Lateral Globe Exposure Associated With Graves Upper Eyelid Retraction: The Influence of the Superior Complex Enlargement and Proptosis.

PURPOSE: To investigate the association of the lateral exposure of the globe with proptosis and the enlargement of the superior complex (SC) (levator palpebrae superioris muscle + superior rectus muscle) in patients with Graves upper eyelid retraction. METHODS: Twenty-eight patients with upper lid retraction secondary to Graves orbitopathy and 28 controls matched by age and gender participated in the study. The variables exophthalmometry, margin-reflex distance 1, and upper lid fissure temporal and nasal areas were assessed. Coronal CT scans were evaluated for the measurement of the SC area. A 5% level of significance was assumed for analysis. RESULTS: Abnormal temporal nasal area differences (T-N), defined as values above the superior limit of the control distribution (15.58mm2) were detected in 18 patients. Multiple regression analysis showed a significant correlation of abnormal temporo-nasal asymmetries with the SC area and the proptosis (T-N = -6.7 + 0.62* proptosis + 12.3 SC area, R2 = 0.37; p = 0.003). CONCLUSION: The etiology of the enhanced lateral globe exposure is not unifactorial. SC enlargement and, to a lesser extent, proptosis are important factors correlated to lateral globe exposure.

Orbital Pigmented Epithelioid Melanocytoma Tumor Associated With Nevus of Ota (Oculodermal Melanocytosis).

The authors report a patient with nevus of Ota (oculodermal melanocytosis) who presented with pigmented epithelioid melanocytoma in the right orbit. A 36-year-old female patient attended with proptosis OD and diplopia for 3 months. MRI disclosed an expansive lesion adhered to the right inferior rectus muscle, enlargement of the superior orbital fissure, and filling of the right cavernous sinus. Excision of the orbital mass through a transconjunctival inferior fornix access disclosed a heavily pigmented lesion. Anatomopathological study revealed a diagnosis of pigmented epithelioid melanocytoma. A positron emission tomography scan did not show any metastasis. The patient was submitted to radiotherapy, had an improvement of the proptosis and diplopia, and showed no distant metastases for 3 years now. Pigmented epithelioid melanocytoma belongs to the group of heavily pigmented neoplasms, as do atypical blue nevus, which is characterized by prominent melanin production and a low degree of malignancy.

Spontaneous Blinking Kinematics After Frontalis Muscle Flap Advancement.

PURPOSE: To measure the spontaneous blinking metrics after blepharoptosis correction with frontalis muscle flap advancement. METHODS: A video system was employed to measure the amplitude and velocity of spontaneous blinking of 24 eyelids after the frontalis muscle flap surgery for blepharoptosis correction. A control group with no eyelid disorders was also measured. The data of 13 eyelids who had frontalis slings with autogenous fascia, which were previously collected with the same method in another study, were used for comparison. Digital images were used to measure the superior margin reflex distance and the presence of lagophthalmos during a gentle closure of the palpebral fissure. Superficial keratitis was assessed by corneal biomicroscopy. RESULTS: The mean amplitude of spontaneous blinking was 6.3 mm in controls, 2.6 mm in the frontalis flap patients, and 2.1 mm in the fascia sling group. The mean blink velocity was 133.8 mm/second in controls, 39.0 mm/second (3.7 standard error) after the frontalis flap, and 36.3 mm/second in patients with frontalis sling with fascia. For these 2 parameters, there was no statistical difference between the surgical groups, but a significant reduction when compared with the control group. No significant association was found between lagophthalmos and keratitis and the surgical procedure. CONCLUSIONS: There is no difference between the blinking metrics of eyelids operated using the frontalis muscle flap advancement technique or frontalis sling with autogenous fascia. The presence of lagophthalmos and keratitis also does not differ between the 2 procedures.

CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers activation of the NLRP3 inflammasome, which promotes inflammation and aggravates severe COVID-19. Here, we report that SARS-CoV-2 induces upregulation and activation of human caspase-4/CASP4 (mouse caspase-11/CASP11), and this process contributes to NLRP3 activation. In vivo infections performed in transgenic hACE2 humanized mice, deficient or sufficient for Casp11, indicate that hACE2 Casp11-/- mice were protected from disease development, with the increased pulmonary parenchymal area, reduced clinical score of the disease, and reduced mortality. Assessing human samples from fatal cases of COVID-19, we found that CASP4 was expressed in patient lungs and correlated with the expression of inflammasome components and inflammatory mediators, including CASP1, IL1B, IL18, and IL6. Collectively, our data establish that CASP4/11 promotes NLRP3 activation and disease pathology, revealing a possible target for therapeutic interventions for COVID-19.

Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation.

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.

Perceived Risk of HIV Infection and Acceptability of PrEP among Men Who Have Sex with Men in Brazil.

The HIV epidemic affects men who have sex with men (MSM) disproportionally in Brazil, and pre-exposure prophylaxis (PrEP) is effective for preventing HIV in this population. However, low perceived risk of HIV may influence the acceptability and decision to use PrEP. This study estimated the association between self-perception of HIV risk and acceptability of daily oral PrEP among Brazilian MSM. Respondent-driven sampling (RDS) was used for behavioral and biological surveillance to recruit 4,176 MSM 18 years or over in 12 Brazilian cities in 2016. Results were weighted using Gile's estimator in RDS Analyst software. Adjusted odds rations (OR) with 95% confidence intervals were calculated using multivariate logistic regression. Acceptability of daily oral PrEP was high (69.7%) among the 3,544 MSM available for analysis. Most participants self-reported low or moderate risk of HIV infection (67.2%) and a small proportion (9.3%) reported high risk. A dose-response relationship was observed between acceptability of PrEP and self-reported risk: PrEP acceptability was 1.88 times higher (OR 1.8; 95% CI: 1.24-2.85) among MSM whose perceived risk of HIV infection was low or moderate, and 5 times higher (OR 5.68; 95% CI: 2.54-12.73) among those who self-reported high risk compared to MSM reporting no HIV risk. MSM with the highest risk perception of HIV reported higher rates of PrEP acceptability. Given the availability of daily oral PrEP in the public health care system in Brazil, we suggest emphasizing counseling about self-perception of HIV risk as part of routine HIV prevention services.

Blinking Parameters Do Not Normalize After Botulinum Toxin Therapy in Blepharospasm and Hemifacial Spasm Patients.

BACKGROUND: Little is known regarding changes induced by botulinum toxin injections on blinking parameters in blepharospasm (BSP) and hemifacial spasm (HFS) patients. The purpose of this study was to investigate objective changes induced by botulinum toxin (BoNT) injections on blinking parameters in BSP and HFS patients. METHODS: Thirty-seven patients with BSP and HFS were evaluated before and 30 days after receiving onabotulinumtoxinA injections. Twelve age-matched control subjects were also assessed. Pretreatment and post-treatment parameters were assessed and compared with normal controls. A high-speed camera and microlight-emitting diodes were used to register the blinking in patients and control groups. Outcomes were blinking frequency, amplitude, and maximum velocity of eyelid closure. RESULTS: BoNT injections led to a significant reduction in all parameters, compared with baseline, in BSP and on the affected side in HFS, respectively: 22% ( P < 0.001) and 20% ( P = 0.015) in amplitude; 21% ( P = 0.04) and 39% in frequency ( P = 0.002); and 41% ( P < 0.001) and 26% ( P = 0.005) in maximum closing velocity. Blinking amplitude ( P = 0.017 and P = 0.019) and velocity ( P < 0.001 for both groups) were significantly lower at 30 days on BSP and on the affected HFS side, when compared with controls. BSP and HFS patients presented a significantly lower velocity of eyelid closure, even before BoNT, compared with controls ( P = 0.004. and P < 0.001, respectively). CONCLUSIONS: Although blinking frequency became close to normal, amplitude and velocity after BoNT applications were significantly lower in BSP and on the affected side of HFS patients when compared with age-matched normal controls, demonstrating that blinking parameters do not normalize after treatment. The velocity of eyelid closure was shown to be significantly lower, even before BoNT treatment, when compared with control subjects.

The Relation of the Anterior Ethmoidal Foramen to the Cranial Base.

PURPOSE: To perform a radiological analysis of the relation of the anterior ethmoidal foramen (AEF) to the cranial base and olfactory fossa (OF). METHODS: Retrospective analysis of computed tomography coronal scans of 35 orbits of 35 patients with Graves orbitopathy. Following a standard multiplanar reconstruction of the orbit, the authors measured the vertical and the horizontal distances of the AEF to the cranial base and to the lateral border of the OF, respectively. The height of the OF was measured at the level of the AEF and at the position of Keros classification. The presence of supraorbital ethmoid cells (SOEC) was also recorded. RESULTS: The vertical distance of the AEF to the cranial base ranged from 0.1 to 7.3 mm with a mean = 2.5 mm (SD = 2.17). In 47.5% of the orbits the foramen was adjacent (<1 mm) to the cranial base. The horizontal distance of the AEF to the lateral border of the OF ranged from 2.3 to 9.5 mm (mean = 5.4 mm, SD = 1.98). The presence of an SOEC (n = 12) increased significantly both the distance from the AEF to the cranial base and to the lateral border of the OF. The height of the OF at the level of AEF is not correlated with the depth of the OF at the level of Keros classification. CONCLUSIONS: In the absence of supraorbital pneumatization, the AEF location is a dangerous landmark for the upper limit of the transconjunctival medial wall decompression.

Bilateral Intraorbital Opticmeningoceles in Joubert Syndrome.

Congenital opticmeningoceles was the term coined to describe large pseudocystic lesions of the intraorbital segment of the optic nerve. This extremely rare congenital anomaly was reported unilaterally only in nonsyndromic patients with fully developed eyes. The authors describe here a 10-month-old girl with a previous diagnosis of Joubert syndrome who presented with the same type of optic nerve malformation in OU. Molecular genetic analysis disclosed a pathogenic variant of the TMEM67 gene which is associated with various types of ciliopathies.

Medial Oblique Eyelid Split Orbitotomy.

PURPOSE: The authors describe their experience with a variant of the split orbitotomy with a small medial oblique transmarginal incision for approaching a variety of lesions involving the superonasal aspect of the orbit. METHODS: Retrospective review of medical records and clinical photographs of all patients who underwent an unilateral medial oblique incision to access various intraconal lesions abutting the superomedial quadrant of the orbit. The curvature of the medial contour of the operated and contralateral eyelids were expressed with Bézier functions and compared using the R-squared coefficient of determination (R 2 ). RESULTS: Twenty-three patients were submitted to this surgical technique for approaching various unilateral lesions on the superonasal quadrant of the orbit. Excellent cosmesis was achieved in all eyelids, with almost imperceptible scars, and no ptosis or retraction. There was no significant difference between the postoperative medial contour of the operated and the contralateral eyelid, with R 2 ranging from 0.896 to 0.999, mean 0.971. CONCLUSIONS: The authors' results show that the modified eyelid split approach provides a wide exposure of the superonasal quadrant of the orbit with no risk of eyelid dysfunctions or significant scars.

A quantitative analysis of the brow shape after frontalis muscle contraction.

PURPOSE: To measure the changes of the eyebrow's contour after frontalis muscle (FM) contraction. METHODS: Two consecutive pictures of the eyes and frontal region of 36 volunteers (15 men and 21 women) were obtained with the forehead relaxed and upon maximal frontalis muscle contraction. Bézier lines representing the brows' contours, obtained with the ImageJ software, were graphically sampled with a resolution of 0.025 mm. The contours of the relaxed and elevated brows were compared regarding the position of the contour peak (CP), the degree of elevation of brow central point, and the medial and lateral areas outlined between the brow contours before and after frontalis contraction. The asymmetry of the brow contour after FM contraction was calculated by the Naeije formula as (Medial-Lateral)/(Medial + Lateral). A difference of 10% or less between the lateral and medial areas was taken as a cutoff value for symmetrical brow elevation. RESULTS: In 62 (86.1%) of the eyes, the location of the brow's CP was lateral to the brow's midpoint. When the brows were raised, the CP of 60% of the brows was displaced medially and 40% laterally. The motion of the CP with medial displacement (mean = 3.7 mm) was significantly larger than those displaced laterally (mean = 1.9 mm) decreasing the number of brows with lateral peaks from 62 (86.1%) to 54 (75%). No difference was observed between the mean elevation of the central point of the brow for males (7.9 mm (3.2 SD) and females (7.4 mm, 3.0 SD). In 58.3% of the sample, the positional change of the medial and lateral sectors of the brows was symmetrical, and among the 41.7% asymmetrical cases, the elevation of the medial side was higher than the lateral in 66.7% of the brows. CONCLUSIONS: The brow changes during FM contraction concur well with the anatomic data of the FM shape. The contour of most brows is displaced toward the medial direction when the brow is elevated. The pattern of brow shape change is an indication of the FM anatomy and must be carefully analyzed before any procedure involving the FM, such as chemodenervation injections or frontalis slings for blepharoptosis correction.

Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila.

Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1-/- (and Casp1/11-/-) mice are only partially susceptible to L. pneumophila and do not phenocopy Nlrc4-/-mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11-/- and Casp8/1/11-/- mice recapitulate the full susceptibility of Nlrc4-/- mice. Gsdmd-/- mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd-/-Casp7-/- mice are as susceptible as the Nlrc4-/- mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.

Involvement of Multiple Trigeminal Nerve Branches in IgG4-Related Orbital Disease.

PURPOSE: To describe the occurrence of multiple trigeminal nerves (TGNs) enlargement in patients with orbital IgG4-related disease. METHODS: Retrospective review of MRI findings and medical records of 6 patients (10 orbits) with orbital IgG4-related disease and enlargement of more than 1 TGN. Orbital biopsies were performed in all cases revealing the typical lymphoplasmacytic infiltrate with significant plasma cell positivity for IgG4 (IgG4+/IgG ratio ≥ 40%). Three experienced neuroradiologists reviewed the MRI sequences using a digital imaging viewer system (Horos, https://horosproject.org/). RESULTS: Bilateral involvement of at least 2 TGNs divisions was detected in all 6 patients. Enlargement of both V1 and V2 nerves was diagnosed in 5 patients, and in 3 cases, all TGN divisions were involved. V2 nerves were the most affected. In this division, all 12 infraorbital nerves were enlarged, followed by lesser palatines (10/83.3%), superior alveolar (10/83.3%), and zygomatic (6/50%). V1 and V3 nerves were less affected albeit 9 (75%) frontal branches (V1), and 50% of the inferior alveolar (V3) nerves were also enlarged. CONCLUSIONS: Widespread involvement of the TGN is an important feature of IgG4-related disease.

Deep lateral orbital decompression for Graves orbitopathy: a systematic review.

PURPOSE: To systematically review the literature on the deep lateral orbital decompression (DLD). METHODS: The authors searched the MEDLINE, Lilac, Scopus, and EMBASE databases for all articles in English, Spanish, and French that used as keywords the terms orbital decompression and lateral wall. Two articles in German were also included. Data retrieved included the number of patients and orbits operated, types of the approach employed, exophthalmometric and horizontal eye position changes, and complications. The 95% confidence intervals (CI) of the mean Hertel changes induced by the surgery were calculated from series with 15 or more data. RESULTS: Of the 204 publications initially retrieved, 131 were included. Detailed surgical techniques were analyzed from 59 articles representing 4559 procedures of 2705 patients. In 45.8% of the reports, the orbits were decompressed ab-interno. Ab-externo and rim-off techniques were used in 25.4% and 28.8% of the orbits, respectively. Mean and 95% CI intervals of Hertel changes, pooled from 15 articles, indicate that the effect of the surgery is not related to the technique and ranges from 2.5 to 4.5 mm. The rate of new onset of diplopia varied from zero to 8.6%. Several complications have been reported including dry eye, oscillopsia, temporal howling, lateral rectus damage, and bleeding. Unilateral amaurosis and subdural hematoma have been described in only one patients each. CONCLUSIONS: The low rate of new-onset diplopia is the main benefit of DLD. Prospective studies are needed to compare the rate of complications induced by the 3 main surgical techniques used.

Evaluation of botulinum toxin effects in hemifacial spasm patients: correlation between clinical rating scales and high-speed video system measurements.

The purpose of this study was to compare the scores of two clinical rating scales and high-speed video system measurements obtained during spontaneous eyelid movements in hemifacial spasm (HFS) patients before and after treatment. Patients were evaluated before and 30 days after receiving treatment with onabotulinumtoxinA injections. Using a high-speed video system, the eyelid movements were recorded bilaterally for 3 min and the energy power generated by the upper eyelid during spontaneous eyelid movements was assessed before and after treatment. The scores of the Jankovic rating scale (JRS) and Hemifacial Spasm Grading System (HSGS) were also assessed before and after treatment. The authors studied 22 patients. Significant reduction in JRS and HSGS scores and in the energy generated by the upper eyelid was observed after treatment. A power spectrum of less than 23,000 was associated with JRS and HSGS scores less than 4 and 6.25, respectively and a power spectrum greater than or equal to 23,000 was associated with JRS and HSGS scores greater than or equal to 4 and 6.25, respectively (p < 0.0001 and p = 0.0025). Rating systems are easy to use, but they may exhibit limitations in sensitivity to assess differences between distinct disease patterns and between subtle differences in treatment responses. The high-speed video system permits a greater degree of accuracy, which allows for the assessment of differences in eyelid movement patterns and would permit better tailoring of treatment to patients. However, simpler devices employing this system would need to be developed, so that it could be used in clinical practice.

Analysis of blink activity and anomalous eyelid movements in patients with hemifacial spasm.

To assess spontaneous blinking and anomalous eyelid movements in patients with hemifacial spasm with an emphasis on interocular differences. Spontaneous eyelid movements were registered bilaterally for 3 min using a high-speed video camera in 28 patients with hemifacial spasm (HFS) who had not been treated with botulinum toxin injections for at least 5 months. The degree of blink conjugacy, maximum velocity, and amplitude of the closing phase of the blinks were determined for the affected and non-affected sides. Out of the 28 subjects, 23 (82%) presented with abnormal nonconjugate spasms that were similar to blinks, and in 17 (61%), high-frequency eyelid twitches were detected between blinks on the affected eye. The rate of nonconjugate blink-like spasms ranged from 0.3 to 24.7 movements/min. With regard for conjugate blinks, there was no significant interocular difference in amplitudes or eyelid closure velocities. The amplitude and velocity were significantly lower for nonconjugate movements than for spontaneous blinks. HFS is a unique condition in which complex patterns of eyelid movements, including both conjugate and nonconjugate movements, are present. Conjugate movements correspond to spontaneous blinking, and the same metrics were observed in affected and non-affected eyes. Nonconjugate movements correspond to anomalous nonconjugate blink-like spasms and high-frequency eyelid twitches in the affected eye, both of which were characterized by lower amplitudes and velocities than were observed in conjugate movements.

Long-Term Results of the Surgical Management of the Upper Eyelids in "Ablepharon"-Macrostomia Syndrome.

PURPOSE: To describe the late results of the placement of skin graft over conjunctiva-Müller muscle complex in 3 patients with ablepharon-macrostomia syndrome (AMS) and to review the procedures used to manage the upper eyelids in AMS. METHODS: The authors searched the Pubmed database for all articles that used the term "ablepharon-macrostomia syndrome" in any field. Data collection included description of eyelid changes, age at surgery, status of the cornea before surgery, type of eyelid repair, and final outcome. Two previously reported siblings were reevaluated 10 and 15 years after a single reconstructive operation. A new case from Peru is also described. RESULTS: Only 15 patients with AMS have been described in 12 articles. In 60% of the cases, the lids were described as absent. The surgical modalities employed to reconstruct the upper eyelids were quite variable, including local flaps, lid sharing procedures, and even a masquerade flap. At long-term follow-up, all 3 cases who underwent upper eyelid lengthening with full thickness skin grafts placed over Müller muscle had clear corneas with a small amount of lagophthalmos. CONCLUSIONS: The lids in AMS are not absent and should not be managed with complex reconstructive techniques. Full thickness skin grafts placed over the inner aspect of the palpebral conjunctiva allow permanent eye protection.The upper eyelids in ablepharon-macrostomia syndrome can be permanently lengthened with full thickness skin grafts over Müller muscle.

Woakes Syndrome: A Rare Cause of Proptosis due to Sinonasal Polyposis.

The authors report 2 consecutive adult male patients, aged 61 and 38 years, who presented with painless unilateral proptosis. Their past medical histories were negative for asthma, allergies, and Graves disease. On examination, the nose bridge of the eldest patient was clearly enlarged. Computed tomography scans of the orbits and paranasal sinuses showed in both patients the same radiologic pattern of hyperdense ethmoidal opacifications and expansion of the inferomedial orbital floor. Histopathological analysis of the ethmoidal cells mucosa obtained during inferomedial decompression revealed benign sinonasal polyposis. These cases demonstrate that asymptomatic sinonasal polyposis can be a rare cause of proptosis.

The Revised Direct Transconjunctival Approach to the Orbital Floor.

PURPOSE: To review common surgical approaches to the orbital floor and to evaluate the utility of canthal-sparing, single incision transconjunctival method. METHODS: A retrospective chart review of a consecutive series of patients who underwent transconjunctival, direct incision surgery without eyelid dissection or lateral canthotomy and inferior cantholysis and review of the literature were conducted. RESULTS: Twenty-three consecutive patients (33 orbits) were operated using a canthal-sparing direct single cut approach, including 10 unilateral pediatric orbital floor fractures, 1 orbital floor implant removal, 2 unilateral post-traumatic enophthalmos repairs, and 10 bilateral orbital floor decompressions. Surgical exposure was adequate to complete the surgical objective in each patient. Mean follow up was 13 months and no complications were observed. CONCLUSIONS: The transconjunctival approach to the orbital floor can be performed using a pre- or post-septal dissection, with infratarsal or fornix incision commonly associated with lateral canthotomy and inferior cantholysis. The direct approach spares the lateral canthus, minimizes lower eyelid dissection, and provides rapid and effective access to the inferior orbital rim and orbital floor. It offers sufficient exposure to allow insertion of large floor implants even in children. Although apparently abandoned in the recent literature, canthal-sparing technique is a useful method for the management of orbital floor fractures, enophthalmos correction, implant removal, and orbital decompression.