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.

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.

The neural pathway for lacrimal gland tear secretion in New Zealand White rabbits.

OBJECTIVE: We investigated the neural pathway for tear secretion from the lacrimal gland of New Zealand White rabbits. METHODS: Nine healthy adult New Zealand White rabbits were randomly divided into three experimental groups, namely, an irritant-stimulated group, a non-stimulated group, and a saline-stimulated group. Sanitized dry cotton swabs with menthol were used to wipe both of the rabbits' eyelids in the irritant-stimulated group, and the non-stimulated group and saline- stimulated group were compared as controls. The animals in the three groups were killed 2h later and the expressions of c-Fos in the frontal cortex, hippocampus, hypothalamus, pons, and medulla oblongata of the rabbits were detected using immunofluorescence labeling. According to the distribution of c-Fos protein expression, 12 healthy adult New Zealand rabbits were similarly divided into three groups for retrograde tract tracing via pseudorabies virus (PRV) injection into the lacrimal gland. Immunofluorescence labeling was used to analyze PRV-infected neurons in the brains of rabbits after survival for 30h, 38h, and 46h. RESULTS: The most c-Fos-positive immunolabeled cells were observed in the menthol-stimulated group, whereas fewer c-Fos-positive immunolabeled cells were observed in the saline-stimulated group.The non-treated group showed the least c-Fos-positive immunolabeled cells. At 30h after PRV injection, PRV-positive neurons were found only in the superior salivary nucleus of the pons (SSN). At 38h, PRV-infected neurons were observed in the lateral nucleus of the superior olive (LSO) and the medial nucleus of the superior olive (MSO). At 46h, PRV-infected neurons were found in the nucleus of the trapezoid body (Tz) and the hypothalamic paraventricular nucleus (PVN), and their distributions were dense in the LSO and MSO. CONCLUSIONS: Menthol-induced c-Fos protein expression and PRV-mediated tract tracing suggest that in New Zealand White rabbits, the neural pathway that regulates tear secretion from the lacrimal gland proceeds from the PVN to the superior olivary complex of the pons to the SSN and finally to the lacrimal gland.

Malignant peripheral nerve sheath tumor of lacrimal nerve: a case report.

BACKGROUND: Orbital and periorbital presentation is rare for malignant peripheral nerve sheath tumors. These tumors are poorly defined spindle cell neoplasms of peripheral nerves and have not been reported to develop in the lacrimal gland to date. AIM: To report a rare presentation of malignant peripheral nerve sheath tumor in the orbital cavity. CASE REPORT: A 65-year-old man was admitted with the chief complaint of prominent right eye. His symptoms began 16 months prior to his admission. He had obvious limited ocular motion in upgaze and lateral gaze directions, as well as diplopia in all directions. He underwent imaging studies, and an iso-dense mass lesion in the lacrimal gland was revealed in orbital CT scan. In the MRI, there was a well-defined iso-intense mass lesion in T1-weighted images that was hyperintense in T2-weighted images and was enhanced with Gadolinium. Excisional biopsy revealed epithelioid and spindle cells with hyperchromatic rather than pleomorphic nuclei. Immunohistochemistry confirmed the presence of positive markers consistent with malignant peripheral nerve sheath tumor. CONCLUSION: Malignant peripheral nerve sheath tumor should be considered in the differential diagnosis of lacrimal gland tumors. Imaging studies may be helpful but tissue biopsy should be performed for accurate diagnosis. Complete excision of the mass lesion and adjunctive chemotherapy and radiotherapy should be considered in these cases.

Neurostimulation of the lacrimal nerve for enhanced tear production.

PURPOSE: To design a proof-of-concept study to assess the effect of lacrimal nerve stimulation (LNS) with an implantable pulse generator (IPG) to increase aqueous tear production. METHODS: Experimental animal study design of 6 Dutch Belted rabbits. Ultra high-resolution optical coherence tomography (UHR-OCT) quantified tear production by measuring the baseline tear volume of each rabbit's OD and OS. A neurostimulator was implanted adjacent to the right lacrimal nerve. After 2 minutes of LNS (100 µs, 1.6 mA, 20 Hz, 5-8 V), the tear volumes were measured with UHR-OCT. The change in tear volume was quantified and compared with the nonstimulated OS. Three rabbits underwent chronic LNS (100 µs, 1.6 mA, 10 Hz, 2 V) and their lacrimal glands were harvested for histopathologic analysis. RESULTS: The UHR-OCT imaging of the OD tear volume showed a 441% average increase in tear production after LNS as a percent of baseline. After stimulation, OD had statistically significant greater increase in tear volumes than OS (p = 0.028, Wilcoxon test). Poststimulation OD tear volumes were significantly greater compared with baseline (p = 0.028, Wilcoxon test). Histopathologic examination of the lacrimal glands showed no discernible tissue damage from chronic neurostimulation. In addition, there were no gross adverse effects on the general well-being of the animals due to chronic stimulation. CONCLUSIONS: LNS with an IPG appears to increase aqueous tear production. Chronic LNS showed no histopathologic lacrimal gland damage. This study suggests that LNS is a promising new treatment strategy to increase aqueous tear production.

Patterns of innervation of the lacrimal gland with clinical application.

Parasympathetic stimulation of the lacrimal gland is responsible for tear production, and this innervation originates from fibers conveyed in the facial nerve. After synapse in the pterygopalatine ganglion, postsynaptic parasympathetic fibers travel within the zygomatic and zygomaticotemporal nerves (ZTN) into the orbit. As described in most anatomy texts, ZTN communicates with the lacrimal nerve (LN) posterior to the gland and then secretomotor fibers enter the gland. This study was performed to gain a better understanding of the innervation of the lacrimal gland. Seventeen cadaver heads were bisected for a total of 34 sides, which then underwent dissection of the superolateral orbital region to observe the course for the LN and ZTN. Three variations of the course of the LN and ZTN were found. In 20 (60.6%) dissections it was documented that the ZTN entered directly into the lacrimal gland with no communication with the LN. In 12 (36.4%) of the bisected heads, ZTN had both a direct connection into the gland and a communicating branch with the LN. In only one (3.0%) bisected head, ZTN communicated with the LN before entering the gland as it is commonly described in anatomy texts. Our study reveals that the ZTN usually takes a different course than is classically described in most anatomy textbooks. A greater understanding of the typical course these nerves take may help surgeons identify them more easily and avoid damaging them.

Randomized, double-blind, controlled study to evaluate the effect of vidian nerve cauterization on lacrimation.

BACKGROUND: After vidian neurectomy, low reported rates of dry eye syndrome (DES) seemed incompatible with the high success rate of nerve severance in previous studies. This study aimed at understanding of the pathophysiology of lacrimation and evaluating the effect of thermal injury through the distal stump on the sphenopalatine ganglion (SPG) after vidian neurectomy. METHODS: A randomized, double-blind, controlled study was performed to evaluate the DES. Eighty precise vidian neurectomies were randomized in a 1:1 ratio to groups 1 and 2. Group 1 represented the cauterization and was used in both distal and proximal nerve stumps, whereas only the proximal nerve stump was cauterized in group 2 subjects. The DES was evaluated with Schirmer's test and ocular surface disease index (OSDI) before and after surgery at 7-10 days and 30 days, respectively. RESULTS: In group 1, the Schirmer's test showed a mean decline of 20 mm (20/30, 66%) at 7-10 days and 15 mm (15/30, 50%) at 30 days. In group 2, the Schirmer's test revealed significantly lesser dry eye problems, with a mean decline of 16 mm (16/30; 52%) at 7-10 days and 2 mm (2/30; 6%) at 30 days. The significantly less postoperative dry eye problems in group 2 can be shown by the OSDI at 7-10 days, but not at 30 days. The mean follow-up period was 24 months. No recurrence of nasal allergy symptoms was noted in the follow up period. CONCLUSION: The significant advantage of preservation of the SPG function is justified by Schirmer's test, although the effect did not appear to be comparable with the clinical manifestations evaluated by OSDI at 30 days. Nevertheless, the preservation of distal stump from preventive cauterization can still offer better eye ball moisture in the early evaluation of DES.

Transection of inferior orbital fissure contents for improved access and visibility in orbital surgery.

BACKGROUND: Selective inferior orbital fissure (IOF) content transection for the purpose of surgical access to the posterior orbital floor is a technique that facilitates visualization of the posterior bony ledges of traumatic orbital floor defects. It also has potential advantages in achieving stable placement of reconstructive materials. Although not new, the surgical technique has not yet been described, and the morbidity of the technique has not been quantified. This article describes the procedure and assesses the morbidity specific to the division of related neural structures. METHODS: The technique and surgical anatomy are described and illustrated with intraoperative photographs. Postoperative assessment of neural structures relevant to the division of IOF contents is performed. These values are compared with the nonoperated side to evaluate the morbidity of the technique. RESULTS: The technique, which is consistently used by the senior author in the repair of orbital floor defects with very small posterior ledges or which extend to and involve the IOF, facilitates better visualization of the posterior ledge and posterolateral ledge in such cases. Surgical outcomes including facial sensation and lacrimal function on the operated side remain within the reference range and are not significantly different when compared with the contralateral nonoperated side. CONCLUSIONS: Selective IOF transection aids in the direct visualization of the posterior bony ledges in the repair of posterior orbital floor defects. It therefore may facilitate the placement of reconstructive materials on bony ledges circumferentially, providing stable reconstruction, potentially reducing implant-related complications without causing increased morbidity.

The nervus intermedius: a review of its anatomy, function, pathology, and role in neurosurgery.

BACKGROUND: Geniculate neuralgia, although uncommon, can be a debilitating pathology. Unfortunately, a thorough review of this pain syndrome and the clinical anatomy, function, and pathology of its most commonly associated nerve, the nervus intermedius, is lacking in the literature. Therefore, the present study aimed to further elucidate the diagnosis of this pain syndrome and its surgical treatment based on a review of the literature. METHODS: Using standard search engines, the literature was evaluated for germane reports regarding the nervus intermedius and associated pathology. A summary of this body of literature is presented. RESULTS: Since 1968, only approximately 50 peer-reviewed reports have been published regarding the nervus intermedius. Most of these are single-case reports and in reference to geniculate neuralgia. No report was a review of the literature. CONCLUSIONS: Neuralgia involving the nervus intermedius is uncommon, but when present, can be life altering. Microvascular decompression may be effective as a treatment. Along its cisternal course, the nerve may be difficult to distinguish from the facial nerve. Based on case reports and small series, long-term pain control can be seen after nerve sectioning or microvascular decompression, but no prospective studies exist. Such studies are now necessary to shed light on the efficacy of surgical treatment of nervus intermedius neuralgia.

Squamous cell carcinoma presenting as an orbital cyst with radiologic evidence of perineural invasion.

PURPOSE: To report clinical and radiologic findings of cystic squamous cell carcinoma (SCC) of the orbit with evidence of perineural involvement. METHODS: Analysis of clinical findings and radiology with a literature review. RESULTS: A 66-year-old man with SCC of the forehead 8 years prior presented with paraesthesias, diplopia, and proptosis. Magnetic resonance imaging showed a well-defined, cystic mass of the orbit with a single, linear structure running through its center. Lateral orbitotomy revealed a cyst adherent to adjacent periorbita containing viscous, clear, yellow substance and a nerve coursing through the center. Histopathology confirmed poorly differentiated spindle cell carcinoma with positive staining for cytokeratin markers, consistent with SCC. CONCLUSIONS: Orbital cysts associated with altered sensation are suggestive of SCC with perineural spread, requiring prompt investigation and treatment to minimize morbidity and mortality. The involved nerve may be seen as a single, linear structure within the mass on imaging.

Evaluation of novel dry eye model: preganglionic parasympathetic denervation in rabbit.

PURPOSE: To evaluate ocular surface status after interruption of preganglionic, parasympathetic neural control after surgical removal of the greater superficial petrosal nerve (GSPN). METHODS: New Zealand White rabbits underwent unilateral section and removal of a 5-mm portion of the GSPN by a route through the inner ear; no ocular or orbital tissue was involved. Before and 7 days after surgery, all animals underwent preliminary examination, including fluorescein staining, rose bengal instillation, blink rate, tear breakup time (BUT), tear flow, and impression cytology. Total tarsorrhaphy was carried out in four additional rabbits, and another four animals underwent unilateral sham procedures. The GSPN, pterygopalatine ganglion, lacrimal gland, and conjunctiva were evaluated by light and transmission electron microscopy (TEM). RESULTS: GSPN sectioning resulted in significant changes of the ocular surface after 7 days: intense rose bengal staining of the conjunctiva, fluorescein staining of the cornea, increased blink rate (P < 0.05), decreased BUT (P < 0.005), decreased tear flow by 26% (P < 0.005), and decreased goblet cell density (P < 0.01). TEM revealed massive accumulation of secretory granules in lacrimal acinar cells. The changes were also seen after tarsorrhaphy. Neither the contralateral control nor the sham eyes were affected. CONCLUSIONS: The effects of GSPN nerve section led to the rapid onset of a dry eye condition in the rabbits that continued for at least 1 week. The authors suggest that continuous neural drive of the pterygopalatine ganglion is necessary to maintain adequate tear flow and mucin secretion. It is likely the trigeminal system is the afferent origin of this continuous neural tone.

Rhinocerebral mucormycosis with perineural spread.

We describe the histopathologic findings of perineural invasion in orbital mucormycosis in a man with diabetes in ketoacidosis. Linear enhancement on MRI beginning at the orbital apex was correlated with fungal tracking of the trigeminal and lacrimal nerves. Mucormycosis can spread considerable distances from its primary focus of infection along peripheral nerves, a phenomenon that can be identified clinically with contrast-enhanced MRI.

[A new approach for better comprehension of diseases of the ocular surface]. / Un nouveau schéma pour mieux comprendre les maladies de la surface oculaire.

The mechanistic view of dry eye disease aims at completing the classic etiological approach that classifies the disease as parallel ocular surface disorders leading to lacrimal film impairment and dry eye. This approach proposes two levels of ocular surface impairment (with standard etiologies, previously validated in the NEI/Industry workshop), which may not be independent diseases but rather risk factors and/or ways to enter a self-stimulated biological process involving the ocular surface. All external disorders proposed in this model, although unlikely to be fully exhaustive, are classical mechanisms considered to be causes of tear film impairment and ocular surface damage, by tear instability and evaporation, tear hyposecretion, or both. These mechanisms, sometimes alone--when severe or becoming chronic or repeatedly present on the ocular surface and when two or more are present--may cause the patient to enter the self-stimulated loop. Tear film instability/imbalance can be considered as the key point of dry eye disease. It will cause local or diffuse hyperosmolarity of the tear film and therefore of superficial epithelial cells of the cornea and/or conjunctiva, stimulating epithelial cells and resident inflammatory cells. Cell damage in the cornea and conjunctiva, by means of apoptosis and direct mechanical and/or osmotic stress, will stimulate the reflex neurosensory arc, in turn stimulating lacrimal gland and neurogenic inflammation, with inflammatory cytokine release, MMP activation, and inflammatory involvement of the conjunctival epithelium. Goblet cell loss is thus directly related to chronic inflammation and surface cell apoptosis subsequent to cell hyperosmolarity and chronic damage, resulting in further tear film instability/imbalance. On the other hand, bacterial changes and an imbalance resulting from specific diseases or from tear film abnormalities may trigger release of endotoxins, lipopolysaccharides, and/or lipase activation, causing eyelid inflammation, meibomian gland dysfunction, and lipidic changes, directly influencing tear film stability and favoring tear evaporation. The lipidic hypothesis therefore participates in the vicious circle as a parallel, independent, or complementary loop. This mechanistic approach proposes a synthetic combination of mechanisms previously validated independently, with two levels of ocular surface impairment, a first level including many possible acute or chronic causes that favor or trigger the imbalance and can be reversible if correctly and specifically managed when possible, and the further involvement of a series of biological cascades centered by tear film imbalance and inflammatory stimulation, finally acting as an independent vicious circle, however the patient entered the loop. Clinically, this approach may explain examples of dry eye syndrome occurring after ocular surgery, contact lens wear, chronic allergy or systemic or topical drugs, and the long-lasting effect even though all causal factors have been removed or have disappeared. This model should be considered as a basis for further reflection on biological mechanisms that could be even more complex but individually constitute potential leads for targeting therapeutic strategies to allow patients to leave the loop even though the triggering factors are still present or can only be attenuated, such as in Sjögren syndrome or ocular rosacea. It also should be considered a complement to more classic etiological and severity classifications aimed at understanding and classifying the large number of diseases that may cause dry eye disease and better assessing the major impairment it causes on the patient's quality of life.

[Facial nerve palsy due to cavernous angioma of the petrous bone. Case report]. / Parálisis facial por angioma cavernoso del peñasco. Caso clínico.

The facial nerve palsy due to extrinsic tumoral compression of the facial nerve at the geniculate ganglium is very rare. We present the case of a patient with a temporal bone cavernoma and symptoms of a torpid peripheral facial House-Brackmann grade IV nerve palsy with dry eye and loss of stapedial reflex. The routine computed tomographic and magnetic resonance imaging studies showed no abnormalities, but the same imaging techniques done after the clinical suspiction identified a less that 1cm lesion that was compatible with an osseous cavernous angioma. The lesion was approached and removed through a microsurgical middle fossa extradural approach with a good postoperative recovery (House-Brackmann grade II).

[Bilateral "crocodile tears syndrome" associated with Melkersson-Rosenthal syndrome--case report]. / Obustronny zespól krokodylich lez w przebiegu zespolu Melkerssona-Rosenthala--opis przypadku.

We present a rare case of bilateral crocodile tears syndrome (CTS) in the course of Melkersson-Rosenthal syndrome. Melkersson-Rosenthal syndrome is characterised by a triad of recurrent orofacial swelling, relapsing facial paralysis, and fissured tongue. The classic triad is infrequent and oligosymptomatic variants are seen more frequently. CTS is a rare complication of facial nerve paralysis characterised by inappropriate lacrimation on the side of the palsy in response to salivary stimuli. It results from aberrant reinnervation of the lacrimal gland by salivary parasympathetic fibres. The therapeutic approach for an acute bout of Melkersson-Rosenthal syndrome consists mainly of steroid administration. CTS management is composed of anticholinergic drugs and surgical procedures. Botulin toxin injection into the lacrimal gland is the most modern therapeutic option. In the case presented CTS developed in a 50-year-old man after 5 incidents of facial palsy due to Melkersson-Rosenthal syndrome. The case deserves attention due to the rarity of the observed symptoms and signs.

Importance of the anatomic features of the lacrimal artery for orbital approaches.

Knowledge of variations in the possible patterns of origin, course, and distribution of the lacrimal artery are necessary for the diagnosis and important for the treatment of orbital disorders. The vascularization of 38 lacrimal glands was studied by orbital dissection subsequent to injection of the arterial bed with red-dyed latex. The origin, calibration, and branches of the lacrimal artery and its topographic relations were investigated. In all subjects, arteria lacrimalis originated from ophthalmic artery. On the right, the lacrimal artery sprang from the angle of the ophthalmic artery in 63.15% of the cases, from the curve of the ophthalmic artery in 26.31%, and from the first part the ophthalmic artery in 5.26%. The outer diameter of the lacrimal artery was measured as 1.02 +/- 0.17 mm on the right and 1.03 +/- 0.16 mm on the left. In 68.42 of the cases on the right and in 52.63 of the cases on the left, the lacrimal artery was present, and the lacrimal nerve was seen in a superolateral position with respect to the origin of the artery. Variability of the glandular branch in its course toward lacrimal gland was observed. Recurrent meningeal branch was seen in six cases on the right and in five on the left. On the right, of the six cases, two passed through meningoorbital foramen, and four passed through superior orbital fissure and entered middle cranial fossa. On the left, of the five cases, two passed through meningoorbital foramen, and three passed through superior orbital fissure and entered middle cranial fossa. In this case, the lacrimal gland is the site of an intraorbital anastomosis between internal and external carotid systems. This article confirms the well-known variability of the lacrimal arterial branches and their relation to the lacrimal gland. These variations have been discussed and described with respect to the embryonic development. A better understanding of the vascular anatomy of the lacrimal gland should allow modification of surgical techniques to reduce bleeding during biopsy or excision of the lacrimal gland.

Age-dependent alterations in mouse exorbital lacrimal gland structure, innervation and secretory response.

Several studies investigated the effect of aging on rat and human lacrimal gland physiology. However, in most of these studies, only two age groups were investigated. Furthermore, those studies did not correlate the age-related histological changes that occur in the lacrimal gland to the functional changes (nerve activity and protein secretion) that might occur with aging. Thus, the purpose of the present study was to investigate the effect of aging on lacrimal gland structure, innervation and function using BALB/c mice at different ages. Exorbital lacrimal glands were removed from 3, 8, 12, 24, and 32-month-old, male BALB/c mice, fixed, embedded and processed for histology and immunohistochemistry. Sections were stained with hematoxylin and eosin to determine morphological changes and lymphocytic infiltration; giemsa to identify mast cells; and Kinyoun's carbol fucsin solution to indicate lipofuscin-like inclusions. Parasympathetic and sympathetic nerves were identified by immunofluorescence techniques. To measure acetylcholine release and protein secretion, lacrimal gland pieces were incubated in Krebs Ringer buffer containing 5 mM KCl (control), 75 mM KCl (depolarizing buffer which activates nerves), carbachol (a cholinergic agonist, 10(-4) M), or phenylephrine (an alpha1-adrenergic agonist, 10(-4) M) for 20 min. The media were collected and analysed for acetylcholine and peroxidase using a spectrofluorometric assay. KCl-, carbachol- and phenylephrine-stimulated peroxidase secretion decreased in lacrimal glands from 8, 12, and 24-month-old mice when compared to 3-month-old animals. Both the density and distribution of parasympathetic and sympathetic nerves surrounding the acini decreased with increasing age. Acetylcholine release from lacrimal gland nerves decreased in 24-month-old mice compared to 3- and 12-month-old animals. Similarly, progressive morphological changes, including increased numbers of lipofuscin-like inclusions, mast cells and lymphocytic infiltration occurred in an age-dependent manner. We conclude that structural alterations of mouse lacrimal gland, including increased accumulation of lipofuscin-like inclusions, chronic inflammation and functional alterations including decreased acetylcholine release and protein secretion occurred with aging.

A novel class of neurons at the trigeminal subnucleus interpolaris/caudalis transition region monitors ocular surface fluid status and modulates tear production.

Reflex tears are produced by many conditions, one of which is drying of the ocular surface. Although peripheral neural control of the lacrimal gland is well established, the afferent pathways and properties of central premotor neurons necessary for this reflex are not known. Male rats under barbiturate anesthesia were used to determine whether neurons at the ventral trigeminal subnucleus interpolaris- caudalis (Vi/Vc) transition or the trigeminal subnucleus caudalis-cervical cord (Vc/C1) junction region in the lower brainstem were necessary for tears evoked by noxious chemical stimulation (CO2 pulses) or drying of the ocular surface. Both the Vi/Vc transition and Vc/C1 junction regions receive a dense direct projection from corneal nociceptors. Synaptic blockade of the Vi/Vc transition, but not the Vc/C1 junction, by the GABA(A) receptor agonist muscimol inhibited CO2-evoked tears. Glutamate excitation of the Vi/Vc transition, but not the Vc/C1 junction, increased tear volume. Single units recorded at the Vi/Vc transition, but not at the Vc/C1 junction, were inhibited by wetting and excited by drying the ocular surface. Nearly all moisture-sensitive Vi/Vc units displayed an initial inhibitory phase to noxious concentrations of CO2 followed by delayed excitation and displayed an inhibitory surround receptive field from periorbital facial skin. Drying of the ocular surface produced many Fos-positive neurons at the Vi/Vc transition, but not at the Vc/C1 junction. This is the first report of a unique class of moisture-sensitive neurons that exist only at the ventral Vi/Vc transition, and not at more caudal portions of Vc, that may underlie fluid homeostasis of the ocular surface.

Regulatory pathways in lacrimal gland epithelium.

Tears are a complex fluid that continuously cover the exposed surface of the eye, namely the cornea and conjunctiva. Tears are secreted in response to the multitude of environmental stresses that can harm the ocular surface such as cold, mechanical stimulation, physical injury, noxious chemicals, as well as infections from various organisms. Tears also provide nutrients and remove waste from cells of the ocular surface. Because of the varied function of tears, tears are complex and are secreted by several different tissues. Tear secretion is under tight neural control allowing tears to respond rapidly to changing environmental conditions. The lacrimal gland is the main contributor to the aqueous portion of the tear film and the regulation of secretion from this gland has been well studied. Despite multiple redundencies in pathways to stimulate secretion from the lacrimal gland, defects can occur resulting in dry eye syndromes. These diseases can have deleterious effects on vision. In this review, we summarize the latest information regarding the regulatory pathways, which control secretion from the lacrimal gland, and their roles in the pathogenesis of dry eye syndromes.