Mikulicz's disease: a new perspective and literature review.

PURPOSE: To report the clinical and pathophysiologic features of two patients with Mikulicz's disease and to further characterize recommendations for diagnosis and management with a review of the literature. METHODS: Retrospective nonrandomized consecutive case series, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA. RESULTS: Mikulicz's disease is characterized by symmetric lacrimal, parotid, and submandibular gland enlargement with associated lymphocytic infiltrations. The authors noted two cases of Mikulicz's disease. The diagnosis of Mikulicz's disease was based on the following criteria: 1) symmetric and persistent swelling of the lacrimal glands and either or both of the major salivary glands (parotid and submandibular); and 2) the exclusion of other diseases that may mimic this presentation, such as sarcoidosis, viral infection, or lymphoproliferative disorders. CONCLUSIONS: Mikulicz's disease is a condition in which there is bilateral lacrimal and salivary gland swelling that is not associated with other systemic conditions. The condition is self-limiting and most often, the diagnosis is a clinical one. Previously, Mikulicz's disease was often considered as a subtype of Sjögren's syndrome (SS). Clinical and immunologic differences between Mikulicz's disease and SS may warrant further consideration of Mikulicz's disease as a specific autoimmune phenomenon separate from SS, and Mikulicz's disease may be amenable to different treatment modalities than those employed in patients with SS.

Lagophthalmos in enophthalmic eyes.

AIMS: To report a case series of enophthalmic patients with lagophthalmos. METHODS: A retrospective review of the electronic medical records at a tertiary health care centre of all patients with the diagnoses of "enophthalmos" and "lagophthalmos". Patients who had a history of diseases (such as Graves' orbitopathy), trauma or surgery of the orbit and eyelid were excluded. Enophthalmos was defined as exophthalmometric reading of 14 mm or less in both eyes. RESULTS: Seven patients (14 eyes) with bilateral enophthalmos were found to have concomitant lagophthalmos. All patients had deep superior sulci bilaterally. The upper eyelids were seen to be severely retro-placed behind the superior orbital rim. The extraocular motilities were full with no focal neurological deficit. The orbicularis oculi function was normal with no facial paralysis. The orbits were soft on retropulsion and no facial asymmetry was noted. The mean exophthalmolmetry reading measured 12.6 (SD 1.1) mm. The lagophthalmos varied from 1-5 mm. One patient (one eye) with 3 mm lagophthalmos developed a corneal ulcer and was treated with topical antibiotics and gold weight placement in the upper eyelid. CONCLUSION: Enophthalmic patients with deep superior sulci and retro-placed upper eyelids may present with lagophthalmos and exposure keratopathy.

Inferior oblique muscle location after enucleation and evisceration.

PURPOSE: To report the location of the inferior oblique muscle after enucleation without primary attachment of the muscle to the orbital implant and after evisceration. METHODS: Interventional case series. Retrospectively, eight orbital magnetic resonance imaging (MRI) studies were analyzed, four after enucleation and four after evisceration, to assess the position of the inferior oblique muscle relative to the orbital implant and the point of insertion. RESULTS: In the enucleation patients, the inferior oblique muscle was anteriorly displaced and the muscle appeared to insert into an inferior subconjunctival scar mass in three of the four patients. In all four of the evisceration patients, the inferior oblique muscle appeared normally positioned and inserted onto the implant in the normal location. CONCLUSION: Enucleation without suturing of the inferior oblique muscle to the implant is associated with healing in an abnormal anterior location and into an inferior subconjunctival scar mass. Evisceration does not appear to disrupt the normal position or insertion of the inferior oblique muscle.

A novel mechanism for benign essential blepharospasm.

PURPOSE: The purpose of this study is to test the hypothesis that the photophobia of benign essential blepharospasm (BEB) is caused by sympathetically maintained pain. METHODS: Nineteen patients with photophobia and BEB were enrolled in an unblinded prospective treatment trial. The intervention was blockade of the superior sympathetic ganglion with local anesthetic. Outcome measures included the patient's subjective report of ocular surface dryness, foreign body sensation, and eyelid spasm. We also obtained video recordings of eyelid movements. RESULTS: Of the 19 patients, 13 reported subjective improvement in BEB symptoms after cervical sympathetic blockade (CSB). Thirteen of 19 patients also had objective evidence of decreased light-induced eyelid spasm after CSB. Ocular surface disease was present in 18 of 19 patients. CONCLUSION: These data support the hypothesis that in many patients with BEB there is a sympathetically maintained pain syndrome associated with external ocular disease. We speculate on a neurologic circuit that may explain these findings.

Management of severe cicatricial entropion using shared mucosal grafts.

OBJECTIVE: To retrospectively analyze our experience using nasal turbinate and hard palate mucosal grafts as shared buttress grafts between the upper and lower eyelid for reconstruction in severe cicatricial entropion. SURGICAL TECHNIQUES: A horizontal tarsectomy is performed in the upper and lower eyelid approximately 2 mm posterior to the gray line. The distal tarsal segments are then dissected and rotated 180 degrees. A graft of nasal turbinate mucosa or hard palate mucosa measuring 1.5 x 3 cm is harvested. The graft is sutured to the cut edge of tarsus in the upper and lower eyelid. The rotated distal tarsal segment is stabilized against the graft using 5 mattress sutures. After 3 weeks, the graft is split by sharp dissection between the upper and lower eyelids. METHODS: The medical records of 12 consecutive patients, representing 15 shared buttress grafts, were reviewed. There were 5 hard palate and 10 nasal turbinate mucosal grafts placed. Follow-up ranged from 2 months to 7 years. RESULTS: The amount of corneal stipple, as well as subjective patient comfort, improved after eyelid margin reconstruction in 12 of the 15 eyes. One patient's visual acuity improved by more than 2 lines after surgery. There were no cases of failure of graft survival and no complications directly related to the shared graft technique. Recurrent entropion and trichiasis were noted in 3 eyelids more than a year after graft placement, reflecting ongoing cicatrization in these eyelids. Hard palate mucosal grafts were irritating to the corneal surface, requiring removal of the epithelium using a diamond burr and bandage contact lens wear. Nasal turbinate mucosal grafts were better tolerated by the corneal surface and had the added benefit of mucous production. CONCLUSIONS: Eyelid reconstruction using nasal turbinate and hard palate mucosal tissues as a shared buttress graft is a viable treatment option for patients with severe cicatricial entropion. Resolution of trichiasis and mechanical corneal abrasion was noted in 13 (86%) of 15 patients with no specific complications related to the technique. The shared buttress technique successfully autostents the healing eyelid margins, makes good use of the large turbinate mucosal graft, and minimizes trips to the operating room. When the mechanical requirements of eyelid margin reconstruction do not require the sturdiness of hard palate mucosa, nasal turbinate mucosa is a preferable graft tissue because it is better tolerated by the corneal surface and produces mucous.

An orbital abscess secondary to acute dacryocystitis.

An orbital abscess is an ophthalmic surgical emergency that is typically caused by the spread of bacteria from adjacent structures, such as the sinuses, eyelids, or teeth. Although acute dacryocystitis is commonly associated with preseptal cellulitis, it rarely causes orbital infection. Infection of the lacrimal sac will typically localize in the preseptal space because the lacrimal sac lies anterior to the orbital septum. To the authors' knowledge, this is the first report of an intraconal abscess secondary to acute dacryocystitis. The key points in the surgical management of this entity are discussed.

A sensitive and specific polymerase chain reaction-based assay for the diagnosis of cytomegalovirus retinitis.

PURPOSE: To develop a sensitive and specific laboratory assay for the diagnosis of cytomegalovirus retinitis. METHOD: We used a polymerase chain reaction-based assay for detection of cytomegalovirus DNA in vitreous samples. We attempted to detect cytomegalovirus DNA in 19 vitreous samples from patients with the acquired immunodeficiency syndrome (AIDS) who had untreated cytomegalovirus retinitis and in 40 vitreous samples from patients with AIDS who had been treated with systemic ganciclovir or foscarnet, or both. We also attempted to detect cytomegalovirus DNA in vitreous samples from 54 immunocompetent patients, including 32 with retinal detachment or macular hole, 11 with vitreous inflammation, and 11 with vitreous hemorrhage. Additionally, we attempted to detect cytomegalovirus DNA in 15 vitreous samples from patients with AIDS who had vitreoretinal inflammation not caused by cytomegalovirus. RESULTS: Cytomegalovirus DNA was detected in 18 of 19 eyes with untreated cytomegalovirus retinitis. We detected cytomegalovirus DNA in 19 of 40 vitreous samples from patients with previously treated cytomegalovirus retinitis. Cytomegalovirus DNA was not detected in any of 69 patients who did not have a clinical diagnosis of cytomegalovirus retinitis. Thus, the assay had an estimated sensitivity of 95% in detecting untreated cytomegalovirus retinitis and a sensitivity of 48% in detecting cytomegalovirus retinitis that had been treated with systemic ganciclovir or foscarnet, or both. The assay did not give false-positive results in patients with vitreous hemorrhage or vitreous inflammation. Most important, the assay did not give false-positive results in AIDS patients with vitreous inflammation from causes other than cytomegalovirus retinitis. CONCLUSION: We have developed a sensitive and specific diagnostic assay that will assist in the diagnosis of cytomegalovirus retinitis.

Traumatic neuropathies of the optic nerve, optic chiasm, and ocular motor nerves.

This review focuses on traumatic chiasmal syndrome and traumatic neuropathies of cranial nerves II, III, IV, and VI. The review highlights common anatomical sites of injury to the above structures. Special emphasis is placed on review of recent literature. Other review of related material include.

Evidence that Ca2(+)-dependent activation of airway epithelia Cl- channels is not dependent on phosphorylation.

Previous studies have shown that an increase in the cytosolic Ca2+ concentration [( Ca2+]c) activates Cl- channels in airway epithelia but that the effect is indirect. Because adenosine 3',5'-cyclic monophosphate (cAMP) and phorbol myristate acetate (PMA) activate Cl- channels via phosphorylation by cAMP-dependent protein kinase and protein kinase C, respectively, we asked whether Ca2(+)-dependent Cl- channel activation is phosphorylation dependent. We measured 125I- efflux as an assay of Cl- channel activation in the intact cell. We found that depletion of cellular ATP prevented cAMP- and PMA-induced activation but did not alter activation produced by the Ca2+ ionophore A23187. Moreover, addition of high concentrations of staurosporine (5 microM), to nonspecifically inhibit kinase activity, blocked cAMP- and PMA-stimulated 125I- efflux but had no effect on A23187-induced efflux. These results suggest that elevation of [Ca2+]c does not activate Cl- channels via phosphorylation.

Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells.

The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR, but not of a mutant form of CFTR (delta F508), corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease.

Apical membrane Cl- channels in airway epithelia: anion selectivity and effect of an inhibitor.

Previous work has investigated the anion selectivity of transepithelial Cl- secretion by airway epithelia and its inhibition by the Cl(-)-channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB). Here we report the anion selectivity of the apical membrane and of the outwardly rectifying Cl- channel and the effect of NPPB on the Cl- channel. The anion selectivity sequence of the apical membrane determined with conventional microelectrodes in the native epithelium was SCN- greater than I- greater than Br- greater than NO3- approximately Cl- much greater than SO(4)2- approximately gluconate-. This contrasts with the observation that Cl- and Br- support transepithelial secretion but that I- does not. Thus the anion selectivity of transepithelial transport is determined by the basolateral membrane Cl- entry step. The anion selectivity of the outwardly rectifying Cl- channel studied in excised patches was the same as that of the apical membrane. We also found that NPPB reversibly blocked the outwardly rectifying Cl- channel from both the internal and external surfaces of the patch. NPPB, 10 microM, completely blocked the channel; lower concentrations caused a decrease in the probability of finding the channel in the open state. NPPB also caused the appearance of a subconductance state of the channel, an occurrence which is rarely observed in the absence of NPPB. These data provide further support for the conclusion that the outwardly rectifying Cl- channel is responsible for Cl- exit from the cell across the apical membrane.

Basolateral K+ channels in airway epithelia. I. Regulation by Ca2+ and block by charybdotoxin.

In airway epithelia, adenosine 3',5'-cyclic monophosphate (cAMP) stimulates Cl- secretion by activating apical membrane Cl- channels and basolateral membrane K+ channels. Cl- channels are regulated by cAMP-dependent phosphorylation, whereas K+ channels are regulated by the cytosolic Ca2+ concentration, [Ca2+]c. Our recent observation that cAMP increases [Ca2+]c suggested that cAMP might indirectly regulate K+ channels by increasing [Ca2+]c. To study regulation of K+ channels we measured 86Rb efflux, single K+ channels in membrane patches, and [Ca2+]c with the fluorescent indicator fura-2. Isoproterenol and Ca2+ ionophore, A23187, transiently increased [Ca2+]c and transiently stimulated 86Rb efflux. Stimulation of 86Rb efflux resulted from release of intracellular Ca2+ stores. 86Rb efflux was blocked by Ba2+ or charybdotoxin, but not by tetraethylammonium. Charybdotoxin prevented all of the 86Rb efflux that was stimulated by A23187 or by forskolin. Charybdotoxin also blocked the low-conductance inwardly rectifying K+ channel (KCLIC) in membrane patches. These results indicate that the KCLIC channel is responsible for the Ca2(+)-dependent increase in K+ permeability in airway epithelial cells. They also indicate that cAMP-induced release of intracellular Ca2+ is sufficient to activate K+ channels.

Basolateral K+ channels in airway epithelia. II. Role in Cl- secretion and evidence for two types of K+ channel.

We previously described a Ca2(+)-activated K+ channel (KCLIC) in airway epithelial cells [J. D. McCann, J. Matsuda, M. Garcia, G. Kaczorowski, and M. J. Welsh. Am. J. Physiol 258 (Lung Cell. Mol. Physiol. 2): L334-L342, 1990]. To determine whether the KCLIC channel is a basolateral membrane channel and to understand its role in Cl- secretion, we studied airway epithelial cells grown on permeable supports. When cells were stimulated with A23187, charybdotoxin (ChTX) inhibited Cl- secretion and 86Rb efflux at the same concentrations, indicating that the KCLIC channel is required for Ca2(+)-stimulated Cl- secretion. We also investigated the function of K+ channels in adenosine 3',5'-cyclic monophosphate-stimulated secretion. Addition of isoproterenol caused a biphasic increase in Cl- secretion; the time course of the transient component correlated with the time course of the isoproterenol-induced increase in Ca2+ concentration [( Ca2+]c). ChTX inhibited the transient component, but not the prolonged component of secretion; Ba2+ inhibited the sustained component. These results suggest that when cells are grown on permeable supports isoproterenol-induced secretion depends on activation of two types of K+ channel: the KCLIC channel that is stimulated initially and a ChTX-insensitive K+ channel that is stimulated during sustained secretion. This conclusion was supported by measurement of 86Rb efflux from cell monolayers.

Bradykinin stimulates airway epithelial Cl- secretion via two second messenger pathways.

In canine airway epithelial cells, bradykinin increases intracellular concentrations of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], cytosolic calcium concentration ([Ca2+]c), and adenosine 3',5'-cyclic monophosphate (cAMP). To determine the role of these second messengers in bradykinin-stimulated Cl- secretion, we studied the secretory response to this peptide using canine tracheal monolayers mounted in Ussing chambers. Bradykinin stimulated Cl- secretion [measured as short-circuit current (Isc)] when added to submucosal or mucosal surfaces; however, secretory responses differed substantially. Submucosal addition of bradykinin induced a biphasic increase in secretion; mucosal addition induced a monophasic increase in secretion. Both responses were mediated by B2 receptors. We show that activation of bradykinin receptors can stimulate Cl- secretion in two ways. 1) Bradykinin added to either surface stimulates prostaglandin synthesis and release at the basolateral surface. This leads to activation of prostaglandin E2-sensitive receptors on the basolateral surface that are coupled to cAMP production and an increase in apical membrane Cl- conductance. 2) In addition, bradykinin added to the submucosal surface increases Ins(1,4,5)P3 and [Ca2+]c levels, which enhance basolateral K+ conductance and the electrical driving force for apical Cl- exit. Whereas secretion requires activation of apical Cl- channels, the data show that Cl- secretion can also be modulated by activation of basolateral K+ channels. These data indicate that bradykinin-induced transepithelial Cl- secretion is mediated by two independent, second messenger pathways. These results provide the first evidence for expression of both pathways in a polar fashion in an epithelial monolayer.

Calcium-dependent regulation of airway epithelial chloride channels.

To determine how cell calcium ([Ca2+]c) regulates apical Cl- channels, we measured the rate of 125-Iodide (125I-) efflux to assay Cl- channel activity in intact cells and examined cell-free membrane patches from cultured canine tracheal epithelial cells. The Ca2+ elevating agonist bradykinin and the calcium ionophore A23187 increased 125I- efflux. This response did not require prostaglandin production. Under several conditions, changes in [Ca2+]c were temporally dissociated from changes in channel activation: a transient increase in [Ca2+]c caused a prolonged stimulation of 125I- efflux. Neither Cl- channel activation nor open-channel probability was affected by varying internal [Ca2+] in excised membrane patches. Adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2(+)-dependent channel activation may be independent: cAMP-stimulated 125I- efflux did not require an increase in [Ca2+]c, Ca2(+)-stimulated efflux did not require an increase in cAMP, and simultaneous addition of A23187 and isoproterenol produced additive effects on 125I- efflux. The data suggest that an increase in [Ca2+]c activates Cl- channels, however, the effect of Ca2+ appears to be indirect, not involving a ligand-type interaction with the channel.

Regulation of Cl- and K+ channels in airway epithelium.

Stimulation of transepithelial Cl- secretion by the airway epithelium requires activation of channels at the two opposite sides of the cell: the apical and basolateral membranes. At the apical membrane, the Cl- channel is regulated by phosphorylation with PKA and PKC. At the basolateral membrane, the KCLIC channel is regulated by [Ca2+]c. Addition of a secretagogue that increases cellular levels of cAMP also causes release of Ca2+ from intracellular stores. The Ca2+ may then regulate basolateral membrane KCLIC channels. The cAMP-induced increase in [Ca2+]c and activation of the KCLIC channel is transient, however, whereas activation of the Cl- channel and stimulation of secretion is a more sustained response. Those results suggest that the presence of a second Ca2(+)-independent K+ channel located at the basolateral membrane, which is only expressed in cells grown on permeable supports.