Uncorrectable ptosis: primary cutaneous signet-ring cell carcinoma.

Primary cutaneous signet-ring cell carcinoma (PCSRCC) is a rare but aggressive tumor. Our case highlights a 60-year-old man who presented with eyelid ptosis, for which he underwent multiple surgical procedures over a 3-year period prior to referral to our clinic. These procedures were complicated by scarring, delayed healing, and poor cosmetic outcome. In addition, the patient was noted to develop progressive enophthalmos. These concerning signs led to a CT scan and subsequent eyelid biopsy, which revealed a diagnosis of PCSRCC. Further management has involved an MRI and orbitotomy with biopsy revealing widespread extension of the carcinoma. Exenteration was performed to reduce the likelihood of metastasis. There are few documented case reports of PCSRCC of the eyelid in the literature. Of the 33 published cases of PCSRCC, 27 cases involve the eyelids and the other 6 cases involve the axilla. The unique clinical features of this case will be discussed, in particular the presentation as ptosis, an otherwise commonplace complaint in the oculoplastics clinic. The surgical course and histopathologic findings will be presented. The literature regarding PCSRCC will be reviewed including demographics, management, and prognosis. Although rare, PCSRCC follows an aggressive course with characteristically delayed diagnosis. Early identification and treatment likely offer a better prognosis. Thus, description of the clinical presentation of this rare tumor may aid in recognition and earlier treatment.

Clinical characteristics in 53 patients with cat scratch optic neuropathy.

OBJECTIVE: To describe the clinical manifestations and to identify risk factors associated with visual outcome in a large cohort of patients with cat scratch optic neuropathy (CSON). DESIGN: Multicenter, retrospective chart review. PARTICIPANTS: Fifty-three patients (62 eyes) with serologically positive CSON from 5 academic neuro-ophthalmology services evaluated over an 11-year period. METHODS: Institutional review board/ethics committee approval was obtained. Data from medical record charts were collected to detail the clinical manifestations and to analyze visual outcome metrics. Generalized estimating equations and logistic regression analysis were used in the statistical analysis. Six patients (9 eyes) were excluded from visual outcome statistical analysis because of a lack of follow-up. MAIN OUTCOME MEASURES: Demographic information, symptoms at presentation, clinical characteristics, length of follow-up, treatment used, and visual acuity (at presentation and final follow-up). RESULTS: Mean patient age was 27.8 years (range, 8-65 years). Mean follow-up time was 170.8 days (range, 1-1482 days). Simultaneous bilateral involvement occurred in 9 (17%) of 53 patients. Visual acuity on presentation ranged from 20/20 to counting fingers (mean, 20/160). Sixty-eight percent of eyes retained a visual acuity of 20/40 or better at final follow-up (defined as favorable visual outcome). Sixty-seven percent of patients endorsed a history of cat or kitten scratch. Neuroretinitis (macular star) developed in 28 eyes (45%). Only 5 patients had significant visual complications (branch retinal artery occlusion, macular hole, and corneal decompensation). Neither patient age nor any other factor except good initial visual acuity and absence of systemic symptoms was associated with a favorable visual outcome. There was no association between visual acuity at final follow-up and systemic antibiotic or steroid use. CONCLUSIONS: Patients with CSON have a good overall visual prognosis. Good visual acuity at presentation was associated with a favorable visual outcome. The absence of a macular star does not exclude the possibility of CSON. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Longitudinal evidence on punctal plug use in an elderly population.

PURPOSE: The purpose of this study was to determine whether changes in Medicare reimbursement for punctal plug insertion were associated with a decrease in the incidence of insertion and dry eye diagnosis. METHODS: Incident cases of dry eye syndrome (DES) diagnoses and punctal plug insertions among Medicare beneficiaries were identified from Medicare 5% Part B from 1994 to 2008, using a 3-year look-back. Dry eye syndrome diagnoses and punctal plug insertion codes were ascertained from the international classification of diseases and current procedural terminology codes. Medicare payment data were obtained from the Centers for Medicare and Medicaid Services from 1994 to 2008 for punctal plug insertion. Rates were calculated for both the incidence of DES and the use of punctal plugs. RESULTS: From 2001 to 2008, inflation-adjusted Medicare reimbursement for punctal plug insertion decreased 55.1%, whereas the Medicare population-adjusted incidence of dry eye diagnosis increased 23.3%. Nine percent of individuals diagnosed with DES between 1991 and 2008 underwent punctal plug placement with a mean of 2.0 plugs placed per patient. Total punctal plug placement increased 322.2% between 1994 and 2003, and then reached a plateau. First-time punctal plug insertion rates within 365 days of DES diagnosis increased 111.8% from 1994 to 2002, and then declined 47.0% from 2002 to 2008. CONCLUSIONS: Although the frequency of DES diagnosis in the Medicare population has increased over time, first-time punctal plug insertion rates, especially within the first year following DES diagnosis, have declined coincidently with the increasing presence of a medical alternative and declining Medicare payment. Choice of therapies may have cost and care implications.

The diagnostic dilemma of neuro-imaging in acute isolated sixth nerve palsy.

PURPOSE OF REVIEW: Microvascular ischemia is a frequent cause of acute isolated cranial nerve six (CN VI) palsy. Alternative etiologies of CN VI palsy with grave neurological implications often cannot be excluded without neuroimaging. However, the practice of obtaining neuro-imaging for every patient presenting with an acute, isolated CN VI palsy is a costly diagnostic paradigm. Recent studies have sought to delineate the risk factors for microvascular ischemic ocular motor cranial neuropathies and to investigate the utility of neuroimaging in the initial evaluation of such cases. The aim of this review is to provide an update on the issues and controversies of neuroimaging in the initial evaluation of an acute isolated CN VI palsy. RECENT FINDINGS: Diabetes mellitus, but not hypertension alone, is a risk factor for microvascular ischemic ocular motor cranial neuropathies. Small-scale prospective studies have suggested that immediate neuroimaging should be considered in the initial evaluation of all patients with CN VI palsy, regardless of the presence of microvascular ischemic risk factors. SUMMARY: There remains a lack of large-scale, prospective, age-specific studies to indicate the diagnostic yield of immediate neuroimaging in the setting of acute isolated CN VI palsy. An algorithm is offered for the evaluation of acute isolated CN VI palsy, which allows for initial expectant observation and re-consideration of obtaining neuroimaging upon follow-up if the ophthalmoplegia does not improve, progresses, or becomes nonisolated.

Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase.

The antiangiogenic protein angiostatin inhibits ATP synthase on the endothelial cell surface, blocking cellular proliferation. To examine the specificity of this interaction, we generated monoclonal antibodies (mAb) directed against ATP synthase. mAb directed against the beta-catalytic subunit of ATP synthase (MAb3D5AB1) inhibits the activity of the F(1) domain of ATP synthase and recognizes the catalytic beta-subunit of ATP synthase. We located the antibody recognition site of MAb3D5AB1 in domains containing the active site of the beta-subunit. MAb3D5AB1 also binds to purified Escherichia coli F(1) with an affinity 25-fold higher than the affinity of angiostatin for this protein. MAb3D5AB1 inhibits the hydrolytic activity of F(1) ATP synthase at lower concentrations than angiostatin. Like angiostatin, MAb3D5AB1 inhibits ATP generation by ATP synthase on the endothelial cell surface in acidic conditions, the typical tumor microenvironment where cell surface ATP synthase exhibits greater activity. MAb3D5AB1 disrupts tube formation and decreases intracellular pH in endothelial cells exposed to low extracellular pH. Neither angiostatin nor MAb3D5AB1 showed an antiangiogenic effect in the corneal neovascularization assay; however, both were effective in the low-pH environment of the chicken chorioallantoic membrane assay. Thus, MAb3D5AB1 shows angiostatin-like properties superior to angiostatin and may be exploited in cancer chemotherapy.

Dynamic indocyanine green angiography-guided focal thermal laser treatment of fibrotic choroidal neovascularization.

PURPOSE: Fibrotic choroidal neovascular membranes (CNV) are the end-stage outcomes of neovascular age-related macular degeneration (AMD). No treatment is currently available for fibrotic CNV. We investigated the role of focal thermal laser ablation of the perfusing afferent arteriole as determined by dynamic indocyanine green angiography (ICGA). METHODS: We conducted a retrospective study of 20 patients with fibrotic CNV associated with significant subretinal fluid or retinal edema, who also demonstrated well-defined perfusing arterioles by dynamic ICGA. Patients underwent focal thermal laser occlusion of the perfusing afferent arteriole. Six, 12 and 24 weeks post-treatment, eyes underwent repeat examination with optical coherence tomography (OCT) and visual acuity testing, and ICGA at 12 weeks. RESULTS: Therapeutic closure of the perfusing afferent arterioles was achieved in 17 of 20 eyes immediately post-treatment. All 17 of these eyes demonstrated significant resolution of retinal edema and subretinal fluid, as evidenced by OCT, which was dramatic in some cases. Seven eyes demonstrated an improvement in visual acuity of 1 line or more. While most eyes demonstrated reperfusion within 3 months, many lesions suggested reduced vascularity and flow. CONCLUSION: Eyes with fibrotic CNV and associated retinal edema often demonstrate well-defined vascularity of the fibrosis with discrete perfusing arterioles when imaged by dynamic ICGA. Thermal laser occlusion of these arterioles can result in resolution of subretinal fluid, and occasionally an improvement in vision. This represents a potential therapeutic intervention for an advanced stage of AMD currently regarded as stable.

Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase.

Angiostatin, a proteolytic fragment of plasminogen, is a potent angiogenesis inhibitor able to suppress tumor growth and metastasis through inhibition of endothelial cell proliferation and migration. Previously, we showed that angiostatin binds and inhibits F(1)F(o) ATP synthase on the endothelial cell surface and that anti-ATP synthase antibodies reduce endothelial cell proliferation. ATP synthase also occurs on the extracellular surface of a variety of cancer cells, where its function is as yet unknown. Here, we report that ATP synthase is present and active on the tumor cell surface, and angiostatin, or antibody directed against the catalytic beta-subunit of ATP synthase, inhibits the activity of the synthase. We show that tumor cell surface ATP synthase is more active at low extracellular pH (pH(e)). Low pH(e) is a unique characteristic of the tumor microenvironment. Although the mechanism of action of angiostatin has not been fully elucidated, angiostatin treatment in combination with acidosis decreases the intracellular pH (pH(i)) of endothelial cells, leading to cell death. We also find that, at low pH(e), angiostatin and anti-beta-subunit antibody induce intracellular acidification of A549 cells, as well as a direct cytotoxicity that is absent in tumor cells with low levels of extracellular ATP synthase. These results establish angiostatin as an antitumorigenic and antiangiogenic agent through a mechanism implicating tumor cell surface ATP synthase. Furthermore, these data provide evidence that extracellular ATP synthase plays a role in regulating pH(i) in cells challenged by acidosis.

Surgical outcome of pediatric dacryocystorhinostomy in Nepal.

PURPOSE: To report the indications and surgical outcome of dacryocystorhinostomy (DCR) in children treated at a single tertiary eye hospital in Nepal. METHODS: The medical records of consecutive pediatric patients who underwent external DCR with silicon tube intubation after failed nasolacrimal irrigation and probing from January 2010 to June 2011 were retrospectively reviewed. Surgical success was defined as resolution of epiphora, normal tear film height, negative fluorescein dye disappearance test and anatomic patency determined by irrigation of the lacrimal system. RESULTS: The etiology of the nasolacrimal duct obstruction was acquired nasolacrimal duct obstruction (NLDO) in 63%, congenital NLDO in 23%, trauma in 1% and congenital bony abnormality in 1 patient. Of the 38 patients who completed follow-up, 37 (97%) had a successful result. CONCLUSIONS: External DCR effectively treated a variety of pediatric NLDO etiologies, with a low rate of complications.

Cell surface F1Fo ATP synthase: a new paradigm?

The mitochondrial F1Fo adenosine triphosphate (ATP) synthase is one of the most thoroughly studied enzyme complexes known. Yet, a number of new observations suggesting that the enzyme is also located on the cell surface necessitate further investigation. While the mitochondrial synthase utilizes the proton gradient generated by oxidative phosphorylation to power ATP synthesis, the cell surface synthase has instead been implicated in numerous activities, including the mediation of intracellular pH, cellular response to antiangiogenic agents, and cholesterol homeostasis. Intriguingly, a common thread uniting these various models of cell surface ATP synthase functions is the apparently caveolar distribution of the enzyme. Recent studies concerning the cell surface ATP synthase manifest applications in the regulation of serum cholesterol levels, cellular proliferation and antitumor strategies. This review addresses the expression, interactions, functions, and consequences of inhibition of cell surface ATP synthase, an enzyme now displaying a shift in paradigm, as well as of location.