Painful Diabetic Polyneuropathy: A Comprehensive Guide for Clinicians

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In , we demonstrated the potential of corneal confocal microscopy CCM as a rapid and non-invasive means to quantify central corneal nerve morphology in early and more advanced DPN 5. Subsequently, many studies have confirmed the utility of CCM in quantifying nerve fibre damage in diabetic neuropathy 3 , 6 , 7 , 8 , 9. We and others have also reported corneal nerve fibre loss at the more distal inferior whorl region of the cornea in patients with DPN 10 , 11 and progressively greater nerve fibre damage when moving from the central cornea to the inferior whorl and corneal epithelium in animal models of DPN This is consistent with a dying back neuropathy affecting the more distal nerve fibres in DPN.

Additionally, the inferior whorl IW is a distinctive spiralled, clockwise sub-basal nerve fibre pattern located in the inferonasal cornea 13 , Because of its unique pattern, it has been suggested that it may be a more reliable landmark for longitudinal and interventional assessment of the corneal sub-basal nerve plexus Two previous reports showed that corneal nerve fibre length at the IW and centre has comparable sensitivity and reliability for detecting DPN 11 , We have also previously suggested that a combination of corneal nerve fibre length at the centre and inferior whorl may increase the sensitivity of CCM in detecting DPN A small study has demonstrated a greater reduction in central corneal nerve fibre length in patients with painful diabetic neuropathy 3.

In the present study, we have compared corneal nerve pathology in the central and inferior whorl regions in relation to the severity and presence of DPN and painful DPN and quality of life. Patients were excluded if they had a history of malignancy, neuropathy of non-diabetic cause, current or active diabetic foot ulceration, deficiency of B12 or folate, chronic renal impairment or liver failure, connective tissue or systemic disease, corneal trauma, systemic disease that involves the cornea and cystic corneal disorders.

Before participation informed consent was obtained from each participant. All participants underwent assessment of body mass index BMI and blood pressure. Neurological deficits were assessed using the Neuropathy Disability Score NDS , which includes an assessment of vibration perception, pinprick, temperature sensation and presence or absence of ankle reflexes This survey consists of 36 questions, measures eight different dimensions, which are scored from 0 to We used SF total score, an average of eight dimensions as a single measure of quality of life.

Six images from the central cornea and four images from inferior whorl at the level of sub-basal nerve plexus were selected and manually quantified using CCMetrics The University of Manchester, Manchester, UK. Images were selected based on their quality and variability using our established protocol 11 , Independent T-test Mann Witney U test for nonparametric variables was used to assess the estimates between two groups.

The analysis of covariance Ancova post hoc LSD was used to compare variables between groups, while statistically controlling for the effects of age. Graphpad Prism Version 7. There was no significant difference in age between control subjects and patients with diabetes Systolic BP mmHg PMNA mV 4.

Corneal nerve fibre density no. The scatterplot Fig.

A Comprehensive Guide for Clinicians

CCM is a rapid, reproducible ophthalmic technique that can quantify corneal nerve fibre abnormalities in diabetic and a number of other peripheral neuropathies 3 , 25 , 26 , 27 , Two recent studies have shown that CCM has a diagnostic ability, which is comparable to the current gold standard technique of skin biopsy 9 , DPN is length-dependent neuropathy and will therefore affect the most distal nerve fibres first 30 i.

Corneal nerve loss has been reported to be comparable at the inferior whorl and central cornea in diabetic patients with and without neuropathy 11 , 15 , Given this difference we postulated that a combination of both corneal nerve fibre length and inferior whorl length, either as a total or average length may be more useful than either measure alone.

Indeed, inferior whorl length, average and total nerve fibre length rather than the standard parameters of corneal nerve fibre density, branch density and length correlate with the quality of life and the presence and severity of painful diabetic neuropathy. Given that new therapies for diabetic neuropathy should induce nerve repair in the most distal part of the nerve, we propose that quantification of inferior whorl length and the average and total nerve fibre length may provide a more powerful means to assess a therapeutic response than has already been demonstrated by quantifying central corneal nerve morphology 31 , 32 , An additional advantage is the unique pattern of the IW, which facilitates its use as a landmark in longitudinal and interventional studies.

To our knowledge the association between CCM parameters and QoL and presence and severity of neuropathic pain has not been previously reported. QoL is an important patient outcome and we used the validated SF questionnaire 34 to assess the QoL in patients in this study. Furthermore, inferior whorl length, average and total nerve fibre length differentiate patients with and without painful neuropathy and correlate with the severity of painful neuropathy, whereas corneal nerve fibre density, branch density and length, do not.

A potential limitation of our study is that the diagnosis of painful diabetic neuropathy was principally based on the VAS and NDS scores, but this is in accord with the IASP definition for neuropathic pain as adopted by a recent large painful neuropathy phenotyping study We believe future studies should better stratify cases in relation to the severity and sub-types of diabetic neuropathy.

In conclusion we have shown that there is more prominent distal corneal nerve fibre damage at the inferior whorl in patients with diabetic neuropathy. It also provides an objective measure of small nerve fibre damage, which relates to the presence of painful diabetic neuropathy and the quality of life. Further studies deploying these novel measures of more distal corneal nerve damage and repair are required in longitudinal studies and in clinical trials of new therapies to define their clinical utility. Boulton, A. Diabetic neuropathies: a statement by the American Diabetes Association.

Diabetes care 28 , — Tesfaye, S. Epidemiology and etiology of diabetic peripheral neuropathies. Advanced Studies in Medicine 4 , S—S Quattrini, C. Surrogate markers of small fiber damage in human diabetic neuropathy. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Malik, R. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients.

Ahmed, A.

Topic Overview

Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: a concurrent validity study. Petropoulos, I. Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy. Maddaloni, E. In vivo corneal confocal microscopy as a novel non-invasive tool to investigate cardiac autonomic neuropathy in Type 1 diabetes. Ziegler, D.

Diabetes, Nerve Pain, and Medication

Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes. Edwards, K. Wide-field assessment of the human corneal subbasal nerve plexus in diabetic neuropathy using a novel mapping technique. Cornea 31 , — Davidson, E.

Differences and similarities in development of corneal nerve damage and peripheral neuropathy and in diet-induced obesity and type 2 diabetic rats. Marfurt, C. Anatomy of the human corneal innervation. Patel, D. Mapping of the normal human corneal sub-Basal nerve plexus by in vivo laser scanning confocal microscopy. Utsunomiya, T. Pritchard, N. Huizinga, M. Clinical Diabetes 25 , 6—15 Abbott, C. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.

Understanding the impact of painful diabetic neuropathy. Themistocleous, A. The Pain in Neuropathy Study PiNS : a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Young, M. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population.

Diabetic Neuropathy Clinical Research Trials | CenterWatch

Diabetologia 36 , — Symptoms of diabetic neuropathy may vary depending on the type of neuropathy you have. Peripheral neuropathy tends to develop slowly over months or years. In general, symptoms may include:. Autonomic neuropathy may affect digestion, the body's ability to regulate temperature, urination, sexual function, and heart and blood vessel function, including blood pressure. Symptoms may get worse during pregnancy. Symptoms of focal neuropathy usually appear suddenly. They may include:. Symptoms of focal neuropathy usually get better over time.

But focal neuropathy may be permanent. A diagnosis of diabetic neuropathy is based largely on your symptoms, medical history and physical examination. During a physical exam, your doctor may check how well you feel light touch, temperature, pain, vibration, and movement.

Your doctor may also check your strength and reflexes. Electromyogram EMG and nerve conduction studies may be done to confirm a diagnosis. These tests measure how well and how quickly the nerves conduct electrical impulses. When nerve damage is present, the speed of nerve function slows.

Problems linked with autonomic neuropathy—which affects the nerves that control internal functions—can be hard to diagnose. When new symptoms develop, more testing may be needed to diagnose the problem, identify the cause, and guide treatment. For example, a study that measures how fast your stomach empties may be done if symptoms like bloating, indigestion, or vomiting suggest gastroparesis , a condition that causes the stomach to take too long to empty.

Nerve problems in people who have diabetes may be caused by other conditions, such as kidney disease, alcohol use disorder , or a vitamin B12 deficiency. A variety of laboratory tests such as a complete blood count may be used to screen for conditions other than diabetes that could be causing symptoms. Your symptoms and medical history will determine which tests are needed. For some diseases, doctors can use screening tests to look for problems before you have any symptoms.

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But doctors can't test for all types of autonomic or focal neuropathy. So it is important to report to your doctor any pain, weakness, or motor problems you have. Also mention any changes in digestion, urination, sexual function, sweating, or dizziness.

Painful Diabetic Polyneuropathy: A Comprehensive Guide for Clinicians

Your doctor will also look for signs of autonomic neuropathy during your physical exams. The American Diabetes Association ADA recommends that people who have diabetes see a doctor to examine their feet for cracked or peeling skin, excessive or reduced sweating, blisters, calluses, ulcers, signs of infection, bone and joint abnormalities, and walking and balance—during each medical visit. The ADA also recommends a complete foot exam by a doctor at least once a year.

This examination can detect a loss of sensation in your feet, which can lead to more serious foot problems.