Corneal Neuropathic Pain: A Patient and Physician Perspective.

Corneal neuropathic pain (CNP) is a debilitating condition characterized by pain in the absence of a noxious stimulus. Symptoms such as ocular stinging, burning, photophobia, irritation, and a deep aching pain can be severe despite a seemingly normal ocular surface on examination. CNP may develop due to either peripheral or central sensitization. Peripheral sensitization develops due to aberrant regeneration of corneal nociceptors and nerve fibers as a result of corneal injury or disease of peripheral corneal nerves. Whereas, central sensitization develops due to upregulation of excitatory neurotransmitters as a result of chronic inflammation, which leads to amplification of neuronal response to stimuli. Unfortunately, due to the disparity in severity of symptomology and the observable signs on examination, patients' symptoms are commonly thought to be "psychological" or "functional", and patients report feeling ignored and neglected. Additionally, diagnosis is often delayed which adversely affects patient outcomes. Research to date has focused on the scientific aspects of corneal neuropathic pain: its pathophysiology, epidemiology, investigations, and management. Research into the patient personal experience and the challenges faced by individual patients and their clinicians is lacking. We present the patient and physician perspective on the journey of both patients in order to provide insights into the challenges faced by patients and physicians in the diagnosis, assessment, and management of corneal neuropathic pain.

Corneal neuropathic pain is a rare disease that causes patients to experience severe eye pain without a painful stimulus. Patients often experience one or more symptoms, such as ocular stinging, burning, irritation, photophobia, and deep aching pains even though ophthalmologists cannot see any abnormality when they examine the eyes. Due to a significant lack of awareness and understanding of the condition, diagnosis is often delayed and patients are left feeling ignored or neglected. Research to date has focused on the scientific aspects of corneal neuropathic pain such as what causes it, the tests doctors use to diagnose it, and the best treatments to manage it. In this article, we present the patient and physician perspective, an understanding of which we believe can improve the care that patients receive and can promote awareness and understanding of the condition, facilitating early diagnosis and treatment.

Investigating the relationship between FRailty And Quality of LIfe in patients with heart faiLure and CKD (FRAIL study).

AIMS: Patients with chronic kidney disease (CKD) or heart failure (HF) are disproportionally affected by frailty, an independent predictor of morbidity. The prevalence of frailty and its impact on quality of life (QoL) in a unique population of patients with both CKD and HF (CKD-HF) is unclear. The aim of this study was to investigate the association between frailty and QoL in patients with CKD-HF. METHODS AND RESULTS: Patients were identified from a tertiary care cardiorenal clinic. Eligible patients had CKD-HF with a stable estimated glomerular filtration rate of <60 mL/min/1.732 . Data were collected from each participant at one point in time using surveys delivered by study personnel between 14 July 2022 and 31 March 2023. Frailty was defined as Modified Frailty Phenotype (MFP) score ≥3. The Medical Outcomes Study 36-item Short Form Health Survey (SF-36) was used to assess QoL. Demographic data were retrospectively collected from electronic patient records. Demographics and QoL were compared between frail and non-frail cohorts using Pearson's R and Student's t-test (two-tailed, alpha-priori = 0.05). One hundred five participants consented, and 103 completed the questionnaires in full. Amongst the 103 participants, 49.5% (n = 51) were frail. Frailty was related to sex (P = 0.021) and medication count (P = 0.007), however not to other clinical measures, including estimated glomerular filtration rate (P = 0.437) and ejection fraction (P = 0.911). Frail patients reported poorer QoL across physical functioning (P < 0.001), general health (P < 0.001), bodily pain (P = 0.004), social functioning (P < 0.001), and energy levels (P < 0.001), however not emotional wellbeing (P = 0.058); 51.5% cited 'better quality of life' as their healthcare priority, over longer survival (23.3%) or avoiding hospital admissions (22.3%). This was consistent across frail and non-frail groups. CONCLUSIONS: A large proportion of CKD-HF patients are frail, regardless of disease severity, and more susceptible to significantly poorer QoL across physical and social domains. Improving QoL is the priority of patients across both frail and non-frail cohorts, further emphasizing the need for prompt recognition of frailty as well as possible intervention and prevention.

A novel apoE-mimetic increases brain apoE levels, reduces Aß pathology and improves memory when treated before onset of pathology in male mice that express APOE3.

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aß). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression. In glia, apoE is lipidated via cholesterol efflux from intracellular pools, primarily by the ATP-binding cassette transporter A1 (ABCA1). Therefore, increasing ABCA1 activity is suggested to be a therapeutic approach for AD. CS-6253 (CS) is a novel apoE mimetic peptide that was developed to bind and stabilize ABCA1 and maintain its localization into the plasma membrane therefore promoting cholesterol efflux. The goal of this study was to determine whether CS could modulate apoE levels and lipidation, Aß pathology, and behavior in a model that expresses human APOE and overproduce Aß. METHODS: In vitro, APOE3-glia or APOE4-glia were treated with CS. In vivo, male and female, E3FAD (5xFAD+/-/APOE3+/+) and E4FAD (5xFAD+/-/APOE4+/+) mice were treated with CS via intraperitoneal injection at early (from 4 to 8 months of age) and late ages (from 8 to 10 months of age). ApoE levels, ABCA1 levels and, apoE lipidation were measured by western blot and ELISA. Aß and amyloid levels were assessed by histochemistry and ELISA. Learning and memory were tested by Morris Water Maze and synaptic proteins were measured by Western blot. RESULTS: CS treatment increased apoE levels and cholesterol efflux in primary glial cultures. In young male E3FAD mice, CS treatment increased soluble apoE and lipid-associated apoE, reduced soluble oAß and insoluble Aß levels as well as Aß and amyloid deposition, and improved memory and synaptic protein levels. CS treatment did not induce any therapeutic benefits in young female E3FAD and E4FAD mice or in any groups when treatment was started at later ages. CONCLUSIONS: CS treatment reduced Aß pathology and improved memory only in young male E3FAD, the cohort with the least AD pathology. Therefore, the degree of Aß pathology or Aß overproduction may impact the ability of targeting ABCA1 to be an effective AD therapeutic. This suggests that ABCA1-stabilizing treatment by CS-6253 works best in conditions of modest Aß levels.

Outer retinal corrugations in late-onset retinal degeneration: a diagnostic finding demonstrated with multimodal imaging.

OBJECTIVE: Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal degeneration that presents in the sixth decade and leads to severe visual loss. The objective of this paper is to describe outer retinal corrugations as a diagnostic feature of L-ORD. METHODS: This retrospective study reviewed consecutive patients diagnosed with L-ORD, confirmed through complete ophthalmic examination, multimodal imaging and genetic tests. Multimodal imaging investigations included spectral domain-optical coherence tomography (SD-OCT) and ultra-wide-field colour and autofluorescence fundus photographs. RESULTS: A total of 13 eyes of 9 patients with L-ORD had outer retinal corrugations identified on OCT scans. CONCLUSION: Outer retinal corrugations may be a diagnostic finding for L-ORD. The detection of this sign may aid diagnosis and characterisation of this disease and help in the differential diagnosis with other acquired pathologies.

Visual loss and optic neuropathy in a patient with Klinefelter's syndrome, open-angle glaucoma, vitamin B12 (cobalamin) and folate deficiency.

A 54-year-old man with Klinefelter's syndrome presented to the neuro-ophthalmology clinic with progressive painless visual blurring in the right eye over 2 years. He was receiving intramuscular testosterone therapy for hypogonadism and hypromellose for dry eye. Acuity was reduced bilaterally, and the right optic nerve head appeared pale and asymmetrically cupped. Optical coherence tomography revealed loss of retinal nerve fibre layer thickness in the right eye and visual field testing showed a developing right-ring scotoma. Blood tests showed vitamin B12 and folate deficiencies and polycythaemia. The patient was managed with intramuscular hydroxocobalamin, oral folate administration and re-initiation of his glaucoma medication. In Klinefelter's syndrome, signs of comorbid deficiency can be masked by the polycythaemic effect of testosterone therapy. For patients on long-term testosterone therapy, such as those with Klinefelter's syndrome, we recommend baseline ophthalmic examination and assessment, including intraocular pressure measurement, pachymetry, gonioscopy and screening 24-2 visual field testing.

Percutaneous Achilles tenotomy under local anaesthetic in the clubfoot clinic was safe during the COVID-19 pandemic, for both children and parents.

PURPOSE: An Achilles tenotomy is routinely required to correct the equinus deformity in Congenital talipes equinovarus (CTEV) patients as part of the gold standard treatment using the Ponseti method. This procedure can be performed in clinic under local anaesthetic or in theatre under general anaesthetic. The COVID-19 pandemic reduced theatre capacity and caused a delay to CTEV patients' treatment. A new standard operating procedure that allowed the tenotomies to be performed under local anaesthetic in the clinic was introduced. This study was looking into the safety, feasibility and parents' perspective of this procedure. METHODS: The study was prospectively registered as a service improvement project and followed the SQUIRE guidelines (Ogrinc et al. in BMJ Qual Saf 25:986-992, 2016). All consecutive patients requiring a tenotomy were included. Data was collected prospectively including demographics, Pirani score and a carers' satisfaction questionnaire. RESULTS: Twenty five patients (36 tenotomies) were included in the study. The median age was 9 weeks. All patients achieved ankle dorsiflexion of greater than 15° post-op. None of the patients nor their parents contracted the COVID 19 virus. All parents reported a positive experience and 99% felt less anxious about having the tenotomy done in clinic rather than theatre. CONCLUSIONS: The new service offering clinic tenotomies was found to be safe and clinically successful. This study is the first to show parents preference and excellent satisfaction with a tenotomy performed under local anaesthetic. The service has improved the allocation of resources and due to its success, will continue beyond the pandemic.

Non-invasive Instrument-Based Tests for Quantifying Anterior Chamber Flare in Uveitis: A Systematic Review.

Purpose: Anterior chamber (AC) flare is a key sign for anterior uveitis. New instrument-based techniques for measuring AC flare can offer automation and objectivity. This review aims to identify objective instrument-based measures for AC flare.Methods: In this systematic review, we identified studies reporting correlation between instrument-based tests versus clinician AC flare grading, and/or aqueous protein concentration, as well as test reliability.Results: Four index tests were identified in 11 studies: laser-flare photometry (LFP), optical coherence tomography, ocular flare analysis meter (OFAM) and the double-pass technique. The correlation between LFP and clinician grading was 0.40-0.93 and 0.87-0.94 for LFP and protein concentration. The double-pass technique showed no correlation with clinician grading and insufficient information was available for OFAM.Conclusion: LFP shows moderate to strong correlation with clinician grading and aqueous protein concentration. LFP could be a superior reference test compared to clinician AC flare grading for validating new index tests.

Instrument-based Tests for Measuring Anterior Chamber Cells in Uveitis: A Systematic Review.

PURPOSE: New instrument-based techniques for anterior chamber (AC) cell counting can offer automation and objectivity above clinician assessment. This review aims to identify such instruments and its correlation with clinician estimates. METHODS: Using standard systematic review methodology, we identified and tabulated the outcomes of studies reporting reliability and correlation between instrument-based measurements and clinician AC cell grading. RESULTS: From 3470 studies, 6 reported correlation between an instrument-based AC cell count to clinician grading. The two instruments were optical coherence tomography (OCT) and laser flare-cell photometry (LFCP). Correlation between clinician grading and LFCP was 0.66-0.87 and 0.06-0.97 between clinician grading and OCT. OCT volume scans demonstrated correlation between 0.75 and 0.78. Line scans in the middle AC demonstrated higher correlation (0.73-0.97) than in the inferior AC (0.06-0.56). CONCLUSION: AC cell count by OCT and LFP can achieve high levels of correlation with clinician grading, whilst offering additional advantages of speed, automation, and objectivity.

Instrument-based tests for quantifying aqueous humour protein levels in uveitis: a systematic review protocol.

BACKGROUND: Inflammation in anterior uveitis is characterised by breakdown of the blood-ocular barrier, which allows leakage of blood constituents of higher molecular weight into the aqueous humour. In routine clinical care, increase in aqueous protein levels can be observed at the slit lamp as 'flare' and the severity can be graded using various clinical grading systems, of which the Standardization of Uveitis Nomenclature (SUN) grading system is most commonly used. Alternative instrument-based technologies are available, which can detect aqueous protein levels in an objective and quantifiable way. This review will identify instruments capable of measuring anterior chamber inflammation in this way, their level of reliability, and how well the measurements correlate with clinical grading and/or actual aqueous protein concentration. METHODS: Standard systematic review methodology will be used to identify, select and extract data from studies that report the use of any instrument-based technology in the assessment of aqueous protein levels. Searches will be conducted through bibliographic databases (MEDLINE, EMBASE and Cochrane Library), clinical trial registries and the grey literature. No restrictions will be placed on language or year of publication. The outcomes of interest are the level of correlation between identified instrument-based test measurements, clinical grading and/or actual aqueous protein concentration, as well as the reliability of each index test identified. Study quality assessment will be based on QUADAS2. Correlation and reliability outcomes will be pooled and meta-analysed if appropriate. DISCUSSION: The assessment of inflammation in anterior chamber protein levels currently relies on crude and subjective clinical examination. The findings of this review will identify non-invasive technologies which show good correlation with actual protein concentration, which could be used in routine clinical practice for objective monitoring of AC inflammation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017084167. Study screening stage has just been completed.

Improving outcomes for multi-drug-resistant tuberculosis in the Peruvian Amazon - a qualitative study exploring the experiences and perceptions of patients and healthcare professionals.

BACKGROUND: Management for multi-drug-resistant tuberculosis (MDR-TB) is challenging and has poor patient outcomes. Peru has a high burden of MDR-TB. The Loreto region in the Peruvian Amazon is worst affected for reasons including high rates of poverty and poor healthcare access. Current evidence identifies factors that influence MDR-TB medication adherence, but there is limited understanding of the patient and healthcare professional (HCP) perspective, the HCP-patient relationship and other factors that influence outcomes. A qualitative investigation was conducted to explore and compare the experiences and perceptions of MDR-TB patients and their dedicated HCPs to inform future management strategies. METHOD: Twenty-six, semi-structured in-depth interviews were conducted with 15 MDR-TB patients and 11 HCPs who were purposively recruited from 4 of the worst affected districts of Iquitos (capital of the Loreto region). Field notes and transcripts of the two groups were analysed separately using thematic content analysis. Ethics approval was received from the Institutional Research Ethics Committee, Department of Health, Loreto, and the University of Birmingham Internal Research Ethics Committee. RESULTS: Four key themes influencing patient outcomes emerged in each participant group: personal patient factors, external factors, clinical factors, and the HCP-patient relationship. Personal factors included high standard patient and population knowledge and education, which can facilitate engagement with treatment by encouraging belief in evidence-based medicine, dispelling belief in natural medicines, health myths and stigma. External factors included the adverse effect of the financial impact of MDR-TB on patients and their families. An open, trusting and strong HCP-patient relationship emerged as a vitally important clinical factor influencing of patient outcomes. The results also provide valuable insight into the dynamic of the relationship and ways in which a good relationship can be fostered. CONCLUSIONS: This study highlights the importance of financial support for patients, effective MDR-TB education and the role of the HCP-patient relationship. These findings add to the existing evidence base and provide insight into care improvements and policy changes that could improve outcomes if prioritised by local and national government.

An update on the use of biologic therapies in the management of uveitis in Behçet's disease: a comprehensive review.

ᅟ: Behçet's disease (BD) is a systemic vasculitis characterised by a relapsing remitting course, affecting multiple organ systems. In the eye, it is a cause of potentially blinding inflammation in the form of uveitis. Management of uveitis in BD often requires the use of systemic immunosuppression, in order to reduce disease activity and prevent accumulation of irreversible damage. Whilst corticosteroids remain the mainstay of treatment, long-term use is limited by the development of adrenocorticotrophic side effects. There has therefore been significant interest in the use of corticosteroid-sparing immunosuppressive agents, and more recently, biologic therapies. Recent publications have demonstrated biologic therapy to have beneficial effects both on overall disease control, and quality of life for patients with BD. Widespread use of such agents is however limited, partly by the lack of high quality research evidence, and partly by the prohibitive cost of biologic treatments. In this review, we discuss the most recent research investigating the use of biologic therapy in uveitis due to BD, with consideration of health economics and quality of life outcomes.

Early radiographic and clinical results of balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures.

STUDY DESIGN: A prospective consecutive cohort study of clinical and radiographic outcomes after kyphoplasty for treatment of osteoporotic vertebral compression fractures. OBJECTIVES: To measure changes in spinal deformity, activity level, and pain after kyphoplasty treatment. SUMMARY OF BACKGROUND DATA: Pain and kyphosis caused by osteoporotic vertebral compression fractures adversely affect quality of life and survival. Kyphoplasty involves the inflation of a balloon bone tamp, percutaneously placed in a fractured vertebral body, followed by deposition of bone cement into the resulting cavity. Previous reports indicate that kyphoplasty improves patient function and restores height of collapsed vertebral bodies, but limited data about the effects of kyphoplasty on spinal sagittal alignment are available. METHODS: Twenty-nine patients with osteoporotic vertebral compression fractures who did not respond to medical therapy were treated by kyphoplasty. These patients underwent 37 operations to treat 61 vertebral compression fractures between T6 and L5. Sagittal alignment was analyzed from standing radiographs (pre- and postkyphoplasty). Patient surveys were used to assess pain relief, improvement in activity, and satisfaction with the surgical procedure. RESULTS: In this cohort, a mean of 8.8 degrees (range 0-29 degrees ) of correction of local spinal kyphosis was achieved with kyphoplasty. Thirty of 52 fractures (17 patients) were considered reducible and had >5 degrees of correction, with a mean improvement in sagittal alignment of this population of 14.2 degrees. Patient surveys revealed significant pain reduction within the first week after surgery and improved activity levels for a majority of patients. CONCLUSIONS: Kyphoplasty improves physical function, reduces pain, and may correct kyphotic deformity associated with vertebral compression fractures.

Treatment of chronic discogenic low back pain with intradiskal electrothermal therapy.

The treatment of chronic, nonradicular, discogenic low back pain remains controversial. The posterior anulus fibrosus appears to be a potential site of origin of the pain, which is mediated by nociceptors in the inner layers of the anulus. Diagnosis requires a thorough history, physical examination, and imaging protocol; provocative diskography is key. Nonsurgical treatment options have been limited to physical therapy and pharmacotherapy. Success rates of spinal fusion range from 39% to 96%. Reported therapeutic success rates of intradiskal electrothermal therapy, a possible intermediate treatment, range from 60% to 80%. Despite this apparent therapeutic effect, however, a more precise quantification of clinical benefits remains to be proved in randomized prospective trials.

Intradiscal electrothermal therapy used to manage chronic discogenic low back pain: new directions and interventions.

STUDY DESIGN: Retrospective literature review. OBJECTIVES: To review the data on the clinical efficacy of intradiscal electrothermal annuloplasty found at this writing in the peer-reviewed literature to date, to discuss the methodologic strengths and flaws of the studies, to discuss the pitfalls of clinical study designs, to emphasize the need for prospective randomized studies and for increased basic science investigation. SUMMARY OF BACKGROUND DATA: Studies published or presented at peer-reviewed societies concerning the clinical efficacy of intradiscal electrothermal annuloplasty are reviewed, including background studies on deafferentation and application of thermal energy to alter biomechanical and structural properties. A proposal for future investigations is presented. METHODS: Background data from intracapsular annuloplasty highlighting the safety and efficacy of intradiscal electrothermal annuloplasty are presented. Current studies on this procedure, including those in the National Registry are reviewed. All the studies share a common study design: prospective cohort with historical or noninterventional groups used as controls. The patients reviewed are similar. All have nonradicular low back pain of at least 3 months duration, failed conservative care, normal neurologic examination, and MRI showing only nondegenerative disc disease and positive concordant discography. All the patients underwent intradiscal electrothermal annuloplasty lesion at one or two levels according to standard protocols. Follow-up evaluation was performed at various intervals up to 2 years. All the studies used data from a visual analog scale, with most using the Short Form 36 (SF-36) as outcome instruments. RESULTS: The reported follow-up periods for the studies ranged from 6 months to 2 years. Three published studies, one with a 6-month follow-up period and two with a 1-year follow-up period, were published in the peer-reviewed literature. Two recent reports presented to the North American Spine Society were reviewed: a study of patients on a manufacturer-sponsored registry with a 1-year follow-up period and a multicenter prospective cohort study of 75 patients in an intent-to-treat group, with a 1-year follow-up period. Using the 7-point criteria of Deyo et al, all the studies suggested a positive effect of treatment, with a decrease in visual analog scale ratings and improvement in SF-36 scales, particularly those for physical function and bodily pain. CONCLUSIONS: The studies published so far suggest that the pain resulting from lumbar disc disease may be diminished by intradiscal electrothermal annuloplasty. All these studies project a positive therapeutic effect. However, all the studies suffer from the same methodologic flaws. A prospective cohort design or a nonrandomized prospective design is used with a biased control. The scientific validity of various study designs is discussed, and a randomized prospective study is recommended. Additionally, more investigation into the basic science of the action of intradiscal electrothermal annuloplasty is required.

The strength of distal fixation of flexor digitorum profundus tendon grafts in human cadavers.

Early active motion limits adhesion formation and thus improves functional performance after tendon grafting. The early strength of distal fixation is critical to successful tendon grafting. We describe a new Y-tunnel technique of distal fixation and compare it with 2 established methods, the Pulvertaft transverse tunnel and the Bunnell button over the fingernail techniques, in a human cadaver model to determine which is the strongest method. Hands with a grafted tendon were rigidly mounted on an anatomic tensiometer testing apparatus and loaded to failure. Mean load to failure (newtons +/- 95% confidence intervals) of the Y-tunnel technique (155.2 +/- 29.4) was greater than those for the Pulvertaft (100.2 +/- 13.2) and Bunnell (57.1 +/- 4.7) techniques. Two-way analysis of variance showed significant differences, and the Bonferroni multiple pairwise comparison test showed that all 3 intergroup comparisons were statistically significant. These results indicate marked improvement in immediate strength with the Y-tunnel technique and lay the groundwork for further studies using a healing tendon model.