Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Clinical features and management of keratoconjunctivitis associated with inadequate tear drainage.

OBJECTIVE: To describe clinical features and management of toxic keratoconjunctivitis associated with punctal and (or) canaliculus stenosis (toxic soup syndrome). DESIGN: Retrospective observational case series. METHODS: Electronic medical record database search for the keywords "toxic soup syndrome" and retrospective chart review were performed. Thirty-five eyes of 25 patients were seen at a tertiary cornea clinic between January 2017 and December 2021. Sex, age, distance-corrected visual acuity, topical medications, symptoms, clinical signs, and outcomes after medical and surgical interventions were analyzed. The main outcome measured was improvement in ocular surface signs and symptoms after interventions. RESULTS: Overall, 35 eyes of 25 patients with a mean age of 66.8 ± 12.8 years, of which 72% were female, were included. The primary complaint was hyperemia and epiphora in all patients. Rosacea or meibomian gland disease were present in all patients, 7 (28%) had glaucoma, and 7 (28%) developed limbal stem cell deficiency. Twenty-two patients (88%) were using topical medications on presentation. All eyes had either punctal plugs, cauterized puncta, or punctal and (or) canaliculus stenosis. Management of all patients consisted of suspension of all preserved topical medications and institution of some type of anti-inflammatory therapy. Nineteen patients (76%) improved after improvement of lacrimal drainage. One patient with severe resistance in the canaliculus required ongoing preservative-free topical steroids. CONCLUSIONS: Chronic drug-induced or pooled inflammatory mediators causing toxic conjunctivitis may be aggravated by punctal and (or) canaliculus stenosis, leading to toxic soup syndrome. Clearance of punctal obstruction leads to improvement in most patients.

Gender and editorship in oculoplastics societal publications.

PURPOSE: The editorship of medical journals is a leadership role that can affect recognition and career advancement. We determine the gender representation of the editorial boards of oculoplastic surgery journals in comparison to the proportion of women in oculoplastics societies. METHODS: The gender composition of the American, European and Asia-Pacific societies of oculoplastic and reconstructive surgery and the editorial boards of their respective society journals were determined with online searches in March 2021. Statistical tests for the equality of proportions were performed. RESULTS: Excluding 44 individuals with missing gender data, the three combined oculoplastics societies comprised 1,230 distinct members, with 29% women. The editorial review boards of the three official society publications comprised 59 medical editors, 22% of which were women. There was no statistically significant difference in the proportion of women editors versus women OPRS members (p = .201) but the study is underpowered to detect a 7% difference. A sensitivity analysis with the missing data did not alter the conclusions. The mean h-index/m-quotient of the women editors was 20.50/0.87 and for the men 21.05/0.84, with no statistically significant difference (p = .903/0.851). CONCLUSION: Women are underrepresented on the editorial boards of oculoplastic journals. Possible methods to improve gender balance include multicriteria objective decision-making criteria for editor nominations, mentoring peer reviewers that are women, and appointing a journal editor for equity, diversity and inclusion.

Guidelines for vismodegib in the management of periocular basal cell carcinoma.

OBJECTIVE: The management of advanced basal cell carcinoma (BCC) in the periocular region remains a clinical challenge. Vismodegib (ErivedgeTM) has been approved in 2013 by Health Canada for adult patients with "histologically confirmed metastatic BCC or locally advanced BCC inappropriate for surgery or radiation." An expert consensus was sought to create a standardised approach in the use of this novel treatment. METHODS: Fourteen practicing oculoplastic surgeons across Canada were involved in formulating and reviewing guidelines until consensus was reached. A consultancy meeting was followed by further ratification of guidelines over email. Two voting surveys were performed of the group to objectively assess agreement over each statement within the guidelines. Ratification continued until at least two-thirds of the group agreed on every guideline statement. RESULTS: The guidelines summarize 21 statements in a major and minor criteria format. A multidisciplinary team review is suggested for each patient with the involvement of recommended specialists. The internal survey revealed 100% agreement over 9 statements, 91.7% agreement over 8 statements, 83.3% agreement over 4 statements, and 2 statements had 66.7% and 58.7% agreement each. All statements with less than 91.7% agreement were surveyed again, and they were kept, modified, or removed on the basis of a consensus of over 66.7%. CONCLUSIONS: These guidelines serve to act as a framework for physicians considering vismodegib for the medical management of patients with advanced or metastatic periocular BCC. Future applications, including neoadjuvant uses of the drug, may become apparent through further research.

Orbital radiation therapy for Graves' ophthalmopathy: measuring clinical efficacy and impact.

PURPOSE: Graves' ophthalmopathy (GO) is an autoimmune condition primarily managed with prolonged courses of glucocorticoids, which can be associated with significant side effects. Orbital radiation therapy (RT) is an alternative treatment that has shown variable efficacy in improving orbital and visual symptoms. In this study, the therapeutic benefit of RT was evaluated in terms of patient's ability to taper their corticosteroid requirements, which may better reflect the proposed mechanism of RT and provide a clinically relevant response endpoint. METHODS AND MATERIALS: This is a retrospective review of consecutive patients treated with orbital RT for GO between 2000 and 2010 at a single tertiary hospital with a dedicated ocular radiation therapy clinic. The primary measure of treatment response was defined as the ability to taper glucocorticoids following RT without any further exacerbation of orbitopathy symptoms. Additional endpoints including ocular symptoms (diplopia, proptosis, visual acuity, extraocular movement) and need for surgical intervention were reported. RESULTS: Of 86 eligible patients, with a mean follow-up of 9.3 months, 81 (94%) patients responded to RT. Of patients taking corticosteroids at baseline, 91% were able to taper off corticosteroids completely and the remaining patients had decreased their doses by 83%. Diplopia, visual acuity, and extraocular movements improved in 29%, 81%, and 58% of patients, respectively. The median reduction in proptosis was 2.5 mm and 2 mm in the left and right eyes, respectively (range, -18 mm to 23 mm). CONCLUSIONS: Orbital RT is a generally well-tolerated treatment that helps minimize the dose and duration of corticosteroid therapy for patients with GO while improving ocular symptoms, including proptosis and diplopia. Prospective research should consider using corticosteroid requirement as a measure of response to orbital RT for GO.

Cadaveric anatomical comparison of the lateral nasal wall after external and endonasal dacryocystorhinostomy.

PURPOSE: Much literature has accumulated espousing the relative merits of endonasal and external dacryocystorhinostomy (DCR). However, there is comparatively little information on the relative anatomic differences between these 2 approaches. The purpose of this study is to investigate the anatomic relationships of the lateral nasal wall for endonasal and external DCR. METHODS: Ten cadaver half heads were used in this study. Half were subject to endonasal and half to external DCR procedures. The lateral nasal wall was then dissected and measurements were taken of ostium and anastomosis size and position relative to other landmarks on the lateral nasal wall. Relationships were compared between the 2 procedures. RESULTS: The dimensions and area of the ostium and the anastomosis were similar between the 2 procedures. The lower portion of the ostium was located more inferiorly in endonasal DCR. Additionally, the ostium was more likely to be found lateral to the axilla of the middle turbinate in endonasal DCR, when compared with anterior for external. External DCR was also more likely to involve opening the anterior ethmoid air cells than endonasal approach. CONCLUSION: Endonasal and external DCR osteomies appear to be of similar size, with the endonasal opening being located slightly lower and more posterior on the lateral nasal wall.

Factors associated with outcome of endonasal dacryocystorhinostomy.

PURPOSE: To identify factors associated with outcome of endonasal dacryocystorhinostomy. METHODS: One hundred thirty-four cases of endonasal dacryocystorhinostomy in 111 patients performed for primary acquired nasolacrimal duct obstruction by a single surgeon between March 12, 2002 and November 10, 2008 were included in a retrospective, noncomparative case series. Variables assessed during the surgery included intranasal view, difficulty of bone removal, size of the lacrimal sac, presence of lacrimal sac stones, orbital fat prolapse and degree of bleeding. Successful outcome was defined as patency to lacrimal irrigation at final follow up. RESULTS: One hundred twenty-one of the 134 cases (90%) were patent to irrigation at final follow up (mean 8.8 ± 8.6 months). A small lacrimal sac opening intraoperatively was associated with higher risk of failure (odds ratio [95% confidence interval] of 5.7 [1.6, 20] [p = 0.0072]). Orbital fat prolapse had a trend toward higher risk of failure that approached statistical significance (odds ratio [95% confidence interval] of 5.3 [0.87, 32] [p = 0.0698]). A narrow intranasal view, difficult bony opening, lacrimal sac stones, and bleeding were not associated with outcome. CONCLUSIONS: A small lacrimal sac opening intraoperatively was associated with failure of endonasal dacryocystorhinostomy.

Bicanalicular laceration repair via an endoscopic retrograde approach.

A 31-year-old man presented 5 days after a left bicanalicular laceration from trauma. Identification of the medial cut ends under direct visualization was unsuccessful. A retrograde endoscopic approach was used to identify the common canaliculus or one of the medial cut ends of the canaliculi by injecting the lacrimal sac with saline and observing fluid egress from the wound. Both canaliculi were stented with a silicone tube and both ends of the tube were passed through the identified medial opening in the lacrimal sac. The tubes were retrieved from the nose and tied, and then left for 6 months before removal. The patient did not complain of epiphora and demonstrated bicanalicular patency on irrigation. This is the first description of using an endoscopic retrograde approach to identify the medial ends of a bicanalicular laceration.

Indications for orbital imaging by the oculoplastic surgeon.

OBJECTIVE: To determine the indications for ordering orbital imaging and the indications for ordering CT versus MRI by oculoplastic surgeons and to assess the correlation between surgeon's clinical indications for imaging and the radiologist's diagnosis. DESIGN: Retrospective review of imaging requisitions and radiology reports. PARTICIPANTS: Patients of 4 oculoplastic surgeons who required CT or MRI scans. METHODS: Imaging requisitions and radiology reports of patients from 4 oculoplastic surgeons were reviewed to determine the indication for ordering a CT or MRI scan between March 2006 and March 2009. The indications were then compared with the radiologist's diagnosis. RESULTS: A total of 735 patients were included: 449 (61.1%) female and 286 (38.9%) male, with an average age of 50.1 years and an age range of 7 months to 93 years. Of these patients, a total of 632 CT and 223 MRI scans were ordered, 135 of which were follow-up scans. CONCLUSIONS: The most common indication for CT scan was thyroid disease, followed by orbital tumors and then inflammatory disease, while the most common indication for MRI scan was orbital tumors, followed by inflammatory disease and then thyroid disease. CT scans were more commonly ordered than MRI, largely for trauma and to rule out orbital foreign body.

Orbital lymphoma presenting with choroidal detachments.

This report describes a case of orbital B-cell lymphoma of extranodal marginal cell type with atypical clinical and radiographic features. This patient presented with choroidal effusion and optic disk swelling of the right eye. A CT scan revealed an intraconal mass surrounding the optic nerve and indenting the globe. A right orbitotomy with biopsy of the mass was performed. Histologic and immunohistochemical analysis confirmed a diagnosis of extranodal marginal zone B-cell lymphoma. This is the first case of primary orbital lymphoma presenting with choroidal effusion described in the literature.

Pain associated with local anesthetic injection in eyelid procedures: Comparison of microprocessor-controlled versus traditional syringe techniques.

PURPOSE: To evaluate the pain associated with local infiltration of the eyelid, using a microprocessor-controlled delivery system (CompuMed, using the Wand), as compared with traditional manual syringe infiltration technique. METHODS: A randomized clinical trial of 30 patients undergoing minor eyelid surgical procedures was performed. Fifteen patients were injected by use of the CompuMed system and 15 patients were injected by the traditional manual syringe technique. The severity of pain was recorded from each patient by using a visual analog scale (0 to 10). The duration of pain experienced by the patient was also recorded. RESULTS: The mean pain level reported was 1.5 in the Wand group and 3.2 in the syringe group (p < 0.01). The mean duration of pain experienced was 1.5 seconds in the Wand group and 34 seconds in the syringe group (p < 0.01). CONCLUSIONS: The Wand was effective at significantly reducing the pain associated with local anesthetic infiltration in minor eyelid surgical procedures. Patients appear to feel pain from the initial needle stick but not during the actual injection.

Aggregated IgG inhibits the differentiation of human fibrocytes.

Fibrocytes are fibroblast-like cells, which appear to participate in wound healing and are present in pathological lesions associated with asthma, pulmonary fibrosis, and scleroderma. Fibrocytes differentiate from CD14+ peripheral blood monocytes, and the presence of serum delays this process dramatically. We previously purified the factor in serum, which inhibits fibrocyte differentiation, and identified it as serum amyloid P (SAP). As SAP binds to Fc receptors for immunoglobulin G (IgG; Fc gammaRs), Fc gammaR activation may be an inhibitory signal for fibrocyte differentiation. Fc gammaR are activated by aggregated IgG, and we find aggregated but not monomeric, human IgG inhibits human fibrocyte differentiation. Monoclonal antibodies that bind to Fc gammaRI (CD64) or Fc gammaRII (CD32) also inhibit fibrocyte differentiation. Aggregated IgG lacking Fc domains or aggregated IgA, IgE, or IgM do not inhibit fibrocyte differentiation. Incubation of monocytes with SAP or aggregated IgG inhibited fibrocyte differentiation. Using inhibitors of protein kinase enzymes, we show that Syk- and Src-related tyrosine kinases participate in the inhibition of fibrocyte differentiation. These observations suggest that fibrocyte differentiation can occur in situations where SAP and aggregated IgG levels are low, such as the resolution phase of inflammation.

Nonadherence with pediatric human immunodeficiency virus therapy as medical neglect.

OBJECTIVE: To examine the results of an interventionist approach applied to human immunodeficiency virus (HIV)-infected children for whom caregiver nonadherence was suspected as the cause of treatment failure. METHODS: The medical records of a cohort of 16 perinatally HIV-infected children whose care was managed at the Arkansas Children's Hospital Pediatric HIV Clinic for an uninterrupted period of >or=3 years were reviewed through July 2003. Data collected included date of birth, dates of and explanations for clinic visits and hospitalizations, dates of laboratory evaluations, CD4(+) T cell percentages, plasma HIV-1 RNA levels, antiretroviral medications, viral resistance tests (eg, phenotype and genotype), and physician-initiated interventions to enhance adherence to the medication regimen. A stepwise interventionist approach was undertaken when patients continued to demonstrate high viral loads, despite documented viral sensitivity to the medication regimen and caregivers' insistence that medications were being administered regularly. Step 1 was prescribing a home health nurse referral, step 2 was administering directly observed therapy (DOT) while the patient was hospitalized for 4 days, and step 3 was submitting a physician-initiated medical neglect report to the Arkansas Department of Human Services. RESULTS: The results for 6 patients for whom this stepwise approach was initiated are reported. Home health nurse referrals failed to result in sustained improvements in adherence in all 6 cases. Viral load assays performed before and after DOT provided an objective measure of the effect of adherence, with 12 hospitalizations resulting in a mean +/- SD decrease in HIV RNA levels of 1.09 +/- 0.5 log(10) copies per mL, with a range of 0.6 to 2.1 log(10) copies per mL. Four families responded to DOT hospitalization, and sustained decreases in the respective patients' viral loads were noted. In 2 cases, medical neglect reports were submitted when DOT did not result in improved adherence. These patients were eventually placed in foster care, with subsequent improvements in their viral loads and CD4(+) T cell percentages. CONCLUSIONS: Nonadherence with antiretroviral therapy can be established on the basis of persistently elevated HIV RNA levels that decrease with DOT. Nonadherence poses a danger to the child that is grave and potentially irreversible. Caregivers should be offered all available resources to help them adhere to a sound treatment plan. In cases of demonstrated inability to provide needed care, it is necessary to consider seeking child protection, even for apparently healthy children.

Impact of the conjugate pneumococcal vaccine in arkansas.

BACKGROUND: On the basis of the success of the early trials in the prevention of invasive pneumococcal disease in infants and children using a heptavalent conjugate pneumococcal vaccine, the American Academy of Pediatrics recommended in August 2000 that the vaccine be given concurrently with other childhood immunizations. METHODS: Data concerning invasive pneumococcal infections from 1998-2000 were compared with 2001-2003 to assess the impact of the heptavalent pneumococcal conjugate vaccine in Arkansas. Basic demographic data were gathered as well as history of vaccination with the pneumococcal vaccine, underlying medical conditions, site of infection and morbidity and mortality. Pneumococcal isolates were serogrouped or serotyped and penicillin susceptibilities were obtained. RESULTS: The incidence of invasive disease decreased from a high of 5.78/100,000 population to 3.02/100,000 population (P = 0.002). Although the percentage of White patients increased from 2001-2003, the overall incidence of disease did not change. The incidence of disease among Blacks fell from 20.5/100,000 population to 4.9/100,000 population. The greatest decrease of disease occurred in children 24 months of age or younger with the incidence rate falling from 44.2/100,00 population to 8.30/100,000 population (P < 0.02). The incidence among White children 24 months of age or younger fell from 19/100,000 population to 1.8/100,000 population, whereas that of Black children 24 months of age or younger declined from 164/100,000 to 35/100,000. From 1998 to 2000, 3.7/100 cases were from nonvaccine serogroups compared with 44/100 cases from 2001 to 2003 (P < 0.001). In children 24 months of age or younger, the number of nonvaccine isolates increased from 1.3/100 cases to 30.5/100 cases (P < 0.001). Overall 56 (44%) were nonsusceptible to penicillin from 1998 to 2000; that was not significantly different from 2001-2003 when 37 (46%) of 81 isolates were nonsusceptible to penicillin. CONCLUSIONS: A significant decrease of invasive pneumococcal disease has been documented in Arkansas. Of concern, however, is the increasing number of invasive isolates not included in the current vaccine.

Infective endocarditis in Arkansan children from 1990 through 2002.

BACKGROUND: Recent medical and surgical advances have increased the potential risk of endocarditis. Epidemiology, pathogens, morbidity and/or mortality may have evolved in the past decade in pediatric patients diagnosed with endocarditis. METHODS: Retrospective reviews of medical records from Arkansas Children's Hospital were done to identify patients with infective endocarditis from January 1990 through December 2002. Basic demographic and clinical data were gathered and reviewed. RESULTS: Of 76 patients identified, 57 were included based on diagnostic criteria. Congenital heart disease with (56%) and without (25%) correction were the most common risk factors. Echocardiograms revealed vegetations in 67%. Echocardiograms remain relatively deficient in patients with complex cyanotic heart disease (50% positive) vs. those with normal anatomy (83% positive). Streptococci (30%) and Staphylococcus aureus (21%) were the most common organisms identified overall; however, we observed a predominance of enterococci in infants <2 years of age (41%). Our study revealed a reduced rate of complications, especially of the central nervous system (7% vs. 25 and 33% in prior studies); however, our rate of S. aureus was lower (21% vs. 32 and 39%), and this pathogen continues to be associated with a higher incidence of complications. CONCLUSIONS: Infective endocarditis continues to present a difficult challenge in pediatrics; its associated pathogens and outcomes have changed little in the past decade.

Genes of the GadX-GadW regulon in Escherichia coli.

Acid in the stomach is thought to be a barrier to bacterial colonization of the intestine. Escherichia coli, however, has three systems for acid resistance, which overcome this barrier. The most effective of these systems is dependent on transport and decarboxylation of glutamate. GadX regulates two genes that encode isoforms of glutamate decarboxylase critical to this system, but additional genes associated with the glutamate-dependent acid resistance system remained to be identified. The gadX gene and a second downstream araC-like transcription factor gene, gadW, were mutated separately and in combination, and the gene expression profiles of the mutants were compared to those of the wild-type strain grown in neutral and acidified media under conditions favoring induction of glutamate-dependent acid resistance. Cluster and principal-component analyses identified 15 GadX-regulated, acid-inducible genes. Reverse transcriptase mapping demonstrated that these genes are organized in 10 operons. Analysis of the strain lacking GadX but possessing GadW confirmed that GadX is a transcriptional activator under acidic growth conditions. Analysis of the strain lacking GadW but possessing GadX indicated that GadW exerts negative control over three GadX target genes. The strain lacking both GadX and GadW was defective in acid induction of most but not all GadX target genes, consistent with the roles of GadW as an inhibitor of GadX-dependent activation of some genes and an activator of other genes. Resistance to acid was decreased under certain conditions in a gadX mutant and even more so by combined mutation of gadX and gadW. However, there was no defect in colonization of the streptomycin-treated mouse model by the gadX mutant in competition with the wild type, and the gadX gadW mutant was a better colonizer than the wild type. Thus, E. coli colonization of the mouse does not appear to require glutamate-dependent acid resistance.

Gene expression profiling of the pH response in Escherichia coli.

Escherichia coli MG1655 acid-inducible genes were identified by whole-genome expression profiling. Cultures were grown to the mid-logarithmic phase on acidified glucose minimal medium, conditions that induce glutamate-dependent acid resistance (AR), while the other AR systems are either repressed or not induced. A total of 28 genes were induced in at least two of three experiments in which the gene expression profiles of cells grown in acid (pH 5.5 or 4.5) were compared to those of cells grown at pH 7.4. As expected, the genes encoding glutamate decarboxylase, gadA and gadB, were significantly induced. Interestingly, two acid-inducible genes code for small basic proteins with pIs of >10.5, and six code for small acidic proteins with pIs ranging from 5.7 to 4.0; the roles of these small basic and acidic proteins in acid resistance are unknown. The acid-induced genes represented only five functional grouping categories, including eight genes involved in metabolism, nine associated with cell envelope structures or modifications, two encoding chaperones, six regulatory genes, and six unknown genes. It is unlikely that all of these genes are involved in the glutamate-dependent AR. However, nine acid-inducible genes are clustered in the gadA region, including hdeA, which encodes a putative periplasmic chaperone, and four putative regulatory genes. One of these putative regulators, yhiE, was shown to significantly increase acid resistance when overexpressed in cells that had not been preinduced by growth at pH 5.5, and mutation of yhiE decreased acid resistance; yhiE could therefore encode an activator of AR genes. Thus, the acid-inducible genes clustered in the gadA region appear to be involved in glutatmate-dependent acid resistance, although their specific roles remain to be elucidated.