Corneal confocal microscopy detects severe small fiber neuropathy in diabetic patients with Charcot neuroarthropathy

Aims/Introduction

The aim of the present study was to identify the extent of small fiber neuropathy in diabetic patients with Charcot neuroarthropathy (CN).

Materials and Methods

A total of 20 patients with CN were compared with 20 age‐ and diabetes duration‐matched patients with type 2 diabetes and 20 age‐matched control participants. All patients underwent corneal confocal microscopy with quantification of corneal nerve morphology and assessment for vibration perception threshold, and a subset of patients with CN underwent assessment of sudomotor function and neuropathic pain.

Results

In patients with CN compared with type 2 diabetes patients and control participants, there was a significant reduction in corneal nerve fiber density (14.94 ± 8.23 vs 23.86 ± 7.71, P = 0.004 vs 34.84 ± 9.13, P < 0.001), corneal nerve branch density (18.61 ± 16.7 vs 41.62 ± 22.67, P = 0.032 vs 76.47 ± 38.44, P < 0.001) and corneal nerve fiber length (8.40 ± 4.83 vs 14.87 ± 4.76, P = 0.001 vs 21.24 ± 6.48, P < 0.001), electrochemical skin conductance on the feet (20.57 ± 13.99 vs 61.50 ± 22.26, P < 0.001 vs 76.23 ± 12.01, P < 0.001) and hands (30.86 ± 18.10 vs 61.13 ± 19.14, P = 0.001 vs 68.31 ± 11.96, P < 0.001), and a significant increase in the vibration perception threshold in the feet (38.46 ± 15.10 vs 14.15 ± 10.25, P < 0.001 vs 7.75 ± 4.01, P < 0.001).

Conclusions

Patients with diabetes and CN have severe large and particularly small fiber neuropathy.     

角膜共聚焦显微镜对糖尿病周围神经病变的诊断价值

目前常用的糖尿病周围神经病变筛查与诊断手段无法做到客观准确以及鉴别高危人群.近年来一种新型检查手段——角膜共聚焦显微镜,可通过无创在体观察和准确定量检测角膜Aδ和C神经纤维的分支密度、长度、迂曲度等,精确诊断糖尿病周围神经病变,且临床研究证明其对糖尿病周围神经病变的早期筛查、预测具有肯定作用,值得在临床推广应用.     

Diagnostic utility of corneal confocal microscopy in type 2 diabetic peripheral neuropathy

Aims/IntroductionThe early pathological changes of diabetic peripheral neuropathy (DPN) are mainly small nerve fiber injuries. Corneal confocal microscopy (CCM) is an easy, rapid, non‐invasive and repeatable technique to detect the damage of small nerve fibers. The purpose of this study was to explore the application of CCM in DPN and other chronic complications of type 2 diabetes mellitus.Materials and MethodsA total of 220 individuals (48 normal healthy control participants and 172 patients with type 2 diabetes mellitus) were included in the study. All participants were assessed and scored for neurological symptoms and neurological deficits, quantitative sensory test, neuroelectrophysiological test, and CCM.ResultsCorneal nerve fiber density, corneal nerve fiber length and corneal nerve branch density were significantly reduced in patients with type 2 diabetes mellitus compared with normal healthy control subjects (P < 0.001, P < 0.001 and P < 0.001, respectively). In the DPN group, corneal nerve fiber density, corneal nerve branch density and corneal nerve fiber length were significantly lower than for patients without DPN (P < 0.001, P < 0.001 and P < 0.001, respectively). Receiver operating characteristic analysis showed that the optimal cut‐off values were 24.68, 39 and 15.315, respectively, in which corneal nerve fiber density and corneal nerve fiber length had moderate sensitivity and specificity.ConclusionThis study provides more support for the clinical use of CCM to diagnose type 2 diabetes mellitus‐related complications, especially DPN.     

Corneal confocal microscopy: Recent progress in the evaluation of diabetic neuropathy

The present brief review discusses recent progress with corneal confocal microscopy for the evaluation of diabetic sensorimotor polyneuropathy. Corneal confocal microscopy is a new, non‐invasive and reproducible diagnostic modality, and it can also be easily applied for patient follow up. It enables new perspectives of studying the natural history of diabetic sensorimotor polyneuropathy, severity of nerve fiber pathology and documenting early nerve fiber regeneration after therapeutic intervention. It shows moderate to high sensitivity and specificity for the timely diagnosis of diabetic sensorimotor polyneuropathy. Currently, corneal confocal microscopy is mainly used in specialized centers, but deserves more widespread application for the assessment of diabetic sensorimotor polyneuropathy. Finally, further progress is required in terms of technical improvements for automated nerve fiber quantification and for analysis of larger images.     

Corneal confocal microscopy: A useful tool for diagnosis of small fiber neuropathy in type 2 diabetes

AimTo investigate the diagnostic utility of corneal confocal microscopy (CCM) for small fiber neuropathy in type 2 diabetes.Materials and MethodsThere were 186 participants with type 2 diabetes enrolled in this cross‐sectional research. Pure small fiber neuropathy and mixed fiber neuropathy were defined using clinical examination, electromyography, and quantitative sensory testing. Demographics and clinical data, corneal confocal microscopy parameters, and other neuropathy measures were compared among the groups. The diagnostic utility of corneal confocal microscopy for small fiber neuropathy was assessed by the receiver operating curve.ResultsOf the 186 patients, 24.7% had a pure small fiber neuropathy and 17.2% of patients were diagnosed with mixed fiber neuropathy. The corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), and corneal nerve fiber length (CNFL) were significantly lower in subjects with pure small fiber neuropathy compared with those without diabetic peripheral neuropathy (all P < 0.05). The receiver operating curve analysis for corneal confocal microscopy diagnosing small fiber neuropathy demonstrated the area under the curve for CNFD of 0.791, CNFL of 0.778, CNBD of 0.710.ConclusionsPatients with type 2 diabetes with pure small fiber neuropathy showed more corneal nerve loss compared with those without diabetic peripheral neuropathy. It was revealed that corneal confocal microscopy can be a reasonable marker in the diagnosis of small fiber neuropathy in type 2 diabetes.     

Diabetic Foot Disease: Emerging Technologies: Corneal Confocal Microscopy to Assess Diabetic Neuropathy: An Eye on the Foot

Accurate detection and quantification of human diabetic peripheral neuropathy are important to define at-risk patients, anticipate deterioration, and assess new therapies. Easily performed clinical techniques such as neurological examination, assessment of vibration perception or insensitivity to the 10 g monofilament only assess advanced neuropathy, i.e., the at-risk foot. Techniques that assess early neuropathy include neurophysiology (which assesses only large fibers) and quantitative sensory testing (which assesses small fibers), but they can be highly subjective while more objective techniques, such as skin biopsy for intra-epidermal nerve fiber density quantification, are invasive and not widely available. The emerging ophthalmic technique of corneal confocal microscopy allows quantification of corneal nerve morphology and enables clinicians to diagnose peripheral neuropathy in diabetes patients, quantify its severity, and potentially assess therapeutic benefit. The present review provides a detailed critique of the rationale, a practical approach to capture images, and a basis for analyzing and interpreting the images. We also critically evaluate the diagnostic ability of this new noninvasive ophthalmic test to diagnose diabetic and other peripheral neuropathies.     

角膜共焦显微镜对于肌萎缩侧索硬化症小纤维神经病变的临床研究

目的通过角膜共焦显微镜(CCM)评价肌萎缩侧索硬化症患者小纤维病变情况及其诊断价值。方法肌萎缩侧索硬化症患者57例, 为2015年6月至2016年2月北京大学第三医院神经内科门诊和住院患者, 男性37例、女性20例, 年龄24～80(52±11)岁。健康对照组30名, 男性21名、女性9名, 年龄23～76(55±13)岁。采用CCM量化分析角膜神经纤维的角膜神经纤维长度(NFL), 神经分支密度(NBD), 神经纤维密度(NFD), 神经纤维弯曲度(NFT), 并同时进行接触性热痛诱发电位(CHEP), 皮肤交感反射(SSR)等检查。计量资料用xˉ±s或M(Q₁, Q₃)表示;计量资料符合正态分布者组间比较用t检验, 偏态分布计量资料可用秩和检验等非参数检验, 计数资料分析用χ2检验。多因素计量资料相关分析用简单相关分析。所有统计分析采用SPSS 12.0软件处理。结果肌萎缩侧索硬化症组角膜NFL、NFD均显著低于健康对照组[(12.2±4.4)mm/mm2比(15.1±4.5)mm/mm2, P=0.028;(50.8±24.0)个/mm...     

老年糖尿病周围神经病变的相关危险因素研究

目的探讨老年糖尿病周围神经病变(diabetic peripheral neuropathy,DNP)的相关危险因素。方法将89例老年糖尿病患者按是否合并周围神经病变分为病变组与对照组,观察2组体质量指数(BMI)、腰臀比(WHR)、糖化血红蛋白(HbA1c)、三酰甘油(TG)、总胆固醇(TC),高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)及末梢神经功能、下肢血管超声等指标并进行比较分析。结果病变组WHR、LDL-C、下肢血管损伤程度均较对照组升高(P<0.05),神经传导速度、HDL-C较对照组降低(P<0.05),多元回归分析提示DNP与HbA1c、LDL-C、TG、血管病变负相关,与HDL-C正相关。结论DNP的发生与血糖、血脂及血管病变有关。     

角膜共焦显微镜检测在糖尿病微血管病变早期诊断及评估中的作用

糖尿病微血管病变的早期诊断及评估至关重要.角膜共焦显微镜(CCM)作为一项全新的临床检测方法,具有非侵入性、可重复性、快速性等特征,对于检测角膜神经纤维的结构、数量及部分功能有一定的作用,在糖尿病神经病变的早期诊断及治疗措施有效性的评估中有着重要的作用,同时,在糖尿病视网膜病变(DR)及糖尿病肾病(DN)中也有相关的应用价值.     

Corneal nerve fiber pathology in Japanese type 1 diabetic patients and its correlation with antecedent glycemic control and blood pressure

Aims/Introduction: Morphological changes to corneal C‐fibers in Japanese type 1 diabetic patients were visualized by corneal confocal microscopy (CCM). The effects of prior glycemic control and blood pressure on morphological parameters were clarified. Materials and Methods: Corneal nerve fibers were visualized by CCM in 38 Japanese type 1 diabetic patients (14 with and 24 without neuropathy) and 38 controls. Morphological parameters were compared and related to annual mean HbA1c, blood pressure, and serum lipid levels of previous years prior to CCM examination. Results: Compared with controls, diabetic patients had reduced corneal nerve fiber length (CNFL; 9.80 ± 0.38 vs 13.65 ± 0.88 mm/mm²; P < 0.001), reduced density (CNFD; 25.32 ± 1.04 vs 36.62 ± 2.37/mm²; P < 0.0005), lower frequency of beading (22.38 ± 0.73 vs 30.44 ± 1.03/0.1 mm; P < 0.0001), and increased tortuosity (3.13 ± 0.09 vs 1.74 ± 0.06; P < 0.0001). These changes were found in patients without neuropathy. There was no difference in nerve branches between controls and diabetic patients. The mean annual HbA1c level for the 7–10 years prior to CCM examination was an independent predictor of reduced CNFL and CNFD; HbA1c levels obtained 1–3 months and 1 year prior to CCM, as well as blood pressure 3, 5, and 6 years prior to CCM, were independent predictors of reduced beading frequency. Conclusions: Corneal confocal microscopy is a novel, noninvasive technique to evaluate morphological changes of corneal C‐fibers in type 1 diabetes. Antecedent hyperglycemia and blood pressure have different time‐dependent effects on CNFL and CNFD and the frequency of beading. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00157.x, 2011)     

Corneal confocal microscopy as a tool for detecting diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes: ADDITION-Denmark

Aims

In this cross-sectional study, we explored the utility of corneal confocal microscopy (CCM) measures for detecting diabetic polyneuropathy (DPN) and their association with clinical variables, in a cohort with type 2 diabetes.

Prevalence and risk factors for diabetic neuropathy in an urban south Indian population: the Chennai Urban Rural Epidemiology Study (CURES-55)

Aims This study was conducted to determine the prevalence of, and risk factors for, diabetic neuropathy (DN) in south Indian Type 2 diabetic subjects. Methods Subjects were recruited from the Chennai Urban Rural Epidemiology Study, conducted on a representative cohort from Chennai city. A total of 1629 diabetic subjects were included, of whom 1291 were known to have diabetes (KD) subjects and 338 were randomly selected newly detected diabetic (NDD) subjects. Neuropathy was diagnosed if vibratory perception threshold at the great toe, measured by biothesiometry, exceeded mean + 2 sd of a healthy non-diabetic study population aged 20–45 years (cut point ≥ 20 V). Results The overall prevalence of DN was 26.1% (age-adjusted 13.1%) with no significant difference in gender. The prevalence of neuropathy was significantly higher in KD subjects compared with NDD subjects (27.8 vs. 19.5%, P = 0.002). The prevalence of diabetic retinopathy (24.1 vs. 15.3%, P < 0.0001) and hypertension (51.1 vs. 40.0%, P < 0.0001) were higher in those with neuropathy compared with those without. The odds ratio for neuropathy in subjects with duration of diabetes > 15 years compared with ≤ 5 years was 5.7 (95% confidence interval: 3.52–9.08, P < 0.0001). Regression analysis showed age (P < 0.0001), glycated haemoglobin (P = 0.001) and duration of diabetes (P = 0.045) to be significantly associated with neuropathy. Conclusions This cross-sectional population-based study shows that, among urban south Indian Type 2 diabetic subjects, the prevalence of DN is 26.1% and that DN is significantly associated with age, glycated haemoglobin and duration of diabetes.     

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

Aims/IntroductionThis 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 MethodsThis 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.ResultsA 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.ConclusionsThe 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.     

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

Aims/IntroductionThis 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 MethodsAdults 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.ResultsA 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.ConclusionsThis 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.     

2型糖尿病心脏自主神经病变临床特征和危险因素分析

目的探讨2型糖尿病心脏自主神经病变(diabetic cardiac autonomic neuropathy,DCAN)的临床特征及相关危险因素。方法纳入2012年2月至2013年1月在广东省人民医院内分泌科就诊的2型糖尿病患者47例(按1999年世界卫生组织建议的糖尿病诊断标准),所有2型糖尿病患者进行葡萄糖耐量试验(OGTT)、胰岛素释放试验、血脂等分析,并以Ewing试验作为诊断DCAN的标准,对DCAN的患病情况、临床特征及可能的主要危险因素进行分析。同时,招募糖耐量正常者19例设为正常对照组。结果以Ewing试验为标准诊断心脏自主神经病变(cardiac autonomic neuropathy,CAN),正常对照组CAN的患病率仅为5.3%(1/19),2型糖尿病组为55.3%(26/47),两组比较差异有统计学意义(P=0.001)。2型糖尿病组中病程≤5年患者的DCAN患病率为45.2%(14/31),>5年患者为75.0%(12/16),两者比较差异有统计学意义(P=0.051)。2型糖尿病组中DCAN患者心率、收缩压、空腹胰岛素、胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)、尿酸与正常对照组患者比较,差异有统计学意义(P<0.05)。静息心率>80次/min、收缩压>140 mm Hg(1 mm Hg=0.133 kPa)、空腹胰岛素>100 pmol/L、胰岛素抵抗指数>5.3或胰岛素分泌指数>102.65、尿酸>350μmol/L的患者的DCAN患病率均较正明显增加,均差异有统计学意义(P<0.05)。Logistic回归分析显示,糖化血红蛋白(HbA1c)(OR=11.788)、胰岛素抵抗指数(OR=17.211)、尿酸(OR=5.757)是DCAN的主要独立危险因素。结论 2型糖尿病患者是CAN的高危人群;糖化血红蛋白、胰岛素抵抗指数、尿酸是DCAN的主要独立危险因素。