Novel insights on diagnosis, cause and treatment of diabetic neuropathy: Focus on painful diabetic neuropathy

Diabetic neuropathy is common, under or misdiagnosed, and causes substantial morbidity with increased mortality. Defining and developing sensitive diagnostic tests for diabetic neuropathy is not only key to implementing earlier interventions but also to ensure that the most appropriate endpoints are employed in clinical intervention trials. This is critical as many potentially effective therapies may never progress to the clinic, not due to a lack of therapeutic effect, but because the endpoints were not sufficiently sensitive or robust to identify benefit. Apart from improving glycaemic control, there is no licensed treatment for diabetic neuropathy, however, a number of pathogenetic pathways remain under active study. Painful diabetic neuropathy is a cause of considerable morbidity and whilst many pharmacological and nonpharmacological interventions are currently used, only two are approved by the US Food and Drug Administration. We address the important issue of the ‘placebo effect’ and also consider potential new pharmacological therapies as well as nonpharmacological interventions in the treatment of painful diabetic neuropathy

Corneal nerve fractal dimension: a novel corneal nerve metric for the diagnosis of diabetic sensorimotor polyneuropathy

Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD). Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements. Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD. Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN

Engaging with community-based public and private mid-level providers for promoting the use of modern contraceptive methods in rural Pakistan: Results from two innovative birth spacing interventions

Background: Family planning (FP) interventions aimed at reducing population growth have negligible during the last two decades in Pakistan. Innovative FP interventions that help reduce the growing population burden are the need of the hour. Marie Stopes Society--Pakistan implemented an operational research project--\u27Evidence for Innovating to Save Lives\u27, to explore effective and viable intervention models that can promote healthy timing and spacing of pregnancy in rural and under-served communities of Sindh, Punjab and Khyber Pakhtunkhwa provinces of Pakistan.Methods: We conducted a quasi-experimental (pre- and post-intervention with control arm) study to assess the effectiveness of each of the two intervention models, (1) Suraj model (meaning \u27Sun\u27 in English), which uses social franchises (SF) along with a demand-side financing (DSF) approach using free vouchers, and (2) Community Midwife (CMW) model, in promoting the use of modern contraceptive methods compared to respective controls. Baseline and endline cross-sectional household surveys were conducted, 24 months apart, by recruiting 5566 and 6316 married women of reproductive age (MWRA) respectively. We used Stata version 8 to report the net effect of interventions on outcome indicators using difference-in-differences analysis. Multivariate Cox proportional hazard regression analysis was used to assess the net effect of the intervention on current contraceptive use, keeping time constant and adjusting for other variables in the model.Results: The Suraj model was effective in significantly increasing awareness about FP methods among MWRA by 14% percentage points, current contraceptive use by 5% percentage points and long term modern method--intrauterine device (IUD) use by 6% percentage points. The CMW model significantly increased contraceptive awareness by 28% percentage points, ever use of contraceptives by 7% percentage points and, IUD use by 3% percentage points. Additionally the Suraj intervention led to a 35% greater prevalence (prevalence ratio: 1.35, 95% CI: 1.22-1.50) of contraceptive use among MWRA.Conclusion: Suraj intervention highlights the importance of embedding subsidized FP services within the communities of the beneficiaries. The outcomes of the CMW intervention also improved the use of long-term contraceptives. These findings indicate the necessity of designing and implementing FP initiatives involving local mid-level providers to expand contraceptive coverage in under-served areas

Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy

OBJECTIVE: To establish if corneal nerve loss, detected using in vivo corneal confocal microscopy (IVCCM), is symmetrical between right and left eyes and relates to the severity of diabetic neuropathy. RESEARCH DESIGN AND METHODS: Patients (n = 111) with type 1 and type 2 diabetes and 47 age-matched healthy control subjects underwent detailed assessment and stratification into no (n = 50), mild (n = 26), moderate (n = 17), and severe (n = 18) neuropathy. IVCCM was performed in both eyes and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) and the tortuosity coefficient were quantified. RESULTS: All corneal nerve parameters differed significantly between diabetic patients and control subjects and progressively worsened with increasing severity of neuropathy. The reduction in CNFD, CNBD, and CNFL was symmetrical in all groups except in patients with severe neuropathy. CONCLUSIONS: IVCCM noninvasively detects corneal nerve loss, which relates to the severity of neuropathy, and is symmetrical, except in those with severe diabetic neuropathy

Corneal nerve fractal dimension: a novel corneal nerve metric for the diagnosis of diabetic sensorimotor polyneuropathy

Objective: Corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD).Methods: A total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements.Results: Manual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD.Conclusions: ACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN

Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy

Purpose. To assess the diagnostic validity of a fully automated image analysis algorithm of in vivo confocal microscopy images in quantifying corneal subbasal nerves to diagnose diabetic neuropathy. Methods. One hundred eighty-six patients with type 1 and type 2 diabetes mellitus (T1/ T2DM) and 55 age-matched controls underwent assessment of neuropathy and bilateral in vivo corneal confocal microscopy (IVCCM). Corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL) were quantified with expert, manual, and fully-automated analysis. The areas under the curve (AUC), odds ratios (OR), and optimal thresholds to rule out neuropathy were estimated for both analysis methods. Results. Neuropathy was detected in 53% of patients with diabetes. A significant reduction in manual and automated CNBD (P &lt;0.001) and CNFD (P &lt;0.0001), and CNFL (P &lt;0.0001) occurred with increasing neuropathic severity. Manual and automated analysis methods were highly correlated for CNFD (r = 0.9, P &lt;0.0001), CNFL (r = 0.89, P &lt;0.0001), and CNBD (r = 0.75, P &lt;0.0001). Manual CNFD and automated CNFL were associated with the highest AUC, sensitivity/specificity and OR to rule out neuropathy. Conclusions. Diabetic peripheral neuropathy is associated with significant corneal nerve loss detected with IVCCM. Fully automated corneal nerve quantification provides an objective and reproducible means to detect human diabetic neuropathy. © 2014 The Association for Research in Vision and Ophthalmology, Inc

Continuation rates and reasons for discontinuation of intra-uterine device in three provinces of Pakistan: Results of a 24-month prospective client follow-up

Background: Long-acting reversible contraceptives, such as the intrauterine device (IUD), remain underutilised in Pakistan with high discontinuation rates. Based on a 24-month prospective client follow-up (nested within a larger quasi-experimental study), this paper presents the comparison of two intervention models, one using private mid-level providers branded as Suraj and the other using community midwives (CMWs) of Maternal Newborn and Child Health Programme, for method continuation among IUD users. Moreover, determinants of IUD continuation and the reasons for discontinuation, and switching behaviour were studied within each arm.Methods: A total of 1,163 IUD users, 824 from Suraj and 339 from the CMW model, were enrolled in this 24-month prospective client follow-up. Participants were followed-up by female community mobilisers physically every second month to ascertain continued IUD usage and to collect information on associated factors, switching behaviour, reasons for discontinuation, and pregnancy occurrence. The probabilities of IUD continuation and the risk factors for discontinuation were estimated by life table analysis and Cox proportional-hazard techniques, respectively.Results: The cumulative probabilities of IUD continuation at 24 months in Suraj and CMW models were 82% and 80%, respectively. The difference between the two intervention areas was not significant. The probability distributions of IUD continuation were also similar in both interventions (Log rank test: χ(2) = 0.06, df = 1, P = 0.81; Breslow test: χ(2) = 0.6, df = 1, P = 0.44). Health concerns (Suraj = 57.1%, CMW = 38.7%) and pregnancy desire (Suraj = 29.3%, CMW = 40.3%) were reported as the most prominent reasons for IUD discontinuation in both intervention arms. IUD discontinuation was significantly associated with place of residence in Suraj and with age (15-25 years) in the CMW model.Conclusion: CMWs and private providers are equally capable of providing quality IUD services and ensuring higher method continuation. Pakistan\u27s National Maternal Newborn and Child Health programme should consider training CMWs and providing IUDs through them. Moreover, private sector mid-level providers could be engaged in promoting the use of IUDs

Small nerve fibre quantification in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal microscopy with intraepidermal nerve fibre density

OBJECTIVE: Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard. RESEARCH DESIGN AND METHODS: Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy. RESULTS: Manual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14). CONCLUSIONS: This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN