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.

Prevalence and risk factors for diabetic peripheral neuropathy, neuropathic pain and foot ulceration in the Arabian Gulf region.

AIMS/INTRODUCTION: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN), painful DPN and diabetic foot ulceration (DFU) in patients with type 2 diabetes in secondary healthcare in Qatar, Kuwait and the Kingdom of Saudi Arabia. MATERIALS AND METHODS: Adults aged 18-85 years with type 2 diabetes were randomly enrolled from secondary healthcare, and underwent clinical and metabolic assessment. DPN was evaluated using vibration perception threshold and neuropathic symptoms and painful Diabetic Peripheral Neuropathy was evaluated using the Douleur Neuropathique 4 questionnaire. RESULTS: A total of 3,021 individuals were recruited between June 2017 and May 2019. The prevalence of DPN was 33.3%, of whom 52.2% were at risk of DFU and 53.6% were undiagnosed. The prevalence of painful DPN was 43.3%, of whom 54.3% were undiagnosed. DFU was present in 2.9%. The adjusted odds ratios for DPN and painful DPN were higher with increasing diabetes duration, obesity, poor glycemic control and hyperlipidemia, and lower with greater physical activity. The adjusted odds ratio for DFU was higher with the presence of DPN, severe loss of vibration perception, hypertension and vitamin D deficiency. CONCLUSIONS: This is the largest study to date from the Middle East showing a high prevalence of undiagnosed DPN, painful DPN and those at risk of DFU in patients with type 2 diabetes, and identifies their respective risk factors.

Loss of corneal nerves and brain volume in mild cognitive impairment and dementia.

Introduction: This study compared the capability of corneal confocal microscopy (CCM) with magnetic resonance imaging (MRI) brain volumetry for the diagnosis of mild cognitive impairment (MCI) and dementia. Methods: In this cross-sectional study, participants with no cognitive impairment (NCI), MCI, and dementia underwent assessment of Montreal Cognitive Assessment (MoCA), MRI brain volumetry, and CCM. Results: Two hundred eight participants with NCI (n = 42), MCI (n = 98), and dementia (n = 68) of comparable age and gender were studied. For MCI, the area under the curve (AUC) of CCM (76% to 81%), was higher than brain volumetry (52% to 70%). For dementia, the AUC of CCM (77% to 85%), was comparable to brain volumetry (69% to 93%). Corneal nerve fiber density, length, branch density, whole brain, hippocampus, cortical gray matter, thalamus, amygdala, and ventricle volumes were associated with cognitive impairment after adjustment for confounders (All P's < .01). Discussion: The diagnostic capability of CCM compared to brain volumetry is higher for identifying MCI and comparable for dementia, and abnormalities in both modalities are associated with cognitive impairment.

Insulin resistance limits corneal nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control.

AIMS/INTRODUCTION: This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy. MATERIALS AND METHODS: This was an exploratory substudy of an open-label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy. RESULTS: A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low-density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05). CONCLUSIONS: Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control.

Painful diabetic neuropathy is associated with increased nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control.

AIMS/INTRODUCTION: Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. MATERIALS AND METHODS: This exploratory substudy of an open-label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal-bolus insulin at baseline and 1-year follow up, and 18 controls at baseline only. RESULTS: Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain. CONCLUSIONS: This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy.

Prevalence and risk factors for diabetic neuropathy and painful diabetic neuropathy in primary and secondary healthcare in Qatar.

AIMS/INTRODUCTION: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN) and painful DPN (pDPN) in patients with type 2 diabetes in primary healthcare (PHC) and secondary healthcare (SHC) in Qatar. MATERIALS AND METHODS: This was a cross-sectional multicenter study. Adults with type 2 diabetes were randomly enrolled from four PHC centers and two diabetes centers in SHC in Qatar. Participants underwent assessment of clinical and metabolic parameters, DPN and pDPN. RESULTS: A total of 1,386 individuals with type 2 diabetes (297 from PHC and 1,089 from SHC) were recruited. The prevalence of DPN (14.8% vs 23.9%, P = 0.001) and pDPN (18.1% vs 37.5%, P < 0.0001) was significantly lower in PHC compared with SHC, whereas those with DPN at high risk for diabetic foot ulceration (31.8% vs 40.0%, P = 0.3) was comparable. The prevalence of undiagnosed DPN (79.5% vs 82.3%, P = 0.66) was comparably high, but undiagnosed pDPN (24.1% vs 71.5%, P < 0.0001) was lower in PHC compared with SHC. The odds of DPN and pDPN increased with age and diabetes duration, and DPN increased with poor glycemic control, hyperlipidemia and hypertension, whereas pDPN increased with obesity and reduced physical activity. CONCLUSIONS: The prevalence of DPN and pDPN in type 2 diabetes is lower in PHC compared with SHC, and is attributed to overall better control of risk factors and referral bias due to patients with poorly managed complications being referred to SHC. However, approximately 80% of patients had not been previously diagnosed with DPN in PHC and SHC. Furthermore, we identified a number of modifiable risk factors for PDN and pDPN.

Association of Cerebral Ischemia With Corneal Nerve Loss and Brain Atrophy in MCI and Dementia.

INTRODUCTION: This study assessed the association of cerebral ischemia with neurodegeneration in mild cognitive impairment (MCI) and dementia. METHODS: Subjects with MCI, dementia and controls underwent assessment of cognitive function, severity of brain ischemia, MRI brain volumetry and corneal confocal microscopy. RESULTS: Of 63 subjects with MCI (n = 44) and dementia (n = 19), 11 had no ischemia, 32 had subcortical ischemia and 20 had both subcortical and cortical ischemia. Brain volume and corneal nerve measures were comparable between subjects with subcortical ischemia and no ischemia. However, subjects with subcortical and cortical ischemia had a lower hippocampal volume (P < 0.01), corneal nerve fiber length (P < 0.05) and larger ventricular volume (P < 0.05) compared to those with subcortical ischemia and lower corneal nerve fiber density (P < 0.05) compared to those without ischemia. DISCUSSION: Cerebral ischemia was associated with cognitive impairment, brain atrophy and corneal nerve loss in MCI and dementia.

Corneal confocal microscopy: ready for prime time.

Corneal confocal microscopy is a non-invasive ophthalmic imaging modality, which was initially used for the diagnosis and management of corneal diseases. However, over the last 20 years it has come to the forefront as a rapid, non-invasive, reiterative, cost-effective imaging biomarker for neurodegeneration. The human cornea is endowed with the densest network of sensory unmyelinated axons, anywhere in the body. A robust body of evidence shows that corneal confocal microscopy is a reliable and reproducible method to quantify corneal nerve morphology. Changes in corneal nerve morphology precede or relate to clinical manifestations of peripheral and central neurodegenerative conditions. Moreover, in clinical intervention trials, corneal nerve regeneration occurs early and predicts functional gains in trials of neuroprotection. In view of these findings, it is timely to summarise the knowledge in this area of research and to explain why the case for corneal confocal microscopy is sufficiently compelling to argue for its inclusion as a Food and Drug Administration endpoint in clinical trials of peripheral and central neurodegenerative conditions.

Corneal confocal microscopy identifies greater corneal nerve damage in patients with a recurrent compared to first ischemic stroke.

OBJECTIVES: Corneal nerve damage may be a surrogate marker for the risk of ischemic stroke. This study was undertaken to determine if there is greater corneal nerve damage in patients with recurrent ischemic stroke. METHODS: Corneal confocal microscopy (CCM) was used to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and corneal nerve fiber tortuosity (CNFT) in 31 patients with recurrent ischemic stroke, 165 patients with a first acute ischemic stroke and 23 healthy control subjects. RESULTS: Triglycerides (P = 0.004, P = 0.017), systolic BP (P = 0.000, P = 0.000), diastolic BP (P = 0.000, P = 0.000) and HbA1c (P = 0.000, P = 0.000) were significantly higher in patients with first and recurrent stroke compared to controls. There was no difference in age, BMI, HbA1c, total cholesterol, triglycerides, LDL, HDL, systolic and diastolic BP between patients with a first and recurrent ischemic stroke. However, CNFD was significantly lower (24.98±7.31 vs 29.07±7.58 vs 37.91±7.13, P<0.05) and CNFT was significantly higher (0.085±0.042 vs 0.064±0.037 vs 0.039±0.022, P<0.05) in patients with recurrent stroke compared to first stroke and healthy controls. CNBD (42.21±24.65 vs 50.46±27.68 vs 87.24±45.85, P<0.001) and CNFL (15.66±5.70, P<0.001 vs 17.38±5.06, P = 0.003) were equally reduced in patients with first and recurrent stroke compared to controls (22.72±5.14). CONCLUSIONS: Corneal confocal microscopy identified greater corneal nerve fibre loss in patients with recurrent stroke compared to patients with first stroke, despite comparable risk factors. Longitudinal studies are required to determine the prognostic utility of corneal nerve fiber loss in identifying patients at risk of recurrent ischemic stroke.

Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study.

INTRODUCTION: To assess the effect of exenatide and pioglitazone or basal-bolus insulin on diabetic peripheral neuropathy (DPN) in patients with poorly controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This is a substudy of the Qatar Study, an open-label, randomized controlled trial. 38 subjects with poorly controlled T2D were studied at baseline and 1-year follow-up and 18 control subjects were assessed at baseline only. A combination of exenatide (2 mg/week) and pioglitazone (30 mg/day) or glargine with aspart insulin were randomly assigned to patients to achieve an HbA1c <53 mmol/mol (<7%). DPN was assessed with corneal confocal microscopy (CCM), DN4, vibration perception and sudomotor function. RESULTS: Subjects with T2D had reduced corneal nerves, but other DPN measures were comparable with the control group. In the combination treatment arm (n=21), HbA1c decreased by 35.2 mmol/mol (3.8 %) (p<0.0001), body weight increased by 5.6 kg (p<0.0001), corneal nerve branch density increased (p<0.05), vibration perception worsened (p<0.05), and DN4 and sudomotor function showed no change. In the insulin treatment arm, HbA1c decreased by 28.7 mmol/mol (2.7 %) (p<0.0001), body weight increased by 4.6 kg (p<0.01), corneal nerve branch density and fiber length increased (p≤0.01), vibration perception improved (p<0.01), and DN4 and sudomotor function showed no change. There was no association between the change in CCM measures with change in HbA1c, weight or lipids. CONCLUSIONS: Treatment with exenatide and pioglitazone or basal-bolus insulin results in corneal nerve regeneration, but no change in neuropathic symptoms or sudomotor function over 1 year.

Corneal Nerve and Brain Imaging in Mild Cognitive Impairment and Dementia.

BACKGROUND: Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer's disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders. OBJECTIVE: To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI. METHODS: Subjects aged 60-85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI. RESULTS: 182 subjects with NCI (n = 36), MCI (n = 80), and dementia (n = 66), including AD (n = 19, 28.8%), VaD (n = 13, 19.7%), and mixed AD (n = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2) (32.0±7.5 versus 24.5±9.6 and 20.8±9.3, p < 0.0001), branch density (CNBD, branches/mm2) (90.9±46.5 versus 59.3±35.7 and 53.9±38.7, p < 0.0001), and fiber length (CNFL, mm/mm2) (22.9±6.1 versus 17.2±6.5 and 15.8±7.4, p < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67-90%), 82% (72-92%), 86% (77-95%) versus 53% (36-69%) and 40% (25-55%), respectively, and for dementia it was 85% (76-94%), 84% (75-93%), 85% (76-94%) versus 86% (76-96%) and 82% (72-92%), respectively. CONCLUSION: The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI.

Association of corneal nerve fiber measures with cognitive function in dementia.

OBJECTIVES: Corneal confocal microscopy (CCM) is a noninvasive ophthalmic technique that identifies corneal nerve degeneration in a range of peripheral neuropathies and in patients with multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. We sought to determine whether there is any association of corneal nerve fiber measures with cognitive function and functional independence in patients with MCI and dementia. METHODS: In this study, 76 nondiabetic participants with MCI (n = 30), dementia (n = 26), and healthy age-matched controls (n = 20) underwent assessment of cognitive and physical function and CCM. RESULTS: There was a progressive reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P < 0.0001) in patients with MCI and dementia compared to healthy controls. Adjusted for confounders, all three corneal nerve fiber measures were significantly associated with cognitive function (P < 0.05) and functional independence (P < 0.01) in MCI and dementia. The area under the ROC curve to distinguish MCI with CNFD, CNBD, and CNFL was 69.1%, 73.2%, and 73.0% and for dementia it was 84.8%, 84.2%, and 86.2%, respectively. INTERPRETATION: CCM demonstrates corneal nerve fiber loss, which is associated with a decline in cognitive function and functional independence in patients with MCI and dementia.

Diagnosing Diabetic Neuropathy: Something Old, Something New.

There are potentially many ways of assessing diabetic peripheral neuropathy (DPN). However, they do not fulfill U.S. Food and Drug Administration (FDA) requirements in relation to their capacity to assess therapeutic benefit in clinical trials of DPN. Over the past several decades symptoms and signs, quantitative sensory and electrodiagnostic testing have been strongly endorsed, but have consistently failed as surrogate end points in clinical trials. Therefore, there is an unmet need for reliable biomarkers to capture the onset and progression and to facilitate drug discovery in DPN. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging modality for in vivo evaluation of sensory C-fibers. An increasing body of evidence from multiple centers worldwide suggests that CCM fulfills the FDA criteria as a surrogate endpoint of DPN.