Corneal confocal microscopy for diagnosis of diabetic peripheral neuropathy: an analysis of patients with diabetes screened as part of the South Manchester Diabetic Retinopathy Screening Service

Background and Aims: Quantitative assessment of small nerve fibre damage is key to the early diagnosis of diabetic peripheral neuropathy (DPN) and assessment of its progression. Corneal confocal microscopy (CCM) is a non-invasive, in-vivo diagnostic technique that provides an accurate surrogate biomarker for small fibre neuropathy. Its diagnostic efficacy has been previously validated in several studies. This thesis uses CCM images obtained, for the first time, in a large cohort of patients whose CCM examinations were undertaken during retinopathy screening in primary care. The following were the primary aims of the study: 1. To determine the prevalence of diabetic peripheral neuropathy, as defined by CCM parameters in a cohort of people with diabetes 2.To assess whether abnormalities in corneal nerve fibre morphology are present during the first two years following diabetes diagnosis. 3. To assess whether abnormalities in corneal nerve morphology are present prior to any retinopathy, defined as grade 1 or more. 4. To assess whether abnormalities in corneal nerve morphology are present prior to clinical evidence of diabetic neuropathy, as defined by diabetic neuropathic symptom (DNS) scoring of 1 or more The hypotheses for these main aims were that firstly, the prevalence of diabetic peripheral neuropathy, defined using CCM parameters would be lower in this population in comparison to previous CCM studies using patients under the hospital eye service to determine prevalence of DPN. There will be evidence of abnormalities in corneal nerve fibre morphology in some, but not all, patients with diabetic disease duration of less than or equal to 2 years, patients with retinopathy and maculopathy grade 0 and patients with a DNS score of 0. Methods: In this retrospective, primary care, cross-sectional study, 427 patients with diabetes (18 T1DM, 407 T2DM, 2 unknown) and 40 healthy controls underwent quantification of corneal nerve parameters using both automated and semi-automated analysis software. Clinical levels of neuropathy were assessed via diabetic neuropathy symptom score (DNS). Diabetic Retinopathy (DR) was graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale. Results: Patients with diabetes demonstrated significant differences in all nerve parameters in comparison to healthy control subjects (p0.05). There was no significant difference in any CCM parameters between white and black patients with diabetes (p>0.05). Automated software showed poor agreement with semi-automated results, with a general underestimation for CNFD, CNFL and CNBD. Conclusion: In patients attending primary care screening, CCM in a sensitive biomarker for DPN. Semi-automated CCM quantification reliably detected corneal nerve abnormalities soon after diagnosis of diabetes. Changes in corneal nerve morphology were present prior to any neuropathy symptoms or retinopathy. CCM measured using automatic software requires development to improve agreement with semi-automated analysis

An investigation into central nervous system involvement in distal symmetrical diabetic neuropathy in type 1 diabetes mellitus.

Diabetes is a leading cause of peripheral neuropathy. It is the main initiating factor for foot ulceration and amputation resulting in considerable morbidity and remarkable consumption of scarce medical resources. Relatively little is known about the pathophysiology underlying DPN. Research into DPN has focused mainly on the peripheral nervous system (PNS) with central nervous system (CNS) involvement relatively overlooked. The studies undertaken have been designed to investigate CNS involvement in DPN. 1. Before embarking on spinal cord studies, I reviewed and modified the techniques employed in the pilot study to improve the precision and accuracy of cord cross sectional area measurements. These modifications were patiented to quality control studies, which are reported in Chapter 2. 2. I performed in-vivo cross-sectional magnetic resonance imaging of the cervical spine and reported evidence of spinal cord shrinkage (atrophy) in Painless DPN (Chapter 3). This study showed spinal cord atrophy to be an early phenomenon, present even in subclinical DPN. As the spinal cord is the caudal portion of the CNS, its involvement made us question whether the brain too may be involved. 3. Using MR spectroscopy I examined thalamic involvement in Painless DPN (Chapter 4). This deep brain nucleus is considered the gateway to all somatosensory information entering the brain, and responsible for modulation of sensory information prior to presentation to the cerebral cortex. I demonstrated thalamic biochemical abnormalities consistent with possible neuronal dysfunction in patients with Painless DPN. 4. The demonstration of thalamic neuronal dysfunction in DPN suggests that CNS involvement is not limited to the spinal cord but other important areas, responsible for somatosensory perception, may also be involved. Although the pathogenesis of thalamic involvement is unknown, it is likely that both vascular and metabolic factors that have been implicated in the pathogenesis of DPN are involved. In Chapter 4, I examined the possible role of metabolic factors in the pathogenesis of thalamic neuronal dysfunction in DPN. Using MR spectroscopy, I demonstrated a significant elevation in thalamic glutamine/glutamate in patients with diabetes. Glutamate is the most abundant excitatory neurotransmitter and implicated in various models of neuronal cell death. Astrocytes, which play an important role in glutamate/glutamine metabolism, were impaired in the thalamus of diabetic patients in this study. The combination of elevated glutamate and impaired thalamic astrocytes may provide a pathophysiological explanation for thalamic dysfunction in DPN. 5. In Chapter 5, an alternative hypothesis for thalamic neuronal dysfunction in DPN was tested. Using dynamic contrast enhanced MR perfusion imaging, I demonstrated that Painful DPN is associated with unique thalamic perfusion abnormalities. Intriguingly, these abnormalities were present in patients with Painful but not Painless DPN. 6. Finally, in Chapter 6, I conducted a randomised, double blind and placebo-control trial (RCT) comparing the efficacy and tolerability of sativex, a cannabis based medicinal extract (CBME), with placebo in the symptomatic treatment of painful DPN. This is the first ever RCT using a CBME in painful DPN. We report no significant difference in the primary outcome measure due to a massive placebo effect and that depression is a potential major confounder in such clinical trials

Diabetic peripheral neuropathy : advances in diagnosis and strategies for screening and early intervention

Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae

Signature for Pain Recovery IN Teens (SPRINT): protocol for a multisite prospective signature study in chronic musculoskeletal pain

INTRODUCTION: Current treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific treatment strategies and conceiving novel approaches that benefit all patients. Given that chronic pain is a biopsychosocial process, this study aims to discover and validate a robust prognostic signature that measures across multiple dimensions in the same adolescent patient cohort with a computational analysis pipeline. This will facilitate risk stratification in adolescent patients with chronic MSK pain and more resourceful allocation of patients to costly and potentially burdensome multidisciplinary pain treatment approaches. METHODS AND ANALYSIS: Here we describe a multi-institutional effort to collect, curate and analyse a high dimensional data set including epidemiological, psychometric, quantitative sensory, brain imaging and biological information collected over the course of 12 months. The aim of this effort is to derive a multivariate model with strong prognostic power regarding the clinical course of adolescent MSK pain and function. ETHICS AND DISSEMINATION: The study complies with the National Institutes of Health policy on the use of a single internal review board (sIRB) for multisite research, with Cincinnati Children's Hospital Medical Center Review Board as the reviewing IRB. Stanford's IRB is a relying IRB within the sIRB. As foreign institutions, the University of Toronto and The Hospital for Sick Children (SickKids) are overseen by their respective ethics boards. All participants provide signed informed consent. We are committed to open-access publication, so that patients, clinicians and scientists have access to the study data and the signature(s) derived. After findings are published, we will upload a limited data set for sharing with other investigators on applicable repositories. TRIAL REGISTRATION NUMBER: NCT04285112