Amantadine-induced corneal edema: A case and literature review.

Purpose: To present a case of irreversible corneal edema after 10 years of amantadine use. A literature review was carried out to describe the clinical characteristics and outcomes of amantadine-induced corneal edema. Observations: A 36-year-old woman presented with a 6-week history of gradually progressive bilateral painless visual loss with visual acuity (VA) of 20/350 and 20/300 in the right and left eye, respectively. Examination showed bilateral diffuse central corneal edema with multiple Descemet membrane folds without endothelial guttata, keratic precipitates or intraocular inflammation. This did not respond to hypertonic saline drops and empirical treatment for presumed herpetic endotheliitis with oral acyclovir. Medication review revealed the use of amantadine 100mg daily for the past 10 years, prescribed by her neurologist for fatigue. Despite discontinuing amantadine, corneal edema was irreversible due to a markedly reduced endothelial cell count of 625 (right) and 680 cells/mm2 (left). Conclusions and Importance: This case highlights the need to consider amantadine as a cause of unexplained bilateral non-guttae corneal edema. A literature review of 33 case reports revealed broadly similar features of amantadine-induced corneal edema; whilst most cases had favorable outcomes with median VA 20/25 (interquartile range IQR 20/20-20/30) and complete resolution of corneal edema within 30 days (IQR 14-35) of amantadine discontinuation, most experienced low endothelial cell density 759 cells/mm2 (IQR 621-1078). Taken together, screening specular microscopy ought to be considered for those in whom amantadine is likely required long-term.

Real-World Implementation and Outcomes of Adalimumab Therapeutic Drug Monitoring in Psoriasis: A National Specialized Center Experience.

Serum adalimumab concentration is a biomarker of treatment response but therapeutic drug monitoring (TDM) is yet to be implemented in routine psoriasis care. We incorporated adalimumab TDM in a national specialized psoriasis service and evaluated it using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science framework. We undertook pre-implementation planning (validating local assays) and implementation interventions targeted to patients (pragmatic sampling at routine reviews), clinicians (introduction of a TDM protocol), and healthcare systems (adalimumab TDM as a key performance indicator). Over 5 months, 170 of 229 (74%) individuals treated with adalimumab received TDM. Clinical improvement after TDM-guided dose escalation occurred in 13 of 15 (87%) nonresponders with serum drug concentrations <8.3 µg/ml (median PASI reduction of 3.2 [interquartile range = 2.2-8.2] after 23.4 weeks) and in all nonresponders who had TDM-guided switch in biologic due to supratherapeutic drug concentrations (>8.3 µg/ml; n = 2) or positive antidrug antibody (n = 2) (PASI reduction of 7.8 [interquartile range = 7.5-12.9] after 20.0 weeks). Proactive TDM led to dose reduction in five individuals with clear skin and subtherapeutic or supratherapeutic drug concentrations; four (80%) sustained clear skin after 50 weeks (range = 42-52). Adalimumab TDM based on pragmatic serum sampling is clinically viable and may lead to patient benefit. Context-specific implementation interventions and systematic implementation assessment may bridge the biomarker research-to-practice gap.

Retinal toxicity secondary to subconjunctival cefuroxime following pars plana vitrectomy: A case report and literature review.

Purpose: To present a case of inadvertent retinal toxicity induced by a standard dose of subconjunctival cefuroxime after epiretinal membrane surgery. Narrative review of cefuroxime overdose or toxicity after intraocular surgery was carried out to describe characteristics of cefuroxime toxicity and their relationship to visual outcome. Observations: A 64-year-old man underwent pars plana vitrectomy (PPV) with epiretinal membrane peel and received a standard dose of subconjunctival cefuroxime as endophthalmitis prophylaxis. At two weeks, visual acuity measured counting fingers, and fundus examination showed haemorrhages and cotton wool spots. Fluorescein angiography confirmed widespread ischaemia involving the macula. Subsequent litigation ruled that inadvertent cefuroxime toxicity after an accidental penetration of sclera was the likely aetiology. Conclusions and importance: In addition to inadvertent overdose due to dilution errors, accidental scleral penetration is another mechanism for drug toxicity following subconjunctival cefuroxime injection. Literature review revealed broadly different manifestations of cefuroxime retinal toxicity. This case highlights the need to consider severe cefuroxime toxicity in patients presenting with unexplained post-PPV visual loss.

Clinical approach to vision loss: a review for general physicians.

Visual loss describes temporary or permanent reduction in visual acuity and/or field. Its aetiology is diverse due to the contributions of the different neuro-ophthalmic structures (eye, optic nerve, and brain) to image formation and perception, but may be categorised into ocular causes (corneal, lenticular, vitreoretinal and macular) or optic neuropathies. Clinical evaluation of visual loss relies on thorough history and examination to guide further tests. In this article, we provide a practical overview of visual loss assessment for general physicians.

Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study.

BACKGROUND: COVID-19 vaccines have robust immunogenicity in the general population. However, data for individuals with immune-mediated inflammatory diseases who are taking immunosuppressants remains scarce. Our previously published cohort study showed that methotrexate, but not targeted biologics, impaired functional humoral immunity to a single dose of COVID-19 vaccine BNT162b2 (Pfizer-BioNTech), whereas cellular responses were similar. Here, we aimed to assess immune responses following the second dose. METHODS: In this longitudinal cohort study, we recruited individuals with psoriasis who were receiving methotrexate or targeted biological monotherapy (ie, tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South-East England. The healthy control cohort were volunteers without psoriasis, not receiving immunosuppression. Immunogenicity was evaluated immediately before, on day 28 after the first BNT162b2 vaccination and on day 14 after the second dose (administered according to an extended interval regimen). Here, we report immune responses following the second dose. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as titres of total spike-specific IgG and of neutralising antibody to wild-type, alpha (B.1.1.7), and delta (B.1.617.2) SARS-CoV-2 variants, and cellular immunity defined as spike-specific T-cell responses (including numbers of cells producing interferon-γ, IL-2, IL-21). FINDINGS: Between Jan 14 and April 4, 2021, 121 individuals were recruited, and data were available for 82 participants after the second vaccination. The study population included patients with psoriasis receiving methotrexate (n=14), TNF inhibitors (n=19), IL-17 inhibitors (n=14), IL-23 inhibitors (n=20), and 15 healthy controls, who had received both vaccine doses. The median age of the study population was 44 years (IQR 33-52), with 43 (52%) males and 71 (87%) participants of White ethnicity. All participants had detectable spike-specific antibodies following the second dose, and all groups (methotrexate, targeted biologics, and healthy controls) demonstrated similar neutralising antibody titres against wild-type, alpha, and delta variants. By contrast, a lower proportion of participants on methotrexate (eight [62%] of 13, 95% CI 32-86) and targeted biologics (37 [74%] of 50, 60-85; p=0·38) had detectable T-cell responses following the second vaccine dose, compared with controls (14 [100%] of 14, 77-100; p=0·022). There was no difference in the magnitude of T-cell responses between patients receiving methotrexate (median cytokine-secreting cells per 106 cells 160 [IQR 10-625]), targeted biologics (169 [25-503], p=0·56), and controls (185 [133-328], p=0·41). INTERPRETATION: Functional humoral immunity (ie, neutralising antibody responses) at 14 days following a second dose of BNT162b2 was not impaired by methotrexate or targeted biologics. A proportion of patients on immunosuppression did not have detectable T-cell responses following the second dose. The longevity of vaccine-elicited antibody responses is unknown in this population. FUNDING: NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London; The Psoriasis Association.

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study.

BACKGROUND: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. METHODS: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. FINDINGS: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31-52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67-87] of 77) than in controls (17 [100%; 80-100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21-73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40-236]) than in controls (317 [213-487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141-418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. INTERPRETATION: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. FUNDING: UK National Institute for Health Research.

Exploratory Study of the Association between the Severity of Idiopathic Intracranial Hypertension and Electroretinogram Photopic Negative Response Amplitude Obtained Using a Handheld Device.

The photopic negative response (PhNR) is a negative component of the photopic flash electroretinogram that follows the b-wave and is thought to arise from the retinal ganglion cells. Reduction in its amplitude in idiopathic intracranial hypertension (IIH) has been previously documented using formal electroretinography. This study explored the use of a handheld device (RETeval, LKC technologies, Gaithersburg, MD, USA) in 72 IIH patients of varying stages and severity (and seven controls) and investigated associations between PhNR parameters and disease severity. PhNR amplitudes at 72 ms (P72) and p-ratio (ratio to b-wave peak value) differed significantly across groups, with a trend towards smaller amplitudes in those with severe IIH, defined as papilloedema with Modified Frisén Scale (MFS) ≥ 3, retinal nerve fibre layer (RNFL) ≥ 150 µm or atrophic papilloedema (p = 0.0048 and p = 0.018 for P72 and p-ratio, respectively). PhNR parameters did not correlate with MFS, RNFL thickness, standard automated perimetry mean deviation or macular ganglion cell layer volume. This study suggests that PhNR measurement using a handheld device is feasible and could potentially augment the assessment of disease severity in IIH. The clinical utility of PhNR monitoring in IIH patients requires further investigation.

Psoriasis: a brief overview.

Psoriasis is a clinically heterogeneous lifelong skin disease that presents in multiple forms such as plaque, flexural, guttate, pustular or erythrodermic. An estimated 60 million people have psoriasis worldwide, with 1.52% of the general population affected in the UK. An immune-mediated inflammatory disease, psoriasis has a major genetic component. Its association with psoriatic arthritis and increased rates of cardiometabolic, hepatic and psychological comorbidity requires a holistic and multidisciplinary care approach. Psoriasis treatments include topical agents (vitamin D analogues and corticosteroids), phototherapy (narrowband ultraviolet B radiation (NB-UVB) and psoralen and ultraviolet A radiation (PUVA)), standard systemic (methotrexate, ciclosporin and acitretin), biologic (tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors) or small molecule inhibitor (dimethyl fumarate and apremilast) therapies. Advances in the understanding of its pathophysiology have led to development of highly effective and targeted treatments.

The role of CT in detecting AF substrate.

Despite technological advancements and evolving ablation strategies, atrial fibrillation catheter ablation outcome remains suboptimal for a cohort of patients. Imaging-based biomarkers have the potential to play a pivotal role in the overall assessment and prognostic stratification of AF patients, allowing for tailored treatments and individualized care. Alongside consolidated evaluation parameters, novel imaging biomarkers that can detect and stage the remodelling process and correlate it to electrophysiological phenomena are emerging. This review aims to provide a better understanding of the different types of atrial substrate, and how Computed Tomography can be used as a pre-ablation risk stratification tool by assessing the various novel imaging biomarkers, providing a valuable insight into the mechanisms that sustain AF and potentially allowing for a patient-specific ablation strategy.

Association Between Ethnicity and Severe COVID-19 Disease: a Systematic Review and Meta-analysis.

OBJECTIVES: This article evaluates if ethnicity is an independent poor prognostic factor in COVID-19 disease. METHODS: MEDLINE, EMBASE, Cochrane, WHO COVID-19 databases from inception to 15/06/2020 and medRxiv. No language restriction. Newcastle-Ottawa Scale (NOS) and GRADE framework were utilised to assess the risk of bias and certainty of evidence. PROSPERO CRD42020188421. RESULTS: Seventy-two articles (59 cohort studies with 17,950,989 participants, 13 ecological studies; 54 US-based, 15 UK-based; 41 peer-reviewed) were included for systematic review and 45 for meta-analyses. Risk of bias was low: median NOS 7 of 9 (interquartile range 6-8). Compared to White ethnicity, unadjusted all-cause mortality was similar in Black (RR: 0.96 [95% CI: 0.83-1.08]) and Asian (RR: 0.99 [0.85-1.16]) but reduced in Hispanic ethnicity (RR: 0.69 [0.57-0.84]). Age- and sex-adjusted risks were significantly elevated for Black (HR: 1.38 [1.09-1.75]) and Asian (HR: 1.42 [1.15-1.75]), but not for Hispanic (RR: 1.14 [0.93-1.40]). Further adjusting for comorbidities attenuated these associations to non-significance: Black (HR: 0.95 [0.72-1.25]); Asian (HR: 1.17 [0.84-1.63]); Hispanic (HR: 0.94 [0.63-1.44]). Subgroup analyses showed a trend towards greater disparity in outcomes for UK ethnic minorities, especially hospitalisation risk. CONCLUSIONS: This review could not confirm a certain ethnicity as an independent poor prognostic factor for COVID-19. Racial disparities in COVID-19 outcomes may be partially attributed to higher comorbidity rates in certain ethnicity.

Impact of obesity on atrial fibrillation ablation.

Obesity is a major risk factor for atrial fibrillation. It also influences the natural history of the disease, leading to more persistent forms and poorer ablation outcomes. This article reviews atrial fibrillation ablation in the obese population, focusing on outcomes, complications and periprocedural management. Through an analysis of the possible pathophysiological mechanism linking obesity and atrial fibrillation, we identify potential strategies to improve post-ablation outcomes in this challenging population.

Validity of inducible ischaemia as a surrogate for adverse outcomes in stable coronary artery disease.

Regional myocardial ischaemia is commonly expressed as exertional angina in patients with stable coronary artery disease (CAD). It also associates with prognosis, risk tending to increase with the severity of ischaemia. The validity of myocardial ischaemia as a surrogate for adverse clinical outcomes, however, has not been well established. Thus, in cohort studies, ischaemia testing has failed to influence rates of myocardial infarction and coronary death. Moreover, in clinical studies, pharmacological and interventional treatments that are effective in correcting ischaemia have rarely been shown to reduce cardiovascular (CV) risk. This contrasts with statins and other anti-inflammatory drugs that have no direct effect on ischaemia but improve CV outcomes by modifying the atherothrombotic disease process. Despite this, and with little evidence of patient benefit, stress testing is commonly used during the follow-up of patients with stable CAD when the demonstration of ischaemic change may be seen as a target for treatment, independently of symptomatic status. Substitution of a symptom-driven management strategy has the potential to reduce rates of non-invasive stress testing, unnecessary downstream revascularisation procedures and use of valuable resources in patients with stable CAD without adverse consequences for CV risk.