epub 2017 Aug 18.

Miami Veterans Administration Medical Center, Miami, Florida, USA.

Background/aims: The frequent lack of association between dry eye (DE) symptoms and signs leads to challenges in diagnosing and assessing the disease.

Methods: Participants underwent ocular surface examinations to evaluate signs of disease and completed questionnaires to assess ocular symptoms, psychological status and medication use. To assess nociceptive system integrity, quantitative sensory testing (QST), including vibratory and thermal threshold measures and temporal summation of pain were obtained at the forearm and forehead. Correlations between DE discordance score (degree of discrepancy between symptom severity and DE signs) and patient characteristics were determined. Higher discordance scores indicated more symptoms than signs.

Results: 326 patients participated (mean age: 62 years; SD: 10 years; 92% men). Age was negatively correlated with DE discordance score (Pearson r=-0.30, p<0.0005), while mental health indices were positively correlated. Chronic pain elsewhere in the body (ie, non-ocular pain conditions) and intensity ratings of prolonged aftersensations of pain evoked by noxious hot and cold stimuli were also significantly correlated with DE discordance score. Multiple linear regression demonstrated that post-traumatic stress disorder and non-ocular pain intensity were important predictors of DE discordance score, Dry Eye Questionnaire-5 and Ocular Surface Disease Index and that DE discordance was also sensitive to QST as well.

Conclusions: The present study provides evidence that the degree of discordance between DE symptom report and measurable signs of ocular surface disease is associated with comorbidities related to clinical pain and to hyperalgesia as demonstrated with QST. Understanding the epidemiology of DE discordance can aid in interpreting the DE exam and individualising treatment.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310633DOI Listing
May 2018

Evidence that Dry Eye Represents a Chronic Overlapping Pain Condition.

Mol Pain 2017 Jan-Dec;13:1744806917729306

John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 7John T. Macdonald Foundation.

Abstract: Recent data suggest that corneal somatosensory dysfunction may be the underlying cause of severe dry eye symptoms in the absence of ocular surface pathology seen in a subset of patients diagnosed with “dry eye syndrome.” This subset of patients tends to demonstrate a unique constellation of symptoms that are persistent, more severe, and generally respond poorly to current dry eye therapies targeting inadequate or dysfunctional tears. A growing body of literature suggests that symptoms in these patients may be better characterized as neuropathic ocular pain rather than dry eye. In these patients, dry eye symptoms are often associated with numerous comorbid pain conditions and evidence of central pain processing abnormalities, where eye pain is just one of multiple overlapping peripheral manifestations. In this review, we discuss the concept and potential mechanisms of chronic overlapping pain conditions as well as evidence for considering neuropathic ocular pain as one of these overlapping pain conditions.
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http://dx.doi.org/10.1177/1744806917729306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584655PMC
September 2018

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.

Mamm Genome 2017 Oct 25;28(9-10):407-415. Epub 2017 May 25.

Department of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

Carbonic anhydrase-8 (Car8 mouse gene symbol) is devoid of enzymatic activity, but instead functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) to regulate this intracellular calcium release channel important in synaptic functions and neuronal excitability. Causative mutations in ITPR1 and carbonic anhydrase-8 in mice and humans are associated with certain subtypes of spinal cerebellar ataxia (SCA). SCA mice are genetically deficient in dorsal root ganglia (DRG) Car8 expression and display mechanical and thermal hypersensitivity and susceptibility to subacute and chronic inflammatory pain behaviors. In this report, we show that DRG Car8 expression is variable across 25 naïve-inbred strains of mice, and this cis-regulated eQTL (association between rs27660559, rs27706398, and rs27688767 and DRG Car8 expression; P < 1 × 10) is correlated with nociceptive responses in mice. Next, we hypothesized that increasing DRG Car8 gene expression would inhibit intracellular calcium release required for morphine antinociception and might correlate with antinociceptive sensitivity of morphine and perhaps other analgesic agents. We show that mean DRG Car8 gene expression is directly related to the dose of morphine or clonidine needed to provide a half-maximal analgesic response (r = 0.93, P < 0.00002; r = 0.83, P < 0.0008, respectively), suggesting that greater DRG Car8 expression increases analgesic requirements. Finally, we show that morphine induces intracellular free calcium release using Fura 2 calcium imaging in a dose-dependent manner; V5-Car8 overexpression in NBL cells inhibits morphine-induced calcium increase. These findings highlight the 'morphine paradox' whereby morphine provides antinociception by increasing intracellular free calcium, while Car8 and other antinociceptive agents work by decreasing intracellular free calcium. This is the first study demonstrating that biologic variability associated with this cis-eQTL may contribute to differing analgesic responses through altered regulation of ITPR1-dependent calcium release in mice.
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http://dx.doi.org/10.1007/s00335-017-9694-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693610PMC
October 2017

The Association of Dry Eye Symptom Severity and Comorbid Insomnia in US Veterans.

Eye Contact Lens 2018 Sep;44 Suppl 1:S118-S124

Research Services (A.G., B.E.S., J.J.P., A.L.M., E.R.F., R.C.L., C.S., D.M.W.), Miami Veterans Administration Medical Center, Miami, FL; Department of Ophthalmology (A.G., W.F.), Bascom Palmer Eye Institute, University of Miami, Miami, FL; Department of Physical Medicine and Rehabilitation (E.R.F.), University of Miami Miller School of Medicine, Miami, FL; Department of Anesthesiology (R.C.L., C.S.), Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL; John P. Hussman Institute for Human Genomics (R.C.L.), University of Miami Miller School of Medicine, Miami, FL; John T Macdonald Foundation Department of Human Genetics (R.C.L.), University of Miami Miller School of Medicine, Miami, FL; and Department of Neurology (D.M.W.), University of Miami Miller School of Medicine, Miami, FL.

Purpose: To investigate the association between dry eye (DE) and insomnia symptom severity.

Methods: Cross-sectional study of 187 individuals seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding insomnia (insomnia severity index [ISI]) and DE symptoms, including ocular pain, followed by a comprehensive ocular surface examination. Using a two-step cluster analysis based on intensity ratings of ocular pain, the patient population was divided into two groups (high and low ocular pain groups: HOP and LOP). A control group was ascertained at the same time from the same clinic as defined by no symptoms of DE (Dry Eye Questionnaire 5 [DEQ5], <6). The main outcome measure was the frequency of moderate or greater insomnia in the DE groups.

Results: The mean age of the study sample was 63 years, and 93% were male. All insomnia complaints were rated higher in the HOP group compared with the LOP and control groups (P<0.0005). Most (61%) individuals in the HOP group experienced insomnia of at least moderate severity (ISI≥15) compared with the LOP (41%) and control groups (18%) (P<0.0005). Black race (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.2-6.0; P=0.02), depression severity (OR, 1.2; 95% CI, 1.1-1.3; P<0.0005), and DE symptom severity (DEQ5; OR, 1.1; 95% CI, 1.01-1.2; P=0.03) were significantly associated with clinical insomnia (ISI≥15) after controlling for potential confounders.

Conclusions: After adjusting for demographics and medical comorbidities, we show that DE symptom severity is positively associated with insomnia severity.
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http://dx.doi.org/10.1097/ICL.0000000000000349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500440PMC
September 2018

Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain.

Br J Ophthalmol 2017 09 18;101(9):1238-1243. Epub 2017 Jan 18.

Miami Veterans Administration Medical Center, Miami, Florida, USA.

Objective: To evaluate how closely neuropathic-like ocular pain (NOP) symptoms align with a metric of central sensitisation (ie, the presence of persistent ocular pain after topical anaesthetic placement) in individuals with dry eye (DE) symptoms.

Design: Cross-sectional study of 224 individuals with DE symptoms seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding DE symptoms, NOP descriptors and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Subsequent analyses were performed to examine for differences between those with and without ocular pain after topical anaesthetic placement.

Results: The mean age was 62 years with 91% being men. DE symptoms and NOP symptoms were higher in subjects with persistent ocular pain after anaesthesia. Most DE signs were not related to persistent pain, with the exception of meibum quality. Individuals with persistent ocular pain also demonstrated greater sensitivity to evoked pain at testing sites on the forehead and forearm. When examining receiver operator characteristic curves considering persistent pain as a gold standard for central sensitisation within the corneal pathway, intensity of ocular pain ratings, Ocular Surface Disease Index scores and sensitivity to light provided the most robust relationships, each with an area under the curve of 0.72.

Conclusions: Individuals with DE symptoms and persistent ocular pain after topical proparacaine (a marker of central sensitisation to pain) more frequently report NOP-like symptoms and demonstrate increased sensitivity to evoked pain.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309658DOI Listing
September 2017

Bulbar conjunctival microvascular responses in dry eye.

Ocul Surf 2017 04 29;15(2):193-201. Epub 2016 Dec 29.

University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, Miami, FL, USA.

Purpose: Conjunctival microvascular responses may be a surrogate metric of efferent neural pathway function innervating the ocular surface as changes in blood flow occur within seconds after a stimulus. As somatosensory dysfunction may partially underlie dry eye (DE), in this study we evaluate whether bulbar conjunctival microvascular alterations correlate with various aspects of DE.

Methods: Fifty-six DE patients were prospectively recruited from a Veterans Affairs ophthalmology clinic over an 11-month period. DE symptoms and ocular pain were assessed along with DE signs. A novel functional slit lamp biomicroscope (FSLB) was used to image the temporal bulbar conjunctiva from the right eye before and after central corneal stimulation with an air puff. Blood flow velocities were measured and noninvasive microvascular perfusion maps (nMPMs) were created.

Results: The bulbar blood flow velocity was 0.50 ± 0.15 mm/s at baseline and increased to 0.55 ± 0.17 mm/s after stimulation (P < 0.001); the average change in velocity was 0.05 ± 0.09. nMPMs values and venule diameter, on the other hand, did not significantly increase after stimulation (1.64 ± 0.004 at baseline, 1.65 ± 0.04 after stimulation, P = 0.22 and 22.13 ± 1.84 μm at baseline, 22.21 ± 2.04 μm after stimulation, P = 0.73, respectively). Baseline blood flow velocity positively associated with Schirmer scores (r = 0.40, P = 0.002). Those with higher self-rated wind hyperalgesia demonstrated less change in blood flow velocity (r = -0.268, P = 0.046) after air stimulation on the central cornea.

Conclusion: Conjunctival blood flow velocity, but not vessel diameter or complexity, increases after wind stimuli. Baseline flow positively correlated with Schirmer scores while change in flow negatively correlated with self-reported wind hyperalgesia.
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http://dx.doi.org/10.1016/j.jtos.2016.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386830PMC
April 2017