Changing Trends in Uveitis in the United Kingdom: 5000 Consecutive Referrals to a Tertiary Referral Centre.

PURPOSE: To demonstrate changes in the demography and diagnosis of uveitis in a specialist clinic in the United Kingdom. METHODS: Retrieval of data including all new referrals to Manchester Uveitis Clinic from 1991 to 2020. The incidence and proportions of diagnoses between 4 quartiles was compared. RESULTS: 5000 patients with uveitis were seen. Referral rates trebled over time. Highly significant increases in referrals were seen for multiple evanescent white dot syndrome-spectrum disorders, syphilis and tuberculosis; increases were also seen for herpetic retinitis, vitreoretinal lymphoma and sarcoidosis. Highly significant decreases were seen for Fuchs' uveitis, Behçet's uveitis and ocular toxoplasmosis. CONCLUSIONS: Subspecialisation and de-skilling has changed referral patterns to specialist clinics; changes cannot be entirely attributed to disease incidences, which also vary between countries. International data are non-comparable. There are clear changes in referral patterns and disease incidence in this population, influenced by evolving diagnosis. Local data should steer care planning.

Detection of Pre-clinical Involvement of the Second Eye in Viral Acute Retinal Necrosis Using Optical Coherence Tomography.

PURPOSE: To report the detection of retinitis in the second eye of a patient with viral acute retinal necrosis (ARN), before the appearance of clinical change, using swept-source optical coherence tomography. RESULTS: A 63 year-old male developed right-sided varicella-zoster virus (VZV) ARN, confirmed with aqueous sampling. High-dose intravenous aciclovir caused renal impairment and was suspended for two-days. One day later, left eye macular SS-OCT revealed focal retinal thickening and disruption of retinal architecture without clinically detectable retinitis. The patient was asymptomatic. Aqueous sampling was VZV PCR positive. He received bilateral foscarnet injections and renal adjusted dose of aciclovir. The left OCT signs improved with full restoration of retinal layers. CONCLUSIONS: We report for the first time the use of OCT to detect pre-clinical second eye retinitis during ARN. Prompt diagnosis and combined systemic and intensive local antiviral therapy resulted in a favourable structural and functional outcome.

White matter abnormalities associated with ADHD outcomes in adulthood.

It remains unclear if previously reported structural abnormalities in children with ADHD are present in adulthood regardless of clinical outcome. In this study, we examined the extent to which focal-rather than diffuse-abnormalities in fiber collinearity of 18 major white matter tracts could distinguish 126 adults with rigorously diagnosed childhood ADHD (ADHD; mean age [SD] = 34.3 [3.6] years; F/M = 12/114) from 58 adults without ADHD histories (non-ADHD; mean age [SD] = 33.9 [4.1] years; F/M = 5/53) and if any of these abnormalities were greater for those with persisting ADHD symptomatology. To this end, a tract profile approach was used. After accounting for age, sex, handedness, and comorbidities, a MANCOVA revealed a main effect of group (ADHD < non-ADHD; F[18,155] = 2.1; p = 0.007) on fractional anisotropy (FA, a measure of fiber collinearity and/or integrity), in focal portions of white matter tracts involved in visuospatial processing and memory (i.e., anterior portion of the left inferior longitudinal fasciculus, and middle portion of the left and right cingulum angular bundle). Only abnormalities in the anterior portion of the left inferior longitudinal fasciculus distinguished probands with persisting versus desisting ADHD symptomatology, suggesting that abnormalities in the cingulum angular bundle might reflect "scarring" effects of childhood ADHD. To our knowledge, this is the first study using a tract profile approach to identify focal or widespread structural abnormalities in adults with ADHD rigorously diagnosed in childhood.

Management of subluxed and dislocated intraocular lenses in patients with uveitis: a practical approach.

Purpose: To describe practical approaches to the management of subluxed or dislocated intraocular lenses (IOL) in patients with uveitis.Patients and methods: Retrospective case series from a specialist uveitis clinicResults: Fifteen IOLs in 13 patients were subluxed inferiorly (12) or dislocated into anterior chamber (2) or vitreous (1) at a mean delay of 12 years after cataract surgery. Six eyes required vitrectomy and seven IOL explantation. A dislocated IOL was repositioned by scleral fixation in one, and a new IOL was implanted in three (two scleral-sutured, one iris-claw). Eight were observed without surgery and 7 were left functionally aphakic (4 corrected with contact lens). The mean final best-corrected visual acuity was 0.6 LogMAR.Conclusions: There are several management choices for IOL dislocation which should take into account the degree of uveitis, patient age and expectations. We present a pragmatic approach: surgery can often be avoided in this high-risk group.

Management of Ganciclovir Resistant Cytomegalovirus Retinitis in a Solid Organ Transplant Recipient: A Review of Current Evidence and Treatment Approaches.

Purpose: Cytomegalovirus retinitis (CMVR) is a serious and potentially sight-threatening infection in immunocompromised individuals. Strategies for the management of drug-resistant CMVR are described. Methods: A case of severe bilateral CMVR in a single lung transplant patient, with UL97 mutation conferring ganciclovir-resistance, is presented. Treatment with standard antiviral agent and adjuvant leflunomide, immunosuppression modifications (calcineurin inhibitors and corticosteroid), intravitreal antiviral therapy and novel use of CMV-immunoglobulin is described. A literature review to support drug-resistant CMVR management is presented. Results: Severe and progressive CMV retinitis was refractory to intravitreal foscarnet and systemic leflunomide. Drug-toxicity restricted systemic antiviral therapy options. The use of combined leflunomide and CMV-immunoglobulins, in the absence of viremia, has not been previously reported. Loss of ganciclovir-resistance was eventually observed permitting successful treatment with systemic and intravitreal ganciclovir. Conclusions: Drug-resistant CMVR is a complex clinical challenge. Multiple systemic and local treatment strategies may be necessary but toxicity, resistance, and co-morbidities may severely restrict available options.

Ocular syphilis: the re-establishment of an old disease.

PurposeTo present the patient profiles, clinical presentations and visual outcomes in those diagnosed with ocular syphilis, attending a subspecialist uveitis service in northern England over a 15-year period.Patients and methodsRetrospective observational case series of patients presenting between January 2002 and December 2016.ResultsA total of 50 eyes of 34 patients had intraocular inflammation due to syphilis. Of these, 94% were male, and 75% were men who had sex with men. Ten (29%), all male, were HIV-positive. Presentations included isolated anterior non-granulomatous uveitis, intermediate uveitis, panuveitis, retinitis, placoid chorioretinitis and papillitis. Concurrent skin rash and/or headache were seen in 41%. Compliance with antibiotic treatment was complete, but there was a high rate of default from ophthalmological follow-up (38%). Visual improvement was seen in 92% of eyes, and at final assessment 71% had acuity of 6/9 or better.ConclusionsOcular syphilis is continuing to increase in incidence, in tandem with the continuing epidemic of early syphilis in the UK (the risk of ocular involvement being about 1%). Almost all are male, and most are men who have sex with men. Clinical presentation is variable; a high index of suspicion and a low threshold for serological testing is important; early treatment can reverse retinal changes and restore visual acuity.

Ultra-widefield fundus fluorescein angiography in the diagnosis and management of retinal vasculitis.

PurposeTo quantify the additional information provided by ultra-widefield fluorescein angiography, compared with 7-field standard imaging, in patients with retinal vasculitis (RV).Patients and methodsRetrospective case series of 106 patients.ResultsRetinal vascular pathology was identified by UWF FFA, but not by standard ETDRS 7-field area, in 62 patients (58.5%) and in 79 eyes (43.4%). The pathology included active RV (47 eyes, 25.8% of eyes); retinal ischaemia, or infarction (53 eyes, 29.1%); and retinal neovascularization (7 eyes, 3.8%). A change to management was made in 36 patients (34%). Of these, 21 (20% of all patients undergoing angiography) were made after the identification of retinal vascular pathology, which was found only on UWF FFA, outside the ETDRS area.ConclusionUltra-widefield fluorescein angiography has clear advantages over standard multi-field imaging. It is currently the standard method of assessment for RV in this centre.

Brain mechanisms of anxiety's effects on cognitive control in major depressive disorder.

BACKGROUND: Adults with major depressive disorder (MDD) demonstrate increased susceptibility to interfering effects of anxiety on cognitive control; although under certain conditions adults with MDD are able to compensate for these effects. The brain mechanisms that may facilitate the ability to compensate for anxiety either via the recruitment of additional cognitive resources or via the regulation of interference from anxiety remain largely unknown. To clarify these mechanisms, we examined the effects of anxiety on brain activity and amygdala-prefrontal functional connectivity in adults diagnosed with MDD. METHOD: A total of 22 unmedicated adults with MDD and 18 healthy controls (HCs) performed the Tower of London task under conditions designed to induce anxiety, while undergoing a functional magnetic resonance imaging assessment. RESULTS: During the easy condition, the MDD group demonstrated equivalent planning accuracy, longer planning times, elevated amygdala activity and left rostrolateral prefrontal cortex (RLPFC) hyperactivity relative to HCs. Anxiety mediated observed group differences in planning times, as well as differences in amygdala activation, which subsequently mediated observed differences in RLPFC activation. During the easy condition, the MDD group also demonstrated increased negative amygdala-dorsolateral prefrontal cortex (DLPFC) connectivity which correlated with improved planning accuracy. During the hard condition, HCs demonstrated greater DLPFC activation and stronger negative amygdala-DLPFC connectivity, which was unrelated to planning accuracy. CONCLUSIONS: Our results suggest that persons with MDD compensate for anxiety-related limbic activation during low-load cognitive tasks by recruiting additional RLPFC activation and through increased inhibitory amygdala-DLPFC communication. Targeting these neural mechanisms directly may improve cognitive functioning in MDD.

Lymphopenia as a predictor of sarcoidosis in patients with uveitis.

AIMS: To investigate the hypothesis that lymphopenia is an independent predictor of sarcoidosis in new patients presenting with uveitis. PATIENTS AND METHODS: Retrospective case-control study of 112 patients with sarcoidosis-associated uveitis (SAU) against 398 controls with other forms of uveitis. RESULTS: Of the patients with SAU, 30/112 (26.8%) had significant lymphopenia (<1.0×10(9)/L), compared with 24/398 (6.0%) for other uveitis (p≤0.0001, OR 5.7 (95% CI 3.2 to 10.3)). The mean lymphocyte count for patients with SAU was 1.43 vs 2.04 for other uveitis (p≤0.0001). Logistic regression modelling using diagnosis of SAU as the independent variable identified age, ACE levels and lymphocyte count as independent predictors of SAU. A new patient with uveitis with significant lymphopenia has a risk of sarcoidosis (from this parameter alone) of 31.6%. CONCLUSIONS: Significant lymphopenia (<1.0×10(9)/L) is an independent predictor of sarcoidosis in new patients presenting with uveitis. We recommend that diagnostic criteria for SAU should be modified to include this phenomenon.

Staphylococcal endogenous endophthalmitis in association with pyogenic vertebral osteomyelitis.

PURPOSE To describe pyogenic vertebral osteomyelitis as a rare infection associated with endogenous endophthalmitis.METHODS A retrospective review of three patients with endogenous endophthalmitis and sepsis due to underlying Staphylococcal vertebral osteomyelitis presenting during a 21-month time period. The ophthalmic and systemic features and management and outcomes are presented.RESULTS One patient developed unilateral endophthalmitis with cervical spine osteomyelitis, Staphylococcus aureus being isolated from blood cultures. The second presented with bilateral endophthalmitis with disseminated Methicillin-resistant S. aureus (MRSA) infection, with thoracic and lumbar discitis and para-spinal abscesses. MRSA was cultured from vitreous, blood, and synovial fluid. Both patients received prolonged courses of intravenous antibiotics. Intravitreal antibiotic therapy was used in the second patient. Excellent visual and systemic outcomes were achieved in both cases with no ocular complications. The third patient developed lumbar osteomyelitis following spinal surgery and presented with disseminated S. aureus sepsis including unilateral endogenous endophthalmitis. Despite systemic antibiotics and intensive care the patient died.CONCLUSIONS Endogenous endophthalmitis should be suspected in septic patients developing eye symptoms. Endogenous endophthalmitis with staphylococcal bone infection is a rare but serious condition. Osteomyelitis should be considered as an infective source in any such patient reporting bone pain or reduced spinal mobility. Prompt investigation and treatment can achieve favourable visual and systemic outcomes.

The Manchester Uveitis Clinic: The first 3000 patients, 2: Uveitis Manifestations, Complications, Medical and Surgical Management.

PURPOSE: To demonstrate the manifestations and complications of uveitis, and their medical and surgical management, in a very large group of patients attending the Manchester Uveitis Clinic (MUC), a specialist uveitis clinic in the Northwest of England, UK. METHODS: Retrospective retrieval of data on a computerized database incorporating all new referrals to MUC from 1991 to 2013. RESULTS: A total of 3000 new patients with uveitis were seen during a 22-year period, of which 25.2% had a single acute episode, 13.6% had acute recurrent uveitis, 20.2% had chronic fluctuating uveitis, and 41.0% had chronic unremitting uveitis. The commonest complications were cataract (35% of patients), macular edema (20.5%), and glaucoma (19.5%). Oral steroids were required in 36% of patients, oral immunosuppression in 16%, and biologic treatment in 2%. Major intraocular surgery was required in 28%. CONCLUSIONS: Oral steroid usage is not an independent risk factor for cataract formation in patients with uveitis. Oral immunosuppression usage has increased 4-fold during this study period.

Spontaneous sub-conjunctival haemorrhage in patients using long-term topical corticosteroids.

PURPOSE: to investigate the observed high prevalence of spontaneous sub-conjunctival haemorrhage (SCH) in patients using long-term topical steroid treatment. PATIENTS AND METHODS: a cross sectional survey of the occurrence of SCH was carried out in 248 patients using steroid eye drops and in a comparison group of 113 patients using topical glaucoma medication. RESULTS: twenty-four patients with uveitis (10% of total) experienced single or recurrent SCH. Of these 71% used prednisolone acetate 1% (compared with 75% for those unaffected). None of 113 glaucoma patients were affected. CONCLUSIONS: the long-term use of topical steroid for chronic uveitis substantially increases the prevalence of spontaneous or minimal-trauma SCH. Steroid-induced vascular fragility is the likely cause.

Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials.

AIMS/HYPOTHESIS: Observational and mechanistic studies have suggested a possible relationship between treatment with metformin and decreased incidence of cancer in participants with type 2 diabetes. We extracted data for malignancies from the ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) randomised controlled clinical trials, in which the efficacy and/or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone. METHODS: Neoplasm occurrences were collected as adverse events in these studies. We reviewed and re-analysed the individual participant data in both studies for serious adverse events, malignancies reported as adverse events and related neoplasms of special interest. RESULTS: In ADOPT, 50 participants (3.4%) on metformin and 55 (3.8%) on each of rosiglitazone and glibenclamide (known as glyburide in the USA and Canada) developed serious adverse event malignancies (excluding non-melanoma skin cancers). This corresponds to 1.03, 1.12 and 1.31 per 100 person-years, giving hazard ratios for metformin of 0.92 (95% CI 0.63-1.35) vs rosiglitazone and 0.78 (0.53-1.14) vs glibenclamide. In RECORD, on a background of sulfonylurea, 69 (6.1%) participants developed malignant neoplasms in the metformin group, compared with 56 (5.1%) in the rosiglitazone group (HR 1.22 [0.86-1.74]). On a background of metformin, 74 (6.7%) participants in the sulfonylurea group developed malignant neoplasms, compared with 57 (5.1%) in the rosiglitazone group (HR 1.33 [0.94-1.88]). CONCLUSIONS/INTERPRETATION: The malignancy rates in these two randomised controlled clinical trials do not support a view that metformin offers any particular protection against malignancy compared with rosiglitazone. However, they do not refute the possibility of a difference compared with sulfonylureas.

Nonprogressive tractional inferior retinal elevation in intermediate uveitis.

PURPOSE: To describe inferior peripheral retinal elevations associated with intermediate uveitis. METHODS: Retrospective review. RESULTS: Eleven eyes of 7 patients developed inferior retinal elevation secondary to intermediate uveitis. Six eyes (54.6%) were believed to have tractional retinoschisis, 2 (18.2%) had tractional retinal detachment, and the remaining 3 (27.3%) had flat retinal elevation of indeterminate type. In 10 eyes there was no evidence of progression during a mean 4-year follow-up. One eye developed extended tractional elevation with macular pucker and failed to respond to surgery. At the most recent visit, visual acuity ranged from 6/5 to NPL with a median of 6/12. CONCLUSION: Intermediate uveitis may cause inferior peripheral retinal elevation. The authors propose that preretinal and pars plana gliosis resulting from chronic pars planitis exerts traction on peripheral retina, causing elevation, but infer that such elevation removes traction and is self-limiting. Surgery should be reserved only for macula threatening lesions.

Low-dose cyclosporine treatment for sight-threatening uveitis: efficacy, toxicity, and tolerance.

AIM: To ascertain the effectiveness, tolerability, and safety of low-dose cyclosporine in the management of sight-threatening uveitis. MATERIALS AND METHODS: This was a retrospective clinical case series of patients using oral low-dose cyclosporine for the management of sight-threatening uveitis in the uvea clinic (UC). Patients receiving cyclosporine were identified from the clinic database. Main outcome measures were degree of intraocular inflammation, visual acuity and dose reduction of oral steroid for effectiveness and adverse symptoms, systemic hypertension, and raised serum creatinine for tolerability and safety. RESULTS: Intraocular inflammation was improved or stable in 97% of patients, visual acuity was improved or stable in 91%, and oral steroid dosage was reduced in 73% (by half or more in 51%). Adverse symptoms were almost universal, the commonest being peripheral paresthesia/burning in 70% and fatigue in 67%. Significant systemic hypertension developed in 27% and raised creatinine in 30%, necessitating dose reduction. Cyclosporine was discontinued in 35%, being intolerable in 20% and ineffective in 15%. CONCLUSIONS: Cyclosporine was found to be effective in reducing inflammation and protecting vision in sight-threatening uveitis. It was safe with proper monitoring, including in children. It had a significant toxicity profile and a high incidence of adverse symptoms which required close supervision, and a prompt dose reduction or drug exchange.

Nurse-led formal health review for immunosuppressed patients with uveitis.

PURPOSE: To describe and analyse a method of detailed formal health review for patients with sight-threatening uveitis using oral immunosuppression. METHODS: Prospective clinical study of 37 patients. RESULTS: Treatment side effects were absent or tolerable in 31 patients (84%) but 34 significant treatment side effects or other significant clinical findings were newly identified. Ten patients underwent a treatment change including three who transferred to a different immunosuppressive. CONCLUSIONS: Formal health review has proved useful in identifying treatment side effects previously not volunteered by patients. A modified form is to be embedded within our clinic management system. We recommend such reviews to enhance drug safety in patients with sight-threatening chronic uveitis using oral immunosuppressives.

Phospholipase C gamma 1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion.

Phospholipase Cgamma1 (PLCgamma1) is activated downstream of a variety of extracellular stimuli and has previously been implicated in the regulation of motility responses central to tumour cell invasion. In this study, we used a novel RNAi vector system to achieve conditional PLCgamma1 knockdown in PC3LN3 human prostate carcinoma cells for further evaluation of PLCgamma1 in tumour cell biology. Using this approach, we revealed a role for PLCgamma1 in the regulation of PC3LN3 cell adhesion that appears to be independent of its effects on tumour cell chemotactic migration and spreading in response to extracellular matrix. Subsequent microarray analysis of PLCgamma1-knockdown cells revealed Rap GEF1 mRNA to be decreased in response to PLCgamma1 loss. This translated into a decrease in Rap GEF1 protein levels and a significant loss of Rap1 activity in PLCgamma1-knockdown cells. Transient knockdown of Rap GEF1 caused a reduction in PC3LN3 adhesion while overexpression of Rap GEF1 rescued the PLCgamma1 knockdown-induced adhesion defect. These data highlight control of the Rap GEF1-Rap1 molecular switch as a specific requirement for PLCgamma1-mediated tumour cell adhesion.

Rosiglitazone RECORD study: glucose control outcomes at 18 months.

AIMS: To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes. METHODS: RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA(1c) of 7.1-9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA(1c) was managed to < or = 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA(1c) of 0.4%. RESULTS: At 18 months, HbA(1c) reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI -0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (-0.09, 0.20)%]. At 6 months, the effect on HbA(1c) was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea -0.36 (-0.74, 0.02) mmol/l, rosiglitazone vs. metformin -0.34 (-0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P < or = 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001]. CONCLUSIONS: In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA(1c) over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain.