Clinical Characteristics of HLA-B27-Associated Anterior Uveitis in a Finnish Population-Based Cohort.

PURPOSE: To evaluate the clinical characteristics, treatment outcomes and ocular complications in patients with HLA-B27-associated AU compared to those without HLA-B27. METHODS: From the population-based data of all adult patients with AU during 2009-2020 (n = 413), 241 patients tested for HLA-B27 were included. Age of the initial onset, gender, etiology, course of uveitis, visual outcomes and complications were studied. RESULTS: 170 patients (71%) were HLA-B27+ and 71 (29%) HLA-B27-. Mean age at uveitis onset was 37 ± 13 in HLA-B27+ (95% CI, 35.4-39.3) and 43 ± 14 (95% CI, 40.3-46.4) in HLA-B27- patients (p = 0.001). Male:female ratio was 1.1:1 among HLA-B27+ and 0.58:1 (p = 0.024) in HLA-B27- patients. Most patients, 63% in HLA-B27+ and 68% in HLA-B27- had chronic uveitis. Recurrences were noted in 31% in HLA-B27+ group compared to 13%in HLA-B27-. 51% and 17% of HLA-B27+ and HLA-B27- patients, respectively, had systemic disease-associated uveitis. Etiology was Idiopathic in 44% and 69% of HLA-B27+ and HLA-B27- patients, respectively (p < 0.001). After the follow-up, +2 and -4 ETDRS letters changes were noted in HLA-B27+ and HLA-B27- patients (p = 0.005). Ocular complications developed in 43% and 47%, and surgical treatment of complications was required in 20% and 33% of patients in HLA-B27+ and HLA-B27- patients (p = 0.009). 1% (HLA-B27+) and 3% (HLA-B27-) developed visual impairment. CONCLUSION: Our results highlight the differences in the age of uveitis onset, gender distribution, course of uveitis, etiology, and treatment outcomes in HLA-B27+ and HLA-B27-uveitis. HLA-B27 seems to be associated with younger age at uveitis onset, more recurrences, systemic diseases, and better treatment outcomes with less complications.

Comparison of 21 artificial intelligence algorithms in automated diabetic retinopathy screening using handheld fundus camera.

BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes and may lead to irreversible visual loss. Efficient screening and improved treatment of both diabetes and DR have amended visual prognosis for DR. The number of patients with diabetes is increasing and telemedicine, mobile handheld devices and automated solutions may alleviate the burden for healthcare. We compared the performance of 21 artificial intelligence (AI) algorithms for referable DR screening in datasets taken by handheld Optomed Aurora fundus camera in a real-world setting. PATIENTS AND METHODS: Prospective study of 156 patients (312 eyes) attending DR screening and follow-up. Both papilla- and macula-centred 50° fundus images were taken from each eye. DR was graded by experienced ophthalmologists and 21 AI algorithms. RESULTS: Most eyes, 183 out of 312 (58.7%), had no DR and mild NPDR was noted in 21 (6.7%) of the eyes. Moderate NPDR was detected in 66 (21.2%) of the eyes, severe NPDR in 1 (0.3%), and PDR in 41 (13.1%) composing a group of 34.6% of eyes with referable DR. The AI algorithms achieved a mean agreement of 79.4% for referable DR, but the results varied from 49.4% to 92.3%. The mean sensitivity for referable DR was 77.5% (95% CI 69.1-85.8) and specificity 80.6% (95% CI 72.1-89.2). The rate for images ungradable by AI varied from 0% to 28.2% (mean 1.9%). Nineteen out of 21 (90.5%) AI algorithms resulted in grading for DR at least in 98% of the images. CONCLUSIONS: Fundus images captured with Optomed Aurora were suitable for DR screening. The performance of the AI algorithms varied considerably emphasizing the need for external validation of screening algorithms in real-world settings before their clinical application.

What is already known on this topic? Diabetic retinopathy (DR) is a common complication of diabetes. Efficient screening and timely treatment are important to avoid the development of sight-threatening DR. The increasing number of patients with diabetes and DR poses a challenge for healthcare.What this study adds? Telemedicine, mobile handheld devices and artificial intelligence (AI)-based automated algorithms are likely to alleviate the burden by improving efficacy of DR screening programs. Reliable algorithms of high quality exist despite the variability between the solutions.How this study might affect research, practice or policy? AI algorithms improve the efficacy of screening and might be implemented to clinical use after thorough validation in a real-life setting.

Evaluation of cerebrovascular events via retinal angiography during transcatheter aortic valve implantation.

OBJECTIVES: Patients receiving transcatheter aortic valve implantation (TAVI) are elderly with multiple comorbidities and at increased risk of perioperative cerebrovascular events. Retinal vasculature represents a surrogate of central nervous system circulation and is noninvasively achievable by retinal imaging. The aim of this study was to evaluate the applicability of retinal angiography of microvascular complications and association to cerebral ischemic events during TAVI. DESIGN: One hundred patients (male 54%, age: median 82 years, range 64-95 years) undergoing TAVI were recruited for this study. Imaging of retinal vasculature was evaluated with a handheld fundus camera before, during and 1 month after. Cerebrovascular events were determined as a part of contemporary clinical evaluation with cerebral CT and CTA imaging when symptoms occurred. RESULTS: Altogether 66/100 patients (66%) were included in the analysis. In-hospital ischemic event (transient ischemic attack, cerebral infarction) was observed in 1/66 patient (1.5%). Retinal vascular abnormalities occurred in 8/66 patients (12.1%); 4/66 patients (6.1%) were detected with a cholesterol plaque in the retinal artery, 2/66 (3%) a capillary leakage, 1/66 (1.5%) and optic disk hemorrhage and 1/66 (1.5%) a macular bleeding. No significant association between retinal vasculature abnormalities and cerebrovascular events was detected mainly due to the low event rate. CONCLUSIONS: Perioperative evaluation of cerebrovascular ischemia with noninvasive imaging of retinal vasculature is possible in most patients undergoing TAVI. More data is needed to evaluate the association of cerebrovascular events and retinal microvascular abnormalities during the procedure.

Visual Outcomes of Anti-VEGF Treatment on Neovascular Age-Related Macular Degeneration: A Real-World Population-Based Cohort Study.

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated promptly. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in the past two decades. We evaluated the visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. The data included parameters for age, sex, age at diagnosis, laterality, chronicity, symptoms, visual outcomes, lens status, and history of intravitreal injections. A total of 1088 eyes (827 patients) with nAMD were included. Visual acuity was stable or improved in 984 eyes (90%) after an average of 36 ± 25 months of follow-up. Bevacizumab was the first-line drug in 1083 (99.5%) eyes. Vision improved ≥15 ETDRS letters in 377 (35%), >5 ETDRS letters in 309 (28%), and was stable (±5 ETDRS letters) in 298 (27%) eyes after anti-VEGF treatment. The loss of 5 ≤ 15 ETDRS letters in 44 (4%) eyes and ≥15 ETDRS letters in 60 (6%) eyes was noted. At the diagnosis of nAMD, 110 out of 827 patients (13%) fulfilled the criteria for visual impairment, whereas 179 patients (22%) were visually impaired after the follow-up. Improvement or stabilization in vision was noted in 90% of the anti-VEGF-treated eyes with nAMD. In addition, anti-VEGF agents are crucial in diminishing nAMD-related visual impairment.

Encouraging visual outcomes in children with idiopathic and JIA associated uveitis: a population-based study.

BACKGROUND: Pediatric uveitis is typically asymptomatic and may become chronic affecting ocular structures and vision. We evaluated visual outcomes, clinical features, medication, and uveitis activity in children with either idiopathic uveitis (idio-U) or juvenile idiopathic arthritis associated uveitis (JIA-U). METHODS: A longitudinal, population-based cohort study of children with uveitis in 2008-2017. The data included parameters for age, gender, age at diagnosis, laterality, chronicity, anatomical distribution, etiology, systemic association, uveitis activity, medication, and visual outcomes. RESULTS: A total of 119 patients aged < 16 years with uveitis were included. Uveitis was idio-U in 23% and associated with JIA in 77% of cases. 37% of the patients in the idio-U group and 65% in the JIA-U were girls (p = 0.014). The mean age at first uveitis was 10.0 (SD 3.4) years in idio-U and 5.5 (SD 3.3) years in JIA-U (p < 0.001). Anterior location of uveitis was noted in 74% in idio-U and 99% in JIA-U (p < 0.001). Mostly, uveitis was chronic (59% in idio-U and 75% in JIA-U) and bilateral (56% in idio-U and 64% in JIA-U). Topical corticosteroids were initially used by 89% and 100%, systemic corticosteroids by 30% and 27% in some extent during the follow-up, disease-modifying antirheumatic drugs (DMARDs) by 33% and 85% (p < 0.001) of the patients in idio-U and JIA-U, respectively. Biologic disease-modifying antirheumatic drugs (bDMARDs) were more common in JIA-U (55% vs. 15% in idio-U, respectively, p < 0.001). Most patients had normal visual acuity (Snellen > 0.8, [6/7.5]) in the affected eye and bilaterally in 85% idio-U and 70% JIA-U. Only 5 patients (4%) had visual impairment in one, but none in both eyes. Uveitis activity by SUN classification was 0 + in 81% and 72%, 0.5 + in 19% and 25%, and 1 + in 0% and 3% in the idio-U and JIA-U, respectively. CONCLUSIONS: Children with uveitis have good visual acuity and a low rate for visual impairment. In addition, modern treatment with DMARDs and bDMARDs seems to save vision.

Incidence and prevalence of neovascular age-related macular degeneration: 15-year epidemiological study in a population-based cohort in Finland.

BACKGROUND/OBJECTIVES: Neovascular age-related macular degeneration (nAMD) is a common cause for visual impairment in the ageing population. An increasing number of nAMD patients causes significant health burden, although intravitreal anti-VEGF agents have revolutionized nAMD treatment during the past 15 years. We aimed to define incidence and prevalence of nAMD in different age-categories in the anti-VEGF era and to estimate the number of the individuals over 75 years of age in 2050. PATIENTS AND METHODS: We conducted an epidemiological study of the nAMD cohort (n = 2121) in a Finnish population of 410,000 inhabitants. Demographic and clinical data were gathered from Oulu University Hospital's database during 2006-2020. The incidence and prevalence rates were calculated using population data from national registers. The three-year moving average of incidence of nAMD per 100,000 person years was estimated. Prevalence figures were calculated per 100,000 age-specific inhabitants. RESULTS: The average age at the diagnosis of nAMD was 788 years, and 62% of the patients were women. The incidence of nAMD was 71 (95% CI 55-90) and 102 (95% CI 88-118) per 100,000 person years in 2006 and 2020, respectively. During 2006-2020, 1.2- and 2.4-fold increases in nAMD incidence were noted in 75-84 and in 85-96 age groups, respectively. In the oldest 75-84 and 85-96 age categories the nAMD prevalence was 2865/100,000 (3%, 95% CI 2665-3079) and 2620/100,000 (3%, 95% CI 2323-2956), respectively. The proportion of the inhabitants >75 years old is estimated to increase from 10% in 2020 to 17% by 2050. CONCLUSIONS: Our results indicate constant 1.2- and 2.4-fold increases in nAMD incidence during the past 15 years in age groups of 75-84 and 85-96 years, respectively, and 3% prevalence of nAMD in 2020. An almost two-fold increase in the ageing population by the year 2050 may also predict the trends in nAMD.KEY MESSAGESThe results of the current population-based study indicate 1.2- and 2.4-fold increases in the incidence of neovascular AMD (nAMD) during the last 15 years in the Finnish population aged 75-84 and 85-96 years and 3% prevalence of nAMD in 2020.An almost two-fold increase in the number of individuals over 75 years of age by the year 2050 is estimated, which may also predict the trends in nAMD.Intravitreal anti-vascular endothelial growth factor (anti-VEGF)- agents have revolutionized the treatment and prognosis of nAMD. Timely recognition and referral of nAMD patients to ophthalmologist can ensure vision-related functionality especially among the ageing population.

The impact of the image conversion factor and image centration on retinal vessel geometric characteristics.

Background: This study aims to use fundus image material from a long-term retinopathy follow-up study to identify problems created by changing imaging modalities or imaging settings (e.g., image centering, resolution, viewing angle, illumination wavelength). Investigating the relationship of image conversion factor and imaging centering on retinal vessel geometric characteristics (RVGC), offers solutions for longitudinal retinal vessel analysis for data obtained in clinical routine. Methods: Retinal vessel geometric characteristics were analyzed in scanned fundus photographs with Singapore-I-Vessel-Assessment using a constant image conversion factor (ICF) and an individual ICF, applying them to macula centered (MC) and optic disk centered (ODC) images. The ICF is used to convert pixel measurements into µm for vessel diameter measurements and to establish the size of the measuring zone. Calculating a constant ICF, the width of all analyzed optic disks is included, and it is used for all images of a cohort. An individual ICF, in turn, uses the optic disk diameter of the eye analyzed. To investigate agreement, Bland-Altman mean difference was calculated between ODC images analyzed with individual and constant ICF and between MC and ODC images. Results: With constant ICF (n = 104 eyes of 52 patients) the mean central retinal equivalent was 160.9 ± 17.08 µm for arteries (CRAE) and 208.7 ± 14.7.4 µm for veins (CRVE). The individual ICFs resulted in a mean CRAE of 163.3 ± 15.6 µm and a mean CRVE of 219.0 ± 22.3 µm. On Bland-Altman analysis, the individual ICF RVGC are more positive, resulting in a positive mean difference for most investigated parameters. Arteriovenous ratio (p = 0.86), simple tortuosity (p = 0.08), and fractal dimension (p = 0.80) agreed well between MC and ODC images, while the vessel diameters were significantly smaller in MC images (p < 0.002). Conclusion: Scanned images can be analyzed using vessel assessment software. Investigations of individual ICF versus constant ICF point out the asset of utilizing an individual ICF. Image settings (ODC vs. MC) were shown to have good agreement.

Outcomes of 35-year duration of type 1 diabetes and proliferative diabetic retinopathy on functional vision and quality of life: Benefits of good glycemic control.

AIMS: To evaluate clinical outcomes, functional vision and quality of life (QoL) after 35-year duration of type 1 diabetes (T1D) and proliferative diabetic retinopathy (PDR). METHODS: A population-based cohort study of T1D. Data from laboratory tests, ophthalmic examinations, multifunctional vision-test, and 15D-QoL measurements were analysed. RESULTS: 35 % of the original cohort (n = 216) had PDR, and 48 % of them were re-evaluated. They were 41 ± 3 [34-46] years old and 62 % were males. The duration of T1D was 35 ± 4 [29-41] years. 76 % had transdermal glucose monitoring. HbA1c had decreased from 80.1 mmol/mol to 63.6 mmol/mol (p < 0.001). Visual acuity was 73-77 ETDRS-letters. Two patients had visual impairment. Visual field sensitivities were lower in PDR vs. healthy controls (23.2 ± 3.9 dB vs. 26.9 ± 1.0 dB, and 14.9 ± 5.6 dB vs. 21.0 ± 2.0 dB, respectively, p < 0.001). Contrast sensitivity was similar, but the reaction time was longer in the PDR group (490.5 ms vs. 462.8 ms, p = 0.004). QoL-parameters concerning sleeping, usual activities, discomfort and symptoms, and sexual activity had decreased, but improved for mobility and distress. CONCLUSIONS: Long-term visual prognosis and QoL remained good despite the declined functional vision caused by PDR.

Visual outcomes of observation, macular laser and anti-VEGF in diabetic macular edema in type 1 diabetes: a real-world study.

BACKGROUND: The treatment for diabetic macular edema (DME) has revolutionized during the last 15 years after the introduction of intravitreal anti-VEGF agents. The aim of the current study is to evaluate the real-world visual outcomes of diabetic macular edema (DME) treatment in patients with type 1 diabetes (T1D) in long-term follow-up. METHODS: A real-world, descriptive, population-based cohort and follow-up of all patients with T1D and DME in 2006-2020 in 34 communities of the Northern Ostrobothnia Hospital District. The main outcome measures included age, gender, duration of T1D at the onset of DME, stage of retinopathy, treatment of DME (observation, laser, intravitreal treatments, combination), and visual outcomes. RESULTS: A total of 304 eyes of 206 T1D patients with DME were included. 75% (n=155) had non-proliferative diabetic retinopathy during the onset of DME. 15% of the cases were observed, 33% had macular laser, 41% intravitreal anti-VEGF and 12% combination of laser and intravitreal injections. Patients in anti-VEGF and in combination groups gained 4.9 and 5.5 ETDRS letters after the initial DME episode (p<0.001 and p<0.001), and the long-term visual improvements were 4.1 and 5.1 ETDRS letters (p<0.001 and p<0.001), respectively. In observation and laser groups the initial gain of 0.1 (p>0.90) and loss of 0.4 ETDRS letter (p=0.61), respectively, was noted. After the follow-up, a 3.7 ETDRS letter decrease was documented in the observation group (p>0.90) and a 1.1 (p=0.14) ETDRS letter decline in the laser group of patients. At the beginning of treatment, eyes subjected to anti-VEGF alone or in combination with laser had lower visual acuity compared to eyes subjected to observation or macular laser. The average of a 6.1±4.8 anti-VEGF injections were needed to dry DME. Visual impairment due to DME decreased from 2.4% to 1.0% during the 15-year period. CONCLUSIONS: Anti-VEGF alone or in combination with macular laser seems to be beneficial in terms of visual outcomes and treatment stability in T1D patients with central DME. Moreover, satisfying long-term visual outcomes were achieved with anti-VEGF treatment in a real-world setting.

Effect of first-line antifungal treatment on ocular complication risk in Candida or yeast blood stream infection.

OBJECTIVES: Ocular candidiasis (OC) can complicate Candida bloodstream infection (BSI). Antifungal treatment improves the prognosis of patients with BSI, but the effects of choice and timing of first-line medication on OC risk are incompletely understood. We explored the early treatments, risk factors and ocular presentations in Candida BSI. METHODS AND ANALYSIS: All patients (n=304) with Candida BSI during 2008-2017 at Oulu University Hospital were included. Those patients in whom clinical condition was appropriate for ocular examination (OE), including biomicroscopy (n=103), were carefully analysed by ophthalmologists. Criteria for patient selection were considered. Candida and yeast species, antifungal medications, echocardiography, underlying diseases and clinical properties of the patients with Candida BSI were analysed. RESULTS: Clinical condition in 103 patients had been considered appropriate for OE. OC was diagnosed in 33 of the 103 patients. Candida albicans was the most common finding (88%) in OC. Patients in intensive care, alcohol-related conditions or poor prognosis were less frequently examined. Persistent candidemia increased the risk of OC. Chorioretinitis and endophthalmitis were diagnosed in 94% and 48% of the patients with OC, respectively. Any early antifungal treatment decreased the endophthalmitis risk. Echinocandin lowered the OC risk in those with central venous catheters (CVCs) or abdominal malignancy. CONCLUSION: Critical condition of patients with Candida BSI affects the selection and results of OE. OC was associated with C. albicans BSI especially among those with persistent candidemia, CVC or abdominal malignancy. Any early antifungal treatment reduced endophthalmitis risk. Early echinocandin treatment may reduce the risk of OC in selected patients.

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection.

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.

Handheld fundus camera performance, image quality and outcomes of diabetic retinopathy grading in a pilot screening study.

PURPOSE: To compare the performance and image quality of the handheld fundus camera to standard table-top fundus cameras in diabetic retinopathy (DR) screening. The reliability and diagnostic accuracy of DR grading performed by an ophthalmologist and a photographer reader were evaluated. MATERIALS AND METHODS: 157 patients with diabetes, attending screening or follow-up of DR, were evaluated by fundus photographs taken in mydriasis by Optomed Aurora and Canon or Zeiss Visucam fundus cameras. The image quality and the severity of DR were evaluated independently by an ophthalmologist and experienced photographer. The sensitivity, specificity and reliability of the assessments were determined. RESULTS: 1884 fundus images from 314 eyes were analysed. In 53% of all eyes, DR was not present. 10% had mild non-proliferative diabetic retinopathy (NPDR), 16% moderate NPDR, 6% severe NPDR and 16% proliferative diabetic retinopathy (PDR). The DR grading outcomes by Aurora highly equalled to those of Canon or Zeiss (κ = 0.93, 95% CI 0.91 to 0.94), and there was almost perfect agreement in grading between the ophthalmologist and photographer (κ = 0.96, 95% CI 0.95 to 0.97). The image quality of Aurora was sufficient for reliable assessment according to both graders in 84-88% of the cases. CONCLUSION: The Optomed Aurora fundus camera seems appropriate for DR screening. The sufficient image quality and high diagnostic accuracy for DR grading are supportive for a less expensive and easily transportable screening system for DR. Immediate image grading carried out by a photographer would further improve and speed up the screening process in all settings.

A Family With A20 Haploinsufficiency Presenting With Novel Clinical Manifestations and Challenges for Treatment.

BACKGROUND: Tumor necrosis factor α-induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. METHODS: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. RESULTS: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. CONCLUSIONS: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.

Prevalence, incidence and epidemiology of childhood uveitis.

PURPOSE: To analyse the prevalence, incidence and aetiology of paediatric uveitis. METHODS: A retrospective, population-based cohort study of Finnish children with uveitis in Northern Ostrobothnia Hospital District in 2008-2017. The data included parameters for age, gender, age at diagnosis, laterality, chronicity, anatomical distribution of the disease, aetiology and systemic association. RESULTS: One hundred fifty patients aged <16 years (mean age 6.9 ± 3.9 years) with uveitis were included, out of whom 53% were girls. The first uveitis episode occurred at 1-6 years in 59%, and 62% of them were girls. In the age group of 7-15 years, boys were diagnosed with uveitis more frequently than girls (61% versus 39%, respectively). Seventy percent of the girls were diagnosed with their first uveitis episode at the age of 1-6 years, whereas only 48% of the boys were diagnosed at that age. The prevalence of uveitis increased from 64/100 000 children <16 years in 2008 (95% CI, 47.7-84.2) to 106/100 000 in 2017 (95% CI, 84.6-130.2). The incidence of childhood uveitis in 2008-2017 was 14/100 000 person-years in children <16 years (95% CI, 11.3-16.5). Eighty-seven percent of the cases were non-infectious, 9% were infectious, and 3% had masquerade syndromes. Sixty-one percent of patients had juvenile idiopathic arthritis (JIA). CONCLUSION: The prevalence of paediatric uveitis has increased during the last decade in both genders. Uveitis is more frequent in girls, and they were diagnosed at a younger age than boys. Idiopathic cases and JIA accounted for a majority of aetiological features.

Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

Comparison of optic disc evaluation methods in neurology emergency patients.

BACKGROUND: The optic disc examination is critical for the diagnostics of several acute neurological disorders. However, dilation of the pupil is not recommended for neurological patients, which complicates ophthalmoscopy. AIMS OF THE STUDY: Present pilot study compared a portable fundus camera to an ophthalmoscope in fundus examinations of neurological emergency patients. To our knowledge, this is the first comparative study of the subject. The fundus photographs were later reviewed with an ophthalmologist. METHODS: The study included 60 adults, volunteer neurological emergency patients with either headache, cerebrovascular disorder, or acute confusional state (delirium). Patients' non-mydriatic fundus examination was conducted with an ophthalmoscope and a Smartscope Pro fundus camera. RESULTS: Fundus photography succeeded in 56 (93%), partially succeeded in 2 (3%), and failed in 2 (3%) cases compared with ophthalmoscopy that succeeded in 35 (58%), partially succeeded in 14 (23%), and failed in 11 (18%) cases (P < .0005). The researcher and the ophthalmologist agreed in the findings in 54 out of 58 cases (93%). In six cases (7%), the researcher had failed to detect a non-critical ophthalmic finding. CONCLUSIONS: The neurological fundus examination by fundus camera seems to be superior to regular ophthalmoscopy in defining the critical optic disc findings in emergency patients.

Intravitreal bevacizumab improves the clearance of vitreous haemorrhage and visual outcomes in patients with proliferative diabetic retinopathy.

OBJECTIVE: To evaluate the occurrence of vitreous haemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR) and the efficacy of intravitreal bevacizumab (IVB) for VH in 5-year real-life data. METHODS AND ANALYSIS: 850 adult patients with type 1 (T1D) or type 2 diabetes (T2D) with PDR were screened for VH. The effect of IVB was evaluated by the clearage of VH and the change in best corrected visual acuity (BCVA). The rates of VHs, reinjections, macular oedema, complications, additional treatments and outcomes of spontaneous resorption, panretinal photocoagulation or pars plana vitrectomy (PPV) for VH were also investigated. RESULTS: VH occurred in 16% of patients with T1D and 9% of patients with T2D with PDR. 336 VHs in 140 eyes of 103 patients were documented. VH was cleared in 92% of cases in less than 3 months by the initial IVB. IVB was superior to other treatment methods in shortening the time for clearance of VH (Kaplan-Meier, p<0.0001). The average rate of IVB reinjections was 1.7±1.1 and the reinjection interval was 7.2±3.9 weeks. BCVA increased 0.73±0.04 logarithm of the minimum angle of resolution units after IVB (generalised estimating equations, p=0.0004). In 5 years, the patients had 2.2±2.7 recurrence of VHs. A simultaneous 72% decrease in the rate of PPVs was documented (p<0.0001). CONCLUSION: VH occurs mostly in patients with T1D. The therapeutic effect of IVB for VH was significant and led to improved clearance of VH and visual outcome. Moreover, IVB prevented persistent and recurrent VHs and decreased the need for costly PPV.

Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation.

OBJECTIVES: TNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease 'haploinsufficiency of A20' (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway. METHODS: NF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein-protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects. RESULTS: The protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signalling, which led to increased NF-κB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients' immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1ß and interleukin-18. CONCLUSIONS: The current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.