Lacrimal Neuralgia: A Case Report and Comprehensive Review of the Literature.

PURPOSE OF REVIEW: Lacrimal neuralgia is a rare periorbital neuralgia. To date, only nine cases have been reported in the literature. Herein, we report a case and a comprehensive overview of the entity with a focus on the differential diagnosis of lacrimal neuralgia. Additionally, we propose putative diagnostic criteria for this rare neuralgia based on cases that have been reported. RECENT FINDINGS: Among the ten cases of lacrimal neuralgia reported (including the one in this review), seven out of ten were idiopathic, and the other three were considered secondary. Most patients reported stabbing and shooting pain that was either paroxysmal or continuous. The most effective therapy was nerve block for seven patients and pregabalin for three patients. The most important clues to differentiate lacrimal neuralgia from other causes of periorbital pain include pain topography and pain with features suggestive of neuralgia. The core feature of lacrimal neuralgia is neuralgic pain located in the area supplied by the lacrimal nerve, and the etiology could be primary or secondary. Responsiveness to anesthetic blockade might better serve as a confirmational, rather than mandatory, criterion for diagnosis.

Molecular nature of ocular surface barrier function, diseases that affect it, and its relevance for ocular drug delivery.

The structural and functional integrity of the ocular surface, a continuous epithelial structure comprised of the cornea, the conjunctiva, and the ductal surface of the lacrimal as well as meibomian glands, is crucial for proper vision. The ocular surface barrier function (OSBF), sum of the different types of protective mechanisms that exist at the ocular surface, is essential to protect the rest of the eye from vision-threatening physical, chemical, and biological insults. OSBF helps maintain the immune privileged nature of the cornea and the aqueous humor by preventing entry of infectious agents, allergens, and noxious chemicals. Disruption of OSBF exposes the dense nerve endings of the cornea to these stimuli, resulting in discomfort and pain. This review summarizes the status of our knowledge related to the molecular nature of OSBF, describes the effect of different ocular surface disorders on OSBF, and examines the relevance of this knowledge for ocular drug delivery.

Crocodile tear syndrome treated with lacrimal gland incobotulinum toxin A injection: a report of two cases.

Crocodile tear syndrome (CTS) is a late complication of facial nerve palsy characterized by unilateral lacrimation in response to gustatory stimulation. We present 2 cases of patients diagnosed with CTS after recovering from unilateral idiopathic facial nerve palsy. Both patients underwent transconjunctival lacrimal gland incobotulinumtoxinA injection, with doses of 5-16 units. The patients were seen in clinic for post-treatment follow-up at 2 weeks, 3 months, and 6 months. Outcomes were measured by treatment efficacy and adverse drug effects. Following treatment, both patients reported resolution of gustatory lacrimation. The patient treated with 16 U experienced transient ptosis and diplopia following injection, whereas the patient treated with 5-7.5 U experienced no adverse effects.

Neurostimulation for dry eye disease.

PURPOSE OF REVIEW: To review the neuroanatomy and physiology of the basal and reflex tearing and present the available and developing therapies using the concept of neurostimulation in dry eye disease (DED). RECENT FINDINGS: The most prevalent current DED treatments seek to supplement low tear volume and tear components or reduce inflammation. Neurostimulation is a unique approach gaining momentum in recent years, geared toward increasing the production of all basal tear components by stimulating the nerves responsible for producing the various tear components. The neuroanatomy of the lacrimal unit provides several possible access points to stimulate tear production through two arms of the sensory trigeminal nerves. Modes of stimulation include chemical or energy in electrical or magnetic form. Research thus far has shown that neurostimulation can achieve lacrimal, goblet cell, and meibomian gland stimulation. Subjectively it improves symptoms of DED. Clinically, neurostimulation has improved the signs and symptoms of DED by increasing basal tear production and tear volume. SUMMARY: Neurostimulation using electrical, mechanical, or chemical means is a novel concept to increase tear production and was demonstrated to be an effective, safe, and well-tolerated method for managing DED.

Nicotinic acetylcholine receptor stimulation: A new approach for stimulating tear secretion in dry eye disease.

Tear secretion is regulated by the lacrimal functional unit consisting of afferent and efferent nerve innervation. The afferent arm consists of trigeminal nociceptors on the ocular surface and nasal mucosa. When stimulated by agonists, nicotinic acetylcholine receptors on nerve endings in the nose initiate a reflex arc resulting in instantaneous tear secretion. Pharmacologic nasal neural stimulation to increase endogenous tear production is a novel approach to treating dry eye disease.

Role of Choline in Ocular Diseases.

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.

Reduced Tearing With Stable Quality of Life After Vidian Neurectomy: A Prospective Controlled Trial.

OBJECTIVES/HYPOTHESIS: Although vidian neurectomy (VN) is associated with decreased lacrimation, its impact on dry eye quality-of-life is not well-defined. Endoscopic endonasal transpterygoid approaches (EETA) may require vidian nerve sacrifice. STUDY DESIGN: A prospective cohort trial. METHODS: A prospective trial evaluating VN during EETA on lacrimation by phenol red thread testing and dry eye severity by the five-item Dry Eye Questionnaire (DEQ-5) was performed. Preservation of the contralateral vidian nerve allowed comparison between the eye subjected to VN and the control eye postoperatively. RESULTS: Twenty-one subjects were enrolled with no preoperative difference in lacrimation between eyes (P = .617) and overall mild dry eye severity. Although the control eye had no difference in lacrimation pre- and postoperatively, decreased tearing was noted in the VN eye at 1 month (20.8 mm vs. 15.8 mm, P = .015) and at 3 months (23.2 mm vs. 15.8 mm, P = .0051) postoperatively. Overall, no difference was noted in the DEQ-5 score for dry eye severity between the pre- and postoperative measures. However, six patients were noted to have moderate to severe dry eye severity postoperatively and five of these six had decreased lacrimation (<20 mm) preoperatively. Patients with decreased tearing preoperatively demonstrated significantly worse postoperative DEQ-5 scores when compared to patients with normal tearing (P < .0056). CONCLUSIONS: VN during EETA results in decreased tearing but is not associated with increased dry eye severity overall. However, patients with decreased tearing preoperatively are at risk for increased dry eye severity and should be counseled for this risk. LEVEL OF EVIDENCE: 2 Laryngoscope, 131:1487-1491, 2021.

The Human Lacrimal Gland: Historical Perspectives, Current Understanding, and Recent Advances.

PURPOSE: The lacrimal glands produce the aqueous component of the pre-ocular tear film, which is essential for ocular health and optimal vision. This review explores its history, current understanding, recent advances, and scope for future research. METHODS: The authors reviewed the major studies discussing the history of lacrimal glands and their anatomical description, including microscopic anatomy, innervation patterns, imaging, and ongoing translational research. RESULTS: The review traces the evolution of human knowledge about the source of tears across several millennia, with specific emphasis on the individuals who made seminal contributions to this field. It provides a detailed update on the morphology, microscopic structure, innervation, vascular supply, and imaging modalities of both the main and accessory lacrimal glands. The review also summarizes the recent advances in lacrimal gland regeneration and repair for the treatment of dry eye disease, particularly the role of mesenchymal stem cells. Lastly, the review gazes into the future of lacrimal gland research, which aims at translating the existing laboratory knowledge into clinical application, with the possibility of transplanting in vitro cultivated lacrimal constructs or the use of cell-based therapies for in situ repair of diseased human lacrimal glands. CONCLUSIONS: Knowledge about the lacrimal glands in health and disease has improved tremendously since its discovery in the mid-eighteenth century. Today we stand at the cusp of exploring potential regenerative approaches for the treatment of lacrimal gland damage in dry eye disease.

Identification of Lacrimal Gland Postganglionic Innervation and Its Regulation of Tear Secretion.

Tear fluid secreted from the exocrine lacrimal gland (LG) has an essential role in maintaining a homeostatic environment for a healthy ocular surface. Tear secretion is regulated by the sympathetic and parasympathetic components of the autonomic nervous system, although the contribution of each component is not fully understood. To investigate LG innervation, we identified sympathetic and parasympathetic postganglionic nerves, specifically innervating the mouse LG, by injecting a retrograde neuronal tracer into the LG. Interruption of neural stimuli to the LG by the denervation of these postganglionic nerves immediately and chronically decreased tear secretion, leading to LG atrophy along with destruction of the lobular structure. This investigation also found that parasympathetic, but not sympathetic, innervation was involved in these alterations.

Anatomical variations of the levator palpebrae superioris, including observations on its innervation and intramuscular nerves' distribution pattern.

BACKGROUND: The levator palpebrae superioris muscle (LPS) acts as the upper eyelid's major elevator and retractor and is innervated by the oculomotor nerve. The muscle's paralysis is manifested by ptosis. MATERIAL AND METHODS: 70 orbits were dissected. After removing the orbital roof, the LPS' shape and anatomical variations (i.e., the presence of accessory muscular bands or atypical formation of the muscle) were assessed. To visualize the distribution of the oculomotor nerve's intramuscular sub-branches, the isolated levator palpebrae superioris muscles were stained using Sihler's staining technique. RESULTS: Several LPS anatomical variations were observed in the specimens examined, in seven of which (7/70; 10%) additional delicate muscular slips arose from the LPS' lateral border and reached the lacrimal gland. Histological examination confirmed the presence of striated skeletal muscle fibers in all those cases. In three other specimens (3/70; 4.28%), supernumerary muscular bands ("tensor trochleae") were found that linked the levator with the superior oblique muscle's trochlea. In the next case, the LPS' origin was double and the muscle was bipartite on its proximal half. In most cases (55/70; 78.6%), muscular branches formed a single bundle that wrapped around the superior rectus muscle's medial border to reach the levator's inferior surface. Intramuscular sub-branches were distributed largely within the proximal two-thirds of the LPS and formed an irregular, tree-like pattern. However, thin sub-branches and small retrograde sub-branches extended as far as the muscle's insertion. CONCLUSIONS: Plastic surgeons and ophthalmologists should be aware of the levator palpebrae superioris muscle's anatomic variations both in planning and conducting surgeries on the upper eyelid.

Chronic Electrical Stimulation for Tear Secretion: Lacrimal vs. anterior ethmoid nerve.

PURPOSE: To evaluate and compare the effect of lacrimal nerve stimulation (LNS) and anterior ethmoid nerve stimulation (AENS) on aqueous tear secretion, and tissue condition following chronic implantation. METHODS: A neurostimulator was implanted in rabbits adjacent to the (1) lacrimal nerve, and (2) anterior ethmoid nerve. Tear volume was measured with Schirmer test strips after stimulation (2.3-2.8 mA pulses at 30 Hz for 3-5 min), and scores were compared to sham stimulation. Lacrimal gland and nasal septal tissue were evaluated histologically after chronic stimulation (2 weeks-7 months). RESULTS: LNS increases tear volume by 32% above sham (p < 0.05, n = 5), compared with 133% for AENS (p ≤ 0.01, n = 6). AENS also significantly increases tear secretion in the fellow, non-stimulated eye (p ≤ 0.01, n = 6), as expected from the tearing reflex pathway. Histologically, chronic LNS is well tolerated by surrounding tissues while chronic AENS results in nasal mucosal fibrosis and implant extrusion within 3 weeks. CONCLUSIONS: AENS is significantly more effective than LNS at enhancing aqueous tear secretion, including the fellow eye. The lacrimal implant is well tolerated, while the nasal implant requires further design optimization to improve tolerability.

Neurostimulation for tear production.

PURPOSE OF REVIEW: Dry eye disease (DED) is a chronic multifactorial disease that affects millions of people worldwide. Despite ongoing research, treatment for DED remains a challenge. Neurostimulation for tear production is a rapidly evolving field that culminated in the development of the intranasal tear neurostimulator (ITN). In this article, we review the neuroanatomy and pathophysiology of tear production and the evolution of neurostimulation for the treatment of DED. RECENT FINDINGS: The ITN was approved for commercial use in April 2017. This innovation stemmed from the success of lacrimal nerve and anterior ethmoid nerve stimulation animal studies. Since then, numerous pilot studies and multicenter randomized controlled trials demonstrate increased aqueous tear production, improved DED-related symptoms, and device safety. Recent studies also report the positive effects of intranasal stimulation on mucin and lipid secretion. SUMMARY: Neurostimulation for enhanced tear production is a promising new treatment option for DED. Stimulation of the lacrimal nerve and anterior ethmoid nerve both effectively increase tear volume. The ITN is a noninvasive device that effectively increases aqueous tear volume and may improve tear composition, including mucin and lipid concentrations. Further studies are needed to determine proper patient selection and the long-term efficacy of neurostimulation for DED.

Bilateral Effect of the Unilateral Corneal Nerve Cut on Both Ocular Surface and Lacrimal Gland.

Purpose: This study investigated the effect of a unilateral cut of the corneal nerve on the bilateral ocular surface and tear secretory function. Methods: Seven-week-old female BALB/c mice were divided into control and nerve-cutting (NC) groups (n = 60). The left cornea was partially incised with a 2-mm circular trephine through the upper half of the stromal layer. Lissamine green corneal staining and tear volume measurements were conducted, and corneal whole-mount staining using class III ß-tubulin antibody was performed to assess corneal nerves. Flow cytometric analyses for dendritic cells (DCs), CD4+/CD8+ and regulatory T cells and ELISA for neuropeptides were performed. Results: The grading of corneal staining increased in the NC group, while the tear volume decreased over the 4 weeks. The nerve density decreased in bilateral corneas over 2 weeks. At day 14, CD11b+ or CD11c+ DCs and the mature DCs expressing CD86 or MHCII increased in bilateral cornea/conjunctiva. At day 28, CD11c+CD86hi, CD11c+MHCIIhi, Th17 and IFN-γ-secreting CD8+ T cells highly increased in bilateral draining lymph nodes. CD4+CD25hiFoxp3hi and CD8+CD25hiFoxp3hi regulatory T cells notably increased in the spleen. In ELISA, neuropeptide Y, calcitonin gene-related peptide, and vasoactive intestinal peptide were generally suppressed in the extraorbital lacrimal glands at day14. Conclusions: The unilateral corneal nerve severing resulted in activation of the immune cells on the ocular surface and dysregulated lacrimal secretion bilaterally through the bidirectional neuronal signals. It suggests that the unilateral corneal nerve damage may alter immune homeostasis and mechanistically participate in the development of bilateral inflammatory disorders such as dry eye.

Characterization of tear production in subjects with dry eye disease during intranasal tear neurostimulation: Results from two pivotal clinical trials.

PURPOSE: The intranasal tear neurostimulator (ITN) activates the nasolacrimal pathway, which is involved with basal and bolus tear secretion. These studies characterized the acute and long-term effectiveness of the ITN in stimulating tear production in subjects with dry eye disease (DED). METHODS: Study 1: Randomized, double-masked, dual-controlled, 1-day crossover. Study 2: Single-arm, open-label, 180-day prospective cohort. Eligible subjects had basal unstimulated Schirmer test (with anesthesia) ≤10 mm and intranasal cotton swab-stimulated Schirmer test at least 7 mm greater in the same eye, and Ocular Surface Disease Index® ≥13 and ≥ 23, in Studies 1 and 2, respectively. Study 1: Subjects (n = 48) received three randomized test applications: active intranasal, extranasal (active control), and sham intranasal (inactive control) stimulation, 3 min/application with 1-hour minimum between applications. Primary outcome measure was the difference in Schirmer test scores during active intranasal and control applications. Study 2: Subjects (n = 97) performed intranasal neurostimulation for ≤3 min/application, 2-10 times/day. Primary outcome measure was the difference in Schirmer scores (stimulated minus unstimulated) at day 180. Both studies recorded device-related adverse events (AEs). RESULTS: Study 1: Schirmer scores (mean ±â€¯SEM) were significantly greater (p < 0.0001) with active intranasal (25.3 ±â€¯1.5 mm) vs extranasal (9.5 ±â€¯1.2 mm) and sham (9.2 ±â€¯1.1 mm) applications. Study 2: Schirmer scores were significantly greater (p < 0.0001) with ITN stimulation vs unstimulated at day 180 (17.3 ±â€¯1.3 mm vs 7.9 ±â€¯0.7 mm). No serious device-related AEs were reported in either study. CONCLUSION: The ITN was well-tolerated and effective in stimulating tear production with acute and long-term use in DED. CLINICALTRIALS. GOV IDENTIFIER: NCT02680158 and NCT02526290.

Tears and ocular surface disorders: Usefulness of biomarkers.

INTRODUCTION: Corroborating data suggest that the analysis of tear fluid might represent an additional tool in the ophthalmological practice. AREAS COVERED: The purpose of this review was to sum up the tear protein profiles in healthy and diseased ocular surface and to highlight biomarker usefulness in the early diagnosis as well as at follow-up. This analysis encompasses a deep examination of the protein profile expression under physiological and pathological conditions. Tear protein profile analysis will allow in the near future discriminating between different grades of inflammation, from acute trauma toward immune-, endocrine-, and nervous-related disorders of the ocular surface. CONCLUDING REMARKS: The review provides an overview of old and recent findings about inflammatory mediators identified at the ocular surface, under physiological and pathological conditions. To date, the analysis of tear fluid represents a new additional approach for diagnosis and management of ocular surface diseases. Understanding the pathophysiological mechanism could also offer significant advantages to develop strategies addressed to better clarify some complex ocular surface disorders. To sum up, the possibility to provide selective biomarkers as a future target of specific diseases should be considered for supporting diagnosis and management of ocular surface diseases.

Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren's Syndrome.

Sjögren's syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1ß), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin⁻plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers.

Lacrimal Gland Denervation Alters Tear Protein Composition and Impairs Ipsilateral Eye Closures and Corneal Nociception.

Purpose: To evaluate spontaneous and evoked ocular sensory responses in rats after denervation of the lacrimal gland, as well as protein changes in tears that may mediate functional changes. Methods: Sprague-Dawley rats served as subjects. The left lacrimal gland was partially denervated with saporin toxin conjugated to p75. Unilateral and bilateral eye closures (winks and blinks) and grooming behaviors were measured weekly. Nociceptive responses were evoked by ocular application of menthol; tear production was assessed using the phenol thread test. Relative changes in tear protein abundances were measured using a Tandem Mass Tagging approach. Results: Denervation of the lacrimal gland reduced eye closure behavior, particularly in the ipsilateral eye, and eye wipe responses to noxious menthol were also reduced. Tear volume did not change, but tear protein composition was altered. Proteins implicated in the structural integrity of epithelial cells and in protective functions were reduced by lacrimal denervation, including keratins, serotransferrin, and beta-defensin. Other proteins that may modulate TRPM8 channels and alter sensory neuronal function were reduced, including arachidonate 15-lipoxygenase B. A low-abundance protein that responds to oxidative stress and injury, proteasome subunit beta type 10, was upregulated in denervated rats. Conclusions: Denervation of the lacrimal gland causes long-lasting hypoalgesia, impairs the blink response, and alters tear proteins. Tear proteins were altered without changing tear volume. We speculate that impaired TRPM8 function in corneal sensory nerves may contribute to ocular hypoalgesia, supporting growing evidence that this transduction molecule is important for both nociceptive and spontaneous blinking behaviors.

Preganglionic Parasympathetic Denervation Rabbit Model for Innervation Studies.

PURPOSE: Tear secretion from the main lacrimal gland (LG) is mainly regulated by parasympathetic nerves. We performed several innervation studies to investigate lacrimation. METHODS: In male rabbits, we performed a retrograde dye-tracing study of LG innervation, evaluated preganglionic parasympathetic denervation, and administered glial cell-derived neurotrophic factor (GDNF) in the surgical area after parasympathetic denervation. RESULTS: Accumulation of fluorescent dye was observed in the pterygopalatine ganglion cells on the same side as the dye injection into the main LG. Fewer stained cells were observed in the cervical and trigeminal ganglia. After parasympathetic denervation surgery, tear secretion was decreased, and fluorescein and rose bengal staining scores were increased at day 1 after surgery and remained increased for 3 months on the denervated side only. Most of the effects in rabbits with parasympathetic denervation were not recovered by administration of GDNF. CONCLUSIONS: The main LG is primarily innervated by parasympathetic nerves to stimulate tear secretion. After preganglionic parasympathetic denervation, lacrimation was decreased, resulting in dry eyes, and this was maintained for at least 3 months. Administration of GDNF only minimally altered the effects of denervation.

Sensory Innervation of the Upper Eyelid.

The aim of this study was to elucidate the sensory territory of the trigeminal nerve on the upper eyelid.Eight hemifaces from Korean cadavers were dissected. The frontal nerve (FN), supraorbital nerve (SON), supratrochlear nerve (STN), infratrochlear nerve (ITN), and lacrimal nerve (LN) were traced.The terminal branches to the eyelid margin of FN were distributed between 1/6 and 2/5 of the palpebral fissure width lateral to the medial canthus and 1/6 of the eyebrow height from eyelid margin. The SON was distributed between 2/5 and 9/10 of the eye width lateral to the medial canthus, at 1/3 of the eyebrow height. The STN was distributed between -1/4 and -1/5 of the eye width medial to the medial canthus, at 1/5 of the eyebrow height. The ITN was distributed at -1/4 and 1/10 of the eye width medial to the medial canthus, and at 1/5 of the eyebrow height. The LN was distributed between approximately 3/5 and 13/10 of the eye width lateral to the medial canthus, and at 1/4 of the eyebrow height. The main branches of FN and SON ran deep to the orbicularis from the supraorbital notch to the upper border of the tarsal plate. In the pretarsal area, they were between the orbicularis and tarsal plate. The STN and ITN were between the orbicularis and the skin. The LN was observed between the orbicularis and the tarsal plate.Upper eyelid was mainly supplied by SON and FN. The medial extremity was supplied by STN and ITN, and the lateral extremity by LN.

A novel treatment for keratitis sicca (Dry eye): Anatomical feasibility study.

Chronic dry eye (keratitis sicca) is a significant problem that in certain populations can result in corneal desiccation and the potential for blindness. Therefore, novel treatments for such disorders might decrease patient morbidity. The present study aimed to investigate a potential treatment for chronic dry eye via a cadaveric feasibility study. On 10 cadaveric sides, the parotid gland branch of the auriculotemporal nerve (ATN) was identified and anastomosed to an anterior superficial temporal branch (STb) of this same nerve. The STb was then transposed anteriorly and sutured to the lacrimal gland. The parotid branch of the ATN was easily identified on all sides. The STb of the ATN was easily identified and mobilized on all sides. This latter nerve had adequate length to be moved to the ipsilateral lacrimal gland on all sides. Rerouting parotid gland secretomotor fibers to the superficial branch of the ATN and then moving this branch to the lacrimal gland is a feasible surgical maneuver based on our cadaveric study. Clinical studies are now necessary to show utility of this procedure in patients with chronic dry eye. Clin. Anat. 30:839-843, 2017. © 2017Wiley Periodicals, Inc.