Corneal confocal microscopy identifies corneal nerve loss and increased Langerhans cells in presymptomatic carriers and patients with hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo. METHODS: This cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed. RESULTS: Corneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density. CONCLUSIONS: CCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy.

Artificial Intelligence Based Analysis of Corneal Confocal Microscopy Images for Diagnosing Peripheral Neuropathy: A Binary Classification Model.

Diabetic peripheral neuropathy (DPN) is the leading cause of neuropathy worldwide resulting in excess morbidity and mortality. We aimed to develop an artificial intelligence deep learning algorithm to classify the presence or absence of peripheral neuropathy (PN) in participants with diabetes or pre-diabetes using corneal confocal microscopy (CCM) images of the sub-basal nerve plexus. A modified ResNet-50 model was trained to perform the binary classification of PN (PN+) versus no PN (PN-) based on the Toronto consensus criteria. A dataset of 279 participants (149 PN-, 130 PN+) was used to train (n = 200), validate (n = 18), and test (n = 61) the algorithm, utilizing one image per participant. The dataset consisted of participants with type 1 diabetes (n = 88), type 2 diabetes (n = 141), and pre-diabetes (n = 50). The algorithm was evaluated using diagnostic performance metrics and attribution-based methods (gradient-weighted class activation mapping (Grad-CAM) and Guided Grad-CAM). In detecting PN+, the AI-based DLA achieved a sensitivity of 0.91 (95%CI: 0.79-1.0), a specificity of 0.93 (95%CI: 0.83-1.0), and an area under the curve (AUC) of 0.95 (95%CI: 0.83-0.99). Our deep learning algorithm demonstrates excellent results for the diagnosis of PN using CCM. A large-scale prospective real-world study is required to validate its diagnostic efficacy prior to implementation in screening and diagnostic programmes.

Corneal confocal microscopy to detect early immune-mediated small nerve fibre loss in AL amyloidosis.

OBJECTIVE: Light chain (AL) amyloidosis is a life-threatening disorder characterised by extracellular deposition of amyloid leading to dysfunction of multiple organs. Peripheral nerve involvement, particularly small fibre neuropathy, may be associated with poorer survival. Corneal confocal microscopy (CCM) is a rapid and non-invasive imaging technique to quantify corneal small nerve fibres and immune cells in vivo. We aimed to evaluate CCM as a tool for early diagnosis of peripheral nerve involvement in AL amyloidosis. METHODS: CCM and nerve conduction studies (NCS) were undertaken in 21 newly diagnosed, treatment-naïve AL amyloidosis patients and 21 age- and sex-matched healthy controls. Corneal nerve fibre density (CNFD), corneal nerve branch density and fibre length, and cell infiltrates were quantified in the sub-basal layer of the cornea. RESULTS: There was a significant reduction in CNFD and nerve fibre length, even without large fibre affection and an increase in cell density, particularly around corneal nerve fibres in patients with AL amyloidosis compared to controls. Additionally, cell infiltration correlated with reduced nerve fibre density in patients with AL amyloidosis, but reduced CNFD did not correlate with laboratory parameters of organ dysfunction. INTERPRETATION: Our study is the first to show that CCM allows rapid non-invasive identification of early small nerve fibre damage associated with immune cell infiltration in patients with AL amyloidosis. CCM detects peripheral nerve involvement more sensitively than NCS.

Comparison of Surgical Site Infection Risk Between Warfarin, LMWH, and Aspirin for Venous Thromboprophylaxis in TKA or THA: A Systematic Review and Meta-Analysis.

BACKGROUND: Infection following arthroplasty can have devastating effects for the patient and necessitate further surgery. Venous thromboembolism (VTE) prophylaxis is required to minimize the risk of deep venous thrombosis and pulmonary embolism. Anticoagulation has been demonstrated to interfere with wound-healing and increase the risk of infection. We hypothesized that different anticoagulation regimes will have differing effects on rates of periprosthetic joint infection. The aim of this study was to compare the surgical site infection risk between the use of warfarin, low-molecular-weight heparin (LMWH), and aspirin for VTE prophylaxis following total knee or hip arthroplasty. METHODS: A systematic literature search was conducted in November 2018 using the PubMed, CINAHL, and Cochrane Central Register of Controlled Trials (CENTRAL) databases to identify studies that compared warfarin, LMWH, and/or aspirin with regard to surgical site infection rates following hip or knee arthroplasty. Meta-analyses were performed to compare the infection and VTE risks between groups. RESULTS: Nine articles involving 184,037 patients met the inclusion criteria. Meta-analysis showed that warfarin prophylaxis was associated with a higher risk of deep infection (or infection requiring reoperation) (odds ratio [OR] = 1.929, 95% confidence interval [CI] = 1.197 to 3.109, p = 0.007) and surgical site infection overall (OR = 1.610, 95% CI = 1.028 to 2.522, p = 0.038) compared with aspirin in primary total joint arthroplasty, with similar findings also seen when primary and revision procedures were combined. There was no significant difference in infection risk between warfarin and LMWH and between LMWH and aspirin. There was a nonsignificant trend for VTE risk to be higher with warfarin compared with aspirin therapy for primary procedures (OR = 1.600, 95% CI = 0.875 to 2.926, p = 0.127), and this was significant when both primary and revision cases were included (OR = 2.674, 95% CI = 1.143 to 6.255, p = 0.023). CONCLUSIONS: These findings caution against the use of warfarin for VTE prophylaxis for hip and knee arthroplasty. Further randomized head-to-head trials and mechanistic studies are warranted to determine how specific anticoagulants impact infection risk. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Modulation of Small Artery Function by Insulin in Young Women: Role of Adiposity.

OBJECTIVES: Vascular dysfunction is common in obesity. Insulin can directly modulate arterial function, but its role is unclear in obesity. We examined the influence of adiposity on direct effects of insulin on human artery responses. METHODS: 22 healthy women were stratified by median BMI into lower (LA) (n=11) and higher adiposity (HA) (n=11). Small arteries from gluteal biopsies were tested for contractile responses to Noradrenaline (NA), the endothelium-dependent dilator Carbachol and the endothelium-independent dilator sodium nitroprusside were examined before and after incubation with 100 mU/ml human insulin. RESULTS: Contractile responses were similar in the two groups. Insulin reduced NA-induced contraction in HA [3.5 (2.4-4.6) vs. 2.4 (1.4-3.4) mN/mm: p=0.004] but not those from LA [4.1 (2.8-5.3) vs. 3.7 (2.5-5.0) mN/mm: p=0.33]. Endothelium-dependent dilation (EDD) was significantly reduced in arteries from women in the HA (34.7 (18.8-50.6%)) compared to those from women in the LA (62.3 (46.2- 78.4); p=0.013). Insulin improved EDD (change in maximal dilation before/after insulin (%)) in arteries from the HA (37.7 (18.0 to 57.3) but not the LA (6.3 (-6.5 to 19.1), p=0.007. CONCLUSION: Reduced EDD evident in arteries from HA subjects improve by incubating in insulin. Hyperinsulinaemia may be necessary in maintaining endothelial function in obesity.

Rapid Corneal Nerve Fiber Loss: A Marker of Diabetic Neuropathy Onset and Progression.

OBJECTIVE: Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables. RESEARCH DESIGN AND METHODS: We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes. RESULTS: Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA1c or its change over follow-up. CONCLUSIONS: An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP.

No Relation Between the Severity of Corneal Nerve, Epithelial, and Keratocyte Cell Morphology With Measures of Dry Eye Disease in Type 1 Diabetes.

Purpose: Patients with diabetes have a propensity to develop dry eye symptoms (DES), with reduced tear secretion and corneal sensitivity. The underlying pathologic basis of DES was explored in patients with Type 1 diabetes. Methods: Forty-two patients with Type 1 diabetes mellitus (T1DM) (age: 49.21 ± 2.53 years, duration of diabetes: 29.98 ± 2.64 years) and 25 control subjects (age: 48.70 ± 2.84 years) underwent assessment of DES using a validated dry eye questionnaire, and tear stability and tear production were assessed using tear breakup time (TBUT) and Schirmer's test, respectively. Corneal confocal microscopy was undertaken to quantify corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), keratocyte density (KD), and corneal epithelial basal cell (CEBC) density and area. Results: The prevalence of DES was significantly higher (P = 0.03), and TBUT (P = 0.006), corneal sensation (P < 0.0001), CNFD (P = 0.001), CNBD (P = 0.001), CNFL (P = 0.003), and KD (P = 0.04) were significantly lower in patients with T1DM compared to control subjects. However, these measures did not differ significantly between T1DM patients with and without dry eye. There was no correlation between DES and TBUT or corneal nerve keratocyte and CEBC morphology. Conclusions: DES and TBUT are significantly increased in patients with T1DM, but are not related to corneal nerve, basal epithelial, or keratocyte cell morphology.

Diabetic neuropathy and painful diabetic neuropathy: Cinderella complications in South East Asia.

The most common and debilitating microvascular complication of diabetes is diabetic peripheral neuropathy (DPN), affecting 50-90% of people with diabetes. The major manifestations of DPN are painful (pDPN) and painless diabetic peripheral neuropathy. Painful symptoms, occur in the feet and are worse at night and whilst they alert both the patient and physician, are often misdiagnosed and mismanaged. The devastating presentation of painless neuropathy with loss of sensation is foot ulceration and Charcot foot. The explosion of diabetes, especially in the South East Asian (SEA) region will result in an increasing prevalence of both painful and painless diabetic peripheral neuropathy. PubMed, EMBASE, Medline and Google Scholar databases were searched between 1990 and 2017. This highlights the widely varying prevalence of DPN and pDPN in the World Health Organization (WHO) defined SEA countries and the dearth of published studies, especially in pDPN. We believe this will provide new direction for future research on DPN in the SEA region.

Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy.

There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.

Diabetic gastroparesis: Therapeutic options.

Gastroparesis is a condition characterized by delayed gastric emptying and the most common known underlying cause is diabetes mellitus. Symptoms include nausea, vomiting, abdominal fullness, and early satiety, which impact to varying degrees on the patient's quality of life. Symptoms and deficits do not necessarily relate to each other, hence despite significant abnormalities in gastric emptying, some individuals have only minimal symptoms and, conversely, severe symptoms do not always relate to measures of gastric emptying. Prokinetic agents such as metoclopramide, domperidone, and erythromycin enhance gastric motility and have remained the mainstay of treatment for several decades, despite unwanted side effects and numerous drug interactions. Mechanical therapies such as endoscopic pyloric botulinum toxin injection, gastric electrical stimulation, and gastrostomy or jejunostomy are used in intractable diabetic gastroparesis (DG), refractory to prokinetic therapies. Mitemcinal and TZP-101 are novel investigational motilin receptor and ghrelin agonists, respectively, and show promise in the treatment of DG. The aim of this review is to provide an update on prokinetic and mechanical therapies in the treatment of DG.