Histologic Evidence of Orbital Inflammation from Retrobulbar Alcohol and Chlorpromazine Injection: A Clinicopathologic Study in Human & Rat Orbits.

PURPOSE: Retrobulbar injections of alcohol and chlorpromazine are used for the treatment of blind, painful eyes. There have been reports of inflammation after retrobulbar injections of these agents, but the histologic effects are not well characterized. A clinical case with histopathologic confirmation of inflammation after retrobulbar alcohol injection led the authors to develop a rat model to examine these effects. METHODS: Adult Lewis rats were given retrobulbar injections of either 0.1 ml of absolute alcohol or 25 mg/ml chlorpromazine in the right orbit, and 0.1 ml of saline in the left orbit as a control. Rats were euthanized, perfused, and postfixed at 1 to 2 weeks after injection. Exenterated orbital tissue was sectioned for histologic staining. Slides were reviewed by a masked ocular pathologist who evaluated the level of orbital inflammation. RESULTS: Histopathology demonstrated foci of granulomatous inflammation in the orbit of the patient and similar inflammation in the rat orbits injected with retrobulbar alcohol. In the chlorpromazine group, only 1 rat demonstrated small foci of inflammation, while the control orbits injected with saline showed no inflammation. On blinded qualitative analysis, the orbits receiving retrobulbar alcohol had greater inflammation than the orbits receiving either saline or chlorpromazine. CONCLUSIONS: Our findings in this preclinical pilot study suggest that retrobulbar alcohol injections incite significant orbital inflammation, whereas retrobulbar chlorpromazine induces little or no inflammation. This potential inflammatory response should be considered when selecting an agent for pain management, particularly if future orbital surgery is anticipated.

Oral methylphenidate for the treatment of refractory facial dystonias.

Oral methylphenidate (Ritalin, Novartis) has been reported to alleviate symptoms of benign essential blepharospasm in an off-label application. This series presents 3 patients with refractory periorbital and facial dystonias, including blepharospasm, apraxia of eyelid opening, and oromandibular dystonia unresponsive to standard treatments who experienced a response to oral methylphenidate therapy. While the mechanisms for facial dystonias have not been elucidated, there is evidence to suggest that they are on the spectrum with Parkinson disease. Given the role of dopamine loss in the pathogenesis of Parkinson, the authors' speculate that methylphenidate may be acting on the pathway directly involved in facial dystonias. To the authors' knowledge, this is the first report of a case of successful treatment of blepharospasm refractory to upper eyelid myectomy with methylphenidate monotherapy.

The last ride of Henry II of France: orbital injury and a king's demise.

Jousting was a popular pastime for royalty in the Renaissance era. Injuries were common, and the eye was particularly at risk from the splinters of the wooden lance. On June 30, 1559, Henry II of France participated in a jousting tournament to celebrate two royal weddings. In the third match, Gabriel de Montgomery struck Henry on the right shoulder and the lance splintered, sending wooden shards into his face and right orbit. Despite being cared for by the prominent physicians Ambroise Paré and Andreas Vesalius, the king died 10 days later and was found to have a cerebral abscess. The wound was not explored immediately after the injury; nevertheless, wooden foreign bodies were discovered in the orbit at the time of autopsy. The dura had not been violated, suggesting that an infection may have traveled from the orbit into the brain. Nostradamus and Luca Guarico, the astrologer to the Medici family, had prophesied the death of Henry II of France, but he ignored their warnings and thus changed the course of history in Renaissance Europe.

Bilateral lacrimal gland disease: clinical features of 97 cases.

OBJECTIVE: Bilateral lacrimal gland (LG) disease is a unique presentation that can result from varied causes. We reviewed the diagnoses, clinical features, and outcomes of 97 patients with this entity. DESIGN: Case series. PARTICIPANTS: Ninety-seven patients with bilateral LG disease. METHODS: Retrospective review and statistical analysis using analysis of variance and the Fisher exact test. MAIN OUTCOME MEASURES: Patient demographics, clinical features, diagnostic testing, diagnosis, and treatment. RESULTS: Patient age ranging from 8 to 84 years (mean, 46 years). The predominant gender was female (77%), and race included black (49%), white (38%), and Hispanic (12%) patients. Diagnoses fell into 4 categories: inflammatory (n = 51; 53%), structural (n = 20; 21%), lymphoproliferative (n = 19; 20%), and uncommon (n = 7; 7%) entities. The most common diagnoses included idiopathic orbital inflammation (IOI; n = 29; 30%), sarcoidosis (n = 19; 20%), prolapsed LG (n = 15; 15%), lymphoma (n = 11; 11%), lymphoid hyperplasia (n = 8; 8%), and dacryops (n = 5; 5%). Inflammatory conditions were more likely in younger patients (P<0.05) and in those with pain (P<0.001) and mechanical blepharoptosis (P<0.01) at presentation, whereas lymphoma was more common in older patients (P<0.001) without active signs of inflammation at presentation. Black patients were more likely to have sarcoidosis (P<0.01). Laboratory results showed high angiotensin converting enzyme level being significantly more likely in patients with sarcoidosis (P<0.05). However, sensitivity was limited to 45%, with 25% of patients diagnosed with IOI also demonstrating positive results. Corticosteroid therapy was the treatment of choice in 38 cases, corresponding to resolution of symptoms in 29% and improvement in an additional 32%. Overall, chronic underlying disease was found in 71% of patients, among whom 26% achieved a disease-free state, whereas 3% succumbed to their underlying disease. CONCLUSIONS: The cause of bilateral lacrimal gland disease most commonly was inflammatory, followed by structural and lymphoproliferative. Patient characteristics and clinical presentations were key features distinguishing between competing possibilities. Despite local control with corticosteroids or radiotherapy, underlying disease continued in 71% of patients and led to death in 3%.

No light perception vision from compressive thyroid orbitopathy.

Thyroid eye disease (TED) is an autoimmune inflammatory disorder that affects the extraocular soft tissues and causes eyelid retraction, proptosis and restrictive extraocular myopathy. Compressive optic neuropathy from extraocular muscle enlargement occurs in less than 5% of patients, in the majority of whom it develops within 18 months of the diagnosis of hyperthyroidism. Vision loss from compressive optic neuropathy in patients with thyroid eye disease is usually bilateral and insidious in onset and progression and is associated with diplopia and elevated intraocular pressure. To our knowledge, there have been no reported cases of acute vision loss to the level of no light perception secondary to thyroid orbitopathy. The authors report a 66-year-old Caucasian male with history of long-standing thyroid eye disease and massive proptosis who progressed from mild compressive symptoms to no light perception within days, despite being clinically stable for over 10 years.

Orbital inflammation after dental procedures.

This study reports 3 cases of acute orbital inflammation that occurred within 3 weeks of various dental procedures and offers a possible mechanism as to their cause. The charts of 3 patients were retrospectively examined. Clinical notes, laboratory testing, and imaging studies were reviewed. The cases involved a 36-year old woman, a 61-year-old woman, and a 44-year-old woman who developed acute dacryoadenitis after tooth extraction in the former case and after routine dental cleaning in the latter 2. All cases were initially treated with an oral steroid taper over 6 to 8 weeks. The first 2 cases resolved promptly and have remained quiescent. The last individual had recurrent symptoms prompting lacrimal gland biopsy that demonstrated chronic, nongranulomatous inflammation without monoclonality. The patient subsequently responded to periorbital steroid injection only to have a recurrent bout of inflammation after repeat dental cleaning. Another periorbital steroid injection resulted in resolution of inflammation. The authors propose that a subset of acute orbital inflammation may represent an autoimmune response triggered by dental manipulation. These cases are suggestive of an atypical variant of noninfectious, microbe-induced inflammation.

The relationship of the globe to the orbital rim.

OBJECTIVE: To present a novel method for accurately characterizing the position of the globe relative to the orbital rim. The appearance and function of the eyelids are dependent on the underlying orbital bony architecture and globe position; however, no comprehensive language to describe these complex 3-dimensional relationships exists. METHODS: Three-dimensional orbital reconstructions were generated from computed tomographic scans of 15 Occidental and 12 Oriental orbits without orbital pathologic disease. Globe and orbital rim anatomy were identified and outlined. Reference points were measured along 2 independent axes: (1) the distance between a plane defined by the corneal apex and the sagittal projection of the orbital rim and (2) the distance between the circumference of the globe and the coronal projection of the orbital rim. RESULTS: For Occidental orbits, the mean (SD) elevation of the sagittal projection of the orbital rim relative to the anterior projection of the globe was 4.6 (4.2) mm superiorly, 5.9 (3.0) mm nasally, 12.6 (3.7) mm inferiorly, and 20.6 (2.6) mm laterally. The mean (SD) radial distance between the coronal projection of the orbital rim and the circumference of the globe was 3.7 (2.1) mm superiorly, 7.6 (1.8) mm nasally, 6.6 (2.2) mm inferiorly, and 4.6 (2.3) mm laterally. For Oriental orbits, the mean (SD) elevation of the sagittal projection of the orbital rim relative to the anterior projection of the globe was 5.0 (4.5) mm superiorly, 6.8 (4.1) mm nasally, 11.1 (4.3) mm inferiorly, and 17.5 (3.3) mm laterally. The mean (SD) radial distance between the coronal projection of the orbital rim and the circumference of the globe was 2.1 (1.2) mm superiorly, 8.2 (2.0) mm nasally, 6.5 (1.9) mm inferiorly, and 4.5 (1.7) mm laterally. CONCLUSIONS: Comparison of Occidental and Oriental orbital rim and globe configurations revealed quantitative and qualitative differences. In addition to differences in soft-tissue anatomy, bony architectural variations may contribute substantially to racial differences in the surface anatomy of the periorbital area. Anatomic analysis, based on 3-dimensional orbital imaging, may provide a rational approach to surgical planning for aesthetic and reconstructive orbitofacial surgery.

Congenital lacrimal sac fistula: intraoperative visualization by polyvinyl siloxane cast.

We report the intraoperative use of polyvinyl siloxane impression material to demonstrate the anatomy of the lacrimal sac, canaliculi, and lacrimal duct in a case of congenital lacrimal sac fistula. A 1-week-old boy was examined for tearing since birth. Examination revealed a left congenital lacrimal sac fistula. After a failed surgery to close the fistula with silicone intubation at 6 months of age, the patient underwent endonasal dacryocystorhinostomy performed at 14 months of age, aided by intraoperative injection of polyvinyl siloxane (trade name Reprosil) to mark and protect the nasolacrimal sac and facilitate endonasal visualization. A polyvinyl siloxane cast demonstrated the anatomy of the accessory canaliculus causing nasolacrimal duct obstruction. Postoperatively, the epiphora resolved and the fistula remained closed. The polyvinyl siloxane cast provides a 3-dimensional "ex vivo " model of the lacrimal sac, upper duct, and canalicular anatomy, and can be used in dacryocystorhinostomy surgery to identify and protect the lacrimal sac.

Enhanced replication of R5 HIV-1 over X4 HIV-1 in CD4(+)CCR5(+)CXCR4(+) T cells.

To enter human cells, HIV-1 usually uses CD4 and 1 of 2 coreceptors: CCR5 and CXCR4. Interestingly, even though CCR5 is expressed on far fewer T cells than is CXCR4, many patients in early- and late-stage HIV disease maintain high levels of CCR5-tropic (R5) viruses. We hypothesized that such high R5 viral loads may be sustained because, relative to CXCR4-tropic (X4) HIV-1 infection, R5 HIV-1 infection of permissive CD4(+)CCR5(+)CXCR4(+) T cells results in the production of significantly more infectious virus particles per target cell. To investigate this possibility, we compared the levels of virus production per target cell after isogenic R5 and X4 HIV-1 infection of 2 in vitro primary human lymphocyte culture systems: T-cell receptor-stimulated blood-derived CD4(+) T cells and tonsil histoculture (which requires no exogenous stimulation for ex vivo infection). We provide evidence that R5 HIV-1 does indeed compensate for a small target cell population by producing, on average, 5 to 10 times more infectious virus per CCR5(+) target cell than X4 HIV-1. This replicative advantage may contribute to the predominance of R5 HIV-1 in vivo.

Cyclosporin a inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells.

PURPOSE: Although the clinical efficacy of cyclosporin A (CSA) in retinoblastoma (RB) has been attributed to multidrug resistance reversal activity, the authors hypothesized that CSA is also directly toxic to RB cells through inhibition of calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling. METHODS: Antiproliferative effects of CSA, PSC-833 (a CSA analogue that does not inhibit CN), and FK506 (a CN inhibitor structurally unrelated to CSA) were evaluated in Y79 and Weri-RB1 cells by WST-1 assay. Apoptosis induction by CSA and PSC-833 was measured by detection of caspase 3/7 activity and by flow cytometry, using annexin-V and 7-AAD stains. Expression of CN was assayed in RB cells by immunocytochemistry. Expression of NFAT, a CN-dependent transcription factor family, and FK506 binding protein 12/12.6 (FKBP12/12.6), effectors of CN inhibition by FK506, was assayed in RB cells by Western blot analysis. NFAT activity was assayed in CSA-treated and -untreated Y79 cells transfected with an NFAT-sensitive reporter gene. RESULTS: CSA induced dose-dependent antiproliferative and proapoptotic effects at clinically achievable levels in Y79 and Weri-RB1 cells. PSC-833 induced antiproliferative effects only at nonphysiologic concentrations with minimal associated apoptosis. FK506 induced minimal antiproliferative effects in RB cell lines, probably due to trace or absent FKBP12/12.6 expression. RB cell lines expressed CN-alpha, CN-beta, NFATc1, and NFATc3. CSA treatment also potently inhibited NFAT-mediated reporter gene transcription. CONCLUSIONS: These results demonstrate functional integrity of the CN/NFAT signaling cascade in RB cells and suggest that CSA is cytotoxic to RB cells through inhibition of this pathway and consequent apoptosis induction.

Nuclear export of Vpr is required for efficient replication of human immunodeficiency virus type 1 in tissue macrophages.

Retroviruses must gain access to the host cell nucleus for subsequent replication and viral propagation. Human immunodeficiency virus type 1 (HIV-1) and other primate lentiviruses are distinguished from the gammaretroviruses by their ability to infect nondividing cells such as macrophages, an important viral reservoir in vivo. Rather than requiring nuclear membrane breakdown during cell division, the HIV-1 preintegration complex (PIC) enters the nucleus by traversing the central aqueous channel of the limiting nuclear pore complex. The HIV-1 PIC contains three nucleophilic proteins, matrix, integrase, and Vpr, all of which have been implicated in nuclear targeting. The mechanism by which Vpr can display such nucleophilic properties and yet also be available for incorporation into virions assembling at the plasma membrane is unresolved. We recently characterized Vpr as a nucleocytoplasmic shuttling protein that contains two novel nuclear import signals and an exportin-1-dependent nuclear export signal (NES). We now demonstrate that mutation of this NES impairs the incorporation of Vpr into newly formed virions. Furthermore, we find that the Vpr NES is required for efficient HIV replication in tissue macrophages present in human spleens and tonsils. These findings underscore how the nucleocytoplasmic shuttling of Vpr not only contributes to nuclear import of the HIV-1 PIC but also enables Vpr to be present in the cytoplasm for incorporation into virions, leading to enhancement of viral spread within nondividing tissue macrophages.