Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

The Importance of Signal Strength Index in Optical Coherence Tomography Angiography:A Study of Eyes with Pseudoexfoliation Syndrome

PURPOSE: To evaluate the effect of the signal strength index (SSI) on a comparison of the vascular and structural OCT measurements between eyes with pseudoexfoliation syndrome (PXF) and healthy controls of Asian-Indian origin. METHODS: In this cross-sectional study, 33 eyes of 33 PXF patients and 40 healthy eyes of 40 controls underwent OCT and OCT angiography (OCTA). Eyes with intraocular pressure (IOP) >21mmHg, glaucomatous disc changes, or any other ocular pathology were excluded. Peripapillary vessel density (VD) and retinal nerve fiber layer (RNFL) thickness were determined from the optic disc scans. Parafoveal VD and ganglion cell complex (GCC) thickness were measured from the macular scans. These parameters were compared between the groups using mixed effect models after adjusting for clinical confounders such as IOP, as well as SSI of the scans. RESULTS: The 2 groups were demographically similar. Average RNFL (94µm vs 100µm, p = 0.01) and GCC (91µm vs 95µm, p = 0.03) were thinner in the PXF group compared to controls. The average peripapillary VD appeared lower in the PXF groups compared to controls (58.2% vs 58.8%, p = 0.04), but after adjusting for IOP and SSI, no difference was noted (p = 0.39). After accounting for confounders, parafoveal VD in the PXF group was significantly lower compared to controls (44.3% vs 46.8%, p = 0.008). CONCLUSION: Peripapillary RNFL thickness, parafoveal GCC thickness and parafoveal VD were decreased in eyes with PXF when compared to controls. VD measurements are associated with the SSI and, therefore, clinicians and researchers evaluating OCTA scans quantitatively must consider the SSI value during analysis and interpretation

A comparison of the diagnostic ability of vessel density and structural measurements of optical coherence tomography in primary open angle glaucoma.

PurposeTo compare the diagnostic abilities of vessel density measurements of the optic nerve head (ONH), peripapillary and macular regions on optical coherence tomography (OCT) angiography in eyes with primary open angle glaucoma (POAG) with that of the ONH rim area, peripapillary retinal nerve fiber layer (RNFL) thickness and the macular ganglion cell complex (GCC) thickness measurements.MethodsIn a cross sectional study, 78 eyes of 50 control subjects and 117 eyes of 67 POAG patients underwent vessel density and structural measurements with spectral domain OCT. POAG was diagnosed based on the masked evaluation of optic disc stereo photographs. Area under receiver operating characteristic curves (AUC) and sensitivities at fixed specificities of vessel densities in ONH, peripapillary and macular regions were compared with rim area, RNFL and GCC thickness.ResultsThe AUC (sensitivity at 95% specificity) of average vessel densities within the ONH, peripapillary and macular region were 0.77 (31%), 0.85 (56%) and 0.70 (18%) respectively. The same of ONH rim area, average RNFL and GCC thickness were 0.94 (83%), 0.95 (72%) and 0.93 (62%) respectively. AUCs of vessel densities were significantly lower (p<0.05) than that of the corresponding structural measurements. Pre-treatment IOP (coefficient: 0.08) affected (p<0.05) the AUC of ONH vessel density but not of any other vessel density or structural measurements.ConclusionsDiagnostic abilities of ONH, peripapillary and the macular vessel densities in POAG were significantly lower than ONH rim area, peripapillary RNFL and macular GCC measurements respectively. At fixed levels of glaucoma severity, the diagnostic ability of the ONH vessel density was significantly greater in eyes with higher pre-treatment IOP

Optical Coherence Tomography Angiography and Visual Field Progression in Primary Angle Closure Glaucoma.

PrecisLower whole enface disc (coefficient: 0.02, P=0.03) and macular vessel densities (coefficient: 0.04, P=0.02) on optical coherence tomography angiography (OCTA) were significantly associated with faster rate of mean deviation (MD) decline.PurposeTo evaluate the association between OCTA features and prior visual field (VF) progression in primary angle closure glaucoma (PACG).MethodsIn a cross-sectional study, 46 eyes of 31 PACG patients with 5 reliable VF examinations performed over ≥3 years of follow-up underwent OCTA imaging. Effect of clinical (age, sex, number of antiglaucoma medications, mean, and SD of intraocular pressure during follow-up), optical coherence tomography (average retinal nerve fiber layer and ganglion cell complex thickness) and OCTA (whole enface vessel density of disc and macular scan, deep-layer microvascular dropout) parameters on the rate of MD change was evaluated using linear mixed models.ResultsAverage (±SD) MD of the baseline VF was -7.4±7.3 dB, and rate of MD change was -0.32±0.29 dB/y. Whole enface vessel density of disc and macular scans was 39.5%±8.1% and 38.7%±4.4%, respectively. Microvascular dropout was noted in 33.3% of the eyes. Multivariate mixed models showed that lower whole enface disc (coefficient: 0.02, P=0.03) and macular vessel densities (coefficient: 0.04, P=0.02) were significantly associated with faster rate of MD decline. Other factors significantly associated with faster progression in multivariate models were older age (coefficient: -0.02, P<0.05) and the presence of systemic hypertension (coefficient: -0.37, P=0.01) and diabetes (coefficient: -0.28, P=0.05).ConclusionsLower superficial vessel density measured using OCTA was significantly associated with faster VF progression in PACG. In these eyes, OCTA parameters can serve as biomarker suggestive of past VF progression

Choroidal Microvascular Dropout in Pseudoexfoliation Glaucoma.

PurposeTo compare the prevalence of choroidal microvasculature dropout (CMvD) in pseudoexfoliation glaucoma (PXG) and disease severity-matched primary open-angle glaucoma (POAG) eyes.MethodsIn a cross-sectional study, 39 eyes with PXG (33 patients) and 39 glaucoma severity-matched POAG eyes (34 patients) underwent visual fields, optical coherence tomography and optical coherence tomography angiography examination. Peripapillary vessel density (VD) was evaluated from the radial peripapillary capillary slab, parafoveal VD was measured on the superficial vascular plexus slab of the macula, and CMvD was evaluated on the choroidal slabs of the optic disc scan.ResultsThe PXG and POAG groups were similar with respect to average mean deviation on visual fields (-12.1 vs. -12.0 decibel, P = 0.96) and average peripapillary retinal nerve fiber layer thickness on optical coherence tomography (71 vs. 74 μ, P = 0.29). Average peripapillary superficial VD (49.7% vs. 51.3%, P = 0.35) and parafoveal VD (44.8% vs. 45.8%, P = 0.33) were similar between the PXG and POAG groups. CMvD was seen in 18 PXG and 31 POAG eyes (46.2% vs. 79.5%, P = 0.002). On multivariate analysis that accounted for the severity of glaucoma, the odds of CMvD was significantly lower in the PXG group when compared with the POAG group (odds ratio: 0.18-0.21, P < 0.01).ConclusionsThe prevalence of CMvD was significantly lower in the PXG eyes when compared with the POAG eyes

Response to Letter to the Editor

PrecisLower whole enface disc (coefficient: 0.02, P=0.03) and macular vessel densities (coefficient: 0.04, P=0.02) on optical coherence tomography angiography (OCTA) were significantly associated with faster rate of mean deviation (MD) decline.PurposeTo evaluate the association between OCTA features and prior visual field (VF) progression in primary angle closure glaucoma (PACG).MethodsIn a cross-sectional study, 46 eyes of 31 PACG patients with 5 reliable VF examinations performed over ≥3 years of follow-up underwent OCTA imaging. Effect of clinical (age, sex, number of antiglaucoma medications, mean, and SD of intraocular pressure during follow-up), optical coherence tomography (average retinal nerve fiber layer and ganglion cell complex thickness) and OCTA (whole enface vessel density of disc and macular scan, deep-layer microvascular dropout) parameters on the rate of MD change was evaluated using linear mixed models.ResultsAverage (±SD) MD of the baseline VF was -7.4±7.3 dB, and rate of MD change was -0.32±0.29 dB/y. Whole enface vessel density of disc and macular scans was 39.5%±8.1% and 38.7%±4.4%, respectively. Microvascular dropout was noted in 33.3% of the eyes. Multivariate mixed models showed that lower whole enface disc (coefficient: 0.02, P=0.03) and macular vessel densities (coefficient: 0.04, P=0.02) were significantly associated with faster rate of MD decline. Other factors significantly associated with faster progression in multivariate models were older age (coefficient: -0.02, P<0.05) and the presence of systemic hypertension (coefficient: -0.37, P=0.01) and diabetes (coefficient: -0.28, P=0.05).ConclusionsLower superficial vessel density measured using OCTA was significantly associated with faster VF progression in PACG. In these eyes, OCTA parameters can serve as biomarker suggestive of past VF progression