Andrej Orszag

Detection of Diabetic Sensorimotor Polyneuropathy by Corneal Confocal Microscopy in Type 1 Diabetes: A concurrent validity study

OBJECTIVE We aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics. RESEARCH DESIGN AND METHODS Concurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis. RESULTS DSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm2 (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm2, sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm2, specificity 93%, positive likelihood ratio 8.5). CONCLUSIONS Among CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.

Prediction of Incident Diabetic Neuropathy Using the Monofilament Examination A 4-year prospective study

OBJECTIVE To determine the specific monofilament examination score that predicts the subsequent 4-year incidence of diabetic neuropathy with the highest degree of diagnostic accuracy. RESEARCH DESIGN AND METHODS Longitudinal follow-up of 175 of 197 (89%) participants in the Toronto Diabetic Neuropathy Cohort without baseline neuropathy for incident neuropathy. We examined the baseline monofilament examination score (and other simple sensory screening tests) by receiver operating characteristic (ROC) curve analysis. RESULTS Incident diabetic neuropathy developed in 50 (29%) participants over a mean follow-up of 4.1 years (interquartile range 2.6–7.1 years). Although male sex, longer diabetes duration, taller height, and higher blood pressure at baseline were associated with incident neuropathy, the strongest association was with a lower baseline monofilament score (score out of 8 was 3.7 ± 2.5 for incident neuropathy vs. 5.7 ± 2.3 for those who did not develop neuropathy; P < 0.001). The optimal threshold score for risk of incident neuropathy was ≤5 sensate stimuli out of 8, with 72% sensitivity, 64% specificity, positive and negative likelihood ratios of 2.5 and 0.35, and positive and negative predictive values of 87 and 46%, respectively (χ2 = 20.7, P < 0.001). Area under the ROC curve was significantly greater for the monofilament examination compared with that for other simple sensory tests. CONCLUSIONS A simple threshold of ≤5 sensate stimuli out of 8 discriminates 4-year risk of diabetic neuropathy with acceptable operating characteristics. Although there are limitations in its specificity for prediction of future neuropathy onset, the monofilament examination is appropriate as a simple diabetic neuropathy screening instrument generalizable to the clinical setting.

Single- and Dual-Hormone Artificial Pancreas for Overnight Glucose Control in Type 1 Diabetes

CONTEXT The added benefit of glucagon in artificial pancreas systems for overnight glucose control in type 1 diabetes has not been fully explored. OBJECTIVE The objective of the study was to compare the efficacy of dual-hormone (insulin and glucagon) artificial pancreas, single-hormone (insulin alone) artificial pancreas, and conventional insulin pump therapy. DESIGN This study was a three-center, three-arm, open-label, randomized, crossover controlled trial involving three interventions, each applied over a night after a high carbohydrate/high fat meal and a second after exercise to mimic real-life glycemic excursions. SETTING The study was conducted in a home setting. PATIENTS Twenty-eight type 1 diabetes participants (21 adults and seven adolescents) participated in the study. INTERVENTIONS Dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional pump therapy was activated from 9:00 PM to 7:00 AM. MAIN OUTCOME The main outcome was a proportion of time in target (4-8 mmol/L) by continuous glucose monitoring from 11:00 PM to 7:00 AM. Analysis was by intention to treat. RESULTS The median (interquartile range) percentage of time-in-target glucose range was 47% (36%-71%) for conventional therapy, higher on both single-hormone (76% [65%-91%], P < .001) and dual-hormone artificial pancreas (81 [68%-93%], P < .001). The median (interquartile range) time spent below 4 mmol/L was 14% (4%-28%) for conventional therapy, lower on both single-hormone (5% [0%-13%], P = .004) and dual-hormone artificial pancreas (1% [0%-8%], P < .001). There were 14 hypoglycemic events on conventional therapy compared with six incidences on the single-hormone artificial pancreas (P = .059) and three incidences on the dual-hormone artificial pancreas (P = .017). None of these outcomes differed significantly between single- and dual-hormone configurations. CONCLUSIONS Single- and dual-hormone artificial pancreas systems both provided better glucose control than conventional therapy. Although the dual-hormone configuration did not increase overnight time-in-target glucose levels, an effect on lowering hypoglycemia risk cannot be ruled out.

Identification and Prediction of Diabetic Sensorimotor Polyneuropathy Using Individual and Simple Combinations of Nerve Conduction Study Parameters

Objective Evaluation of diabetic sensorimotor polyneuropathy (DSP) is hindered by the need for complex nerve conduction study (NCS) protocols and lack of predictive biomarkers. We aimed to determine the performance of single and simple combinations of NCS parameters for identification and future prediction of DSP. Materials and Methods 406 participants (61 with type 1 diabetes and 345 with type 2 diabetes) with a broad spectrum of neuropathy, from none to severe, underwent NCS to determine presence or absence of DSP for cross-sectional (concurrent validity) analysis. The 109 participants without baseline DSP were re-evaluated for its future onset (predictive validity). Performance of NCS parameters was compared by area under the receiver operating characteristic curve (AROC). Results At baseline there were 246 (60%) Prevalent Cases. After 3.9 years mean follow-up, 25 (23%) of the 109 Prevalent Controls that were followed became Incident DSP Cases. Threshold values for peroneal conduction velocity and sural amplitude potential best identified Prevalent Cases (AROC 0.90 and 0.83, sensitivity 80 and 83%, specificity 89 and 72%, respectively). Baseline tibial F-wave latency, peroneal conduction velocity and the sum of three lower limb nerve conduction velocities (sural, peroneal, and tibial) best predicted 4-year incidence (AROC 0.79, 0.79, and 0.85; sensitivity 79, 70, and 81%; specificity 63, 74 and 77%, respectively). Discussion Individual NCS parameters or their simple combinations are valid measures for identification and future prediction of DSP. Further research into the predictive roles of tibial F-wave latencies, peroneal conduction velocity, and sum of conduction velocities as markers of incipient nerve injury is needed to risk-stratify individuals for clinical and research protocols.

Diabetic Neuropathy and Axon Reflex-Mediated Neurogenic Vasodilatation in Type 1 Diabetes

Objective Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating may reflect early, pre-clinical small fibre dysfunction. We aimed to evaluate the distribution of the vascular flare area measured by laser doppler imaging (“LDIFLARE area”) in type 1 diabetes and in healthy volunteers. Research and Methods Concurrent with clinical and electrophysiological examination to classify diabetic sensorimotor polyneuropathy (DSP), LDIFLARE area (cm2) was determined in 89 type 1 diabetes subjects matched to 64 healthy volunteers. We examined the association and diagnostic performance of LDI with clinical and subclinical measures of DSP and its severity. Results Compared to the 64 healthy volunteers, the 56 diabetes controls without DSP had significantly lower LDIFLARE area (p = 0.006). The 33 diabetes cases with DSP had substantially lower LDIFLARE area as compared to controls without DSP (p = 0.002). There was considerable overlap in LDIFLARE area between all groups such that the ROC curve had an AUC of 0.72 and optimal sensitivity of 70% for the detection of clinical DSP. Use of a subclinical definition for DSP, according to subclinical sural nerve impairment, was associated with improved AUC of 0.75 and sensitivity of 79%. In multivariate analysis higher HbA1c and body mass index had independent associations with smaller LDIFLARE area. Conclusions Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating is a biomarker of early nerve dysfunction in DSP. Its independent association with glycemic exposure in diabetes subjects and both glycemic exposure and BMI in healthy volunteers highlights the existence of small-fibre dysfunction in the natural history of DSP.

Heart Rate Variability and Sensorimotor Polyneuropathy in Type 1 Diabetes

OBJECTIVE Reduced heart rate variability (HRV) is classically viewed as an early phenomenon in diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the characteristics of HRV across the spectrum of clinical DSP in type 1 diabetes. RESEARCH DESIGN AND METHODS Eighty-nine diabetic subjects and 60 healthy volunteers underwent assessment of RR interval variation (RRvar) during deep breathing and clinical and electrophysiological examination. We examined the distribution of age-standardized RRvar across the spectrum of clinical DSP, identified variables associated with RRvar in multivariate regression, and compared RRvar with validated measures of neuropathy. RESULTS Age-standardized RRvar had a significant, step-wise, inverse relationship with ordinal categories of increasing DSP severity (β = −5.4, P < 0.0001) among subjects with diabetes. Case subjects with DSP had substantially lower age-standardized RRvar compared with diabetic control subjects without DSP (β = −5.2, P < 0.01), although there was substantial overlap of RRvar between diabetic case subjects and control subjects and the healthy volunteer cohort. In multivariate analysis, advanced age was independently associated with lower RRvar in both healthy volunteers and diabetic subjects, whereas higher glycated hemoglobin A1c and systolic blood pressure were independently associated with lower RRvar in diabetic subjects. RRvar had a significant association with validated measures of large and small fiber neuropathy. CONCLUSIONS HRV may be a biomarker for clinical DSP and is associated cross-sectionally with both early and late measures of neuropathy. The low HRV observed in some control subjects without DSP and in most case subjects with severe DSP may signify that HRV has different prognostic implications in these groups, requiring further longitudinal study.

Validation of cooling detection threshold as a marker of sensorimotor polyneuropathy in type 2 diabetes

AIM We aimed to validate the performance cooling detection thresholds (CDT) to detect diabetic sensorimotor polyneuropathy (DSP) in type 2 diabetes. METHODS Two hundred and twenty participants with type 2 diabetes underwent clinical and electrophysiological examinations including 3 small fiber function tests: CDT, heart rate variability (HRV) and LDIFLARE. Clinical DSP was defined by consensus criteria whereas preclinical DSP was defined by presence of at least one electrophysiological abnormality. Area under the curve (AUC) and optimal thresholds were determined by receiver operating characteristic curves. RESULTS Participants were aged 63 ± 11 years with mean HbA1c of 7.5 ± 1.6%. The 139 (63%) clinical DSP cases had mean CDT values of 18.3 ± 8.9°C; the 52 (24%) preclinical DSP cases had 25.3 ± 3.5°C; and the 29 (13%) controls had 27.1 ± 3.8°C; (p-value<0.02 for all comparisons). For identification of clinical DSP cases, AUCCDT was 0.79 which exceeded AUCHRV (0.60, p=<0.0001) and AUCLDI FLARE (0.69, p=0.0003), optimal threshold <22.8°C (64% sensitivity, 83% specificity). Preclinical DSP AUCCDT was 0.80, also exceeding the other 2 measures (p<0.02 for both comparisons), optimal threshold ≤27.5°C (83% sensitivity, 72% specificity). CONCLUSIONS CDT had good diagnostic performance for identification of both clinical and preclinical neuropathy in type 2 diabetes. Its use as a non-invasive screening tool should be considered for research and clinical practice.

Higher magnification lenses versus conventional lenses for evaluation of diabetic neuropathy by corneal in vivo confocal microscopy

We tested agreement for small fibre morphology using corneal in vivo confocal microscopy between the recently available higher-magnification 300 μm(2) and the conventional 400 μm(2) field-of-view lenses. We found insignificant bias for corneal nerve fibre length indicating that either lens could reasonably be applied to research and clinical screening for diabetic neuropathy.

Agreement between automated and manual quantification of corneal nerve fiber length: Implications for diabetic neuropathy research

AIMS Quantification of corneal nerve fiber length (CNFL) by in vivo corneal confocal microscopy represents a promising diabetic neuropathy biomarker, but applicability is limited by resource-intensive image analysis. We aimed to evaluate, in cross-sectional analysis of non-diabetic controls and patients with type 1 and type 2 diabetes with and without neuropathy, the agreement between manual and automated analysis protocols. METHODS Sixty-eight controls, 139 type 1 diabetes, and 249 type 2 diabetes participants underwent CNFL measurement (N=456). Neuropathy status was determined by clinical and electrophysiological criteria. CNFL was determined by manual (CNFLManual, reference standard) and automated (CNFLAuto) protocols, and results were compared for correlation and agreement using Spearman coefficients and the method of Bland and Altman (CNFLManual subtracted from CNFLAuto). RESULTS Participants demonstrated broad variability in clinical characteristics associated with neuropathy. The mean age, diabetes duration, and HbA1c were 53±18years, 15.9±12.6years, and 7.4±1.7%, respectively, and 218 (56%) individuals with diabetes had neuropathy. Mean CNFLManual was 15.1±4.9mm/mm2, and mean CNFLAuto was 10.5±3.7mm/mm2 (CNFLAuto underestimation bias, -4.6±2.6mm/mm2 corresponding to -29±17%). Percent bias was similar across non-diabetic controls (-33±12%), type 1 (-30±20%), and type 2 diabetes (-28±16%) subgroups (ANOVA, p=0.068), and similarly in diabetes participants with and without neuropathy. Levels of CNFLAuto and CNFLManual were both inversely associated with neuropathy status. CONCLUSIONS Although CNFLAuto substantially underestimated CNFLManual, its bias was non-differential between diverse patient groups and its relationship with neuropathy status was preserved. Determination of diagnostic thresholds specific to CNFLAuto should be pursued in diagnostic studies of diabetic neuropathy.

Measurement of Cooling Detection Thresholds for Identification of Diabetic Sensorimotor Polyneuropathy in Type 1 Diabetes

Objective Compared to recently-studied novel morphological measures, conventional small nerve fiber functional tests have not been systematically studied for identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine and compare the diagnostic performance of cooling detection thresholds (CDT) in a cross-sectional type 1 diabetes cohort. Research Design and Methods 136 subjects with type 1 diabetes and 52 healthy volunteers underwent clinical and electrophysiological examination for DSP classification concomitantly with the Toronto Clinical Neuropathy Score (TCNS) and three small fiber function tests: CDT, heart rate variability (HRV), and laser doppler imaging of axon-mediated neurogenic flare responses to cutaneous heating (LDIFLARE). Area under the curve (AUC) and optimal thresholds were determined by receiver operating characteristic (ROC) curves in the type 1 diabetes cohort. Results Type 1 diabetes subjects were 42±17 years of age with mean HbA1c 7.9±1.7%. Fifty-nine (45%) met the case definition for DSP. CDT values were lowest in cases with DSP (18.3±8.4°C) compared to controls without DSP (28.4±3.5°C) and to healthy volunteers (29.6±1.8°C; p-value for both comparisons<0.0001). AUCCDT was 0.863 which was similar to AUCTCNS (0.858, p = 0.24) and AUCHRV (0.788, p = 0.05), but exceeded AUCLDIFLARE (0.750, p = 0.001). The threshold of <25.1°C was equivalent to the lower bound of the healthy volunteer 95% distribution [25.1, 30.8°C] and performed with 83% sensitivity and 82% specificity. Conclusions Akin to novel small fiber morphological measures, CDT is a functional test that identifies DSP with very good diagnostic performance. These findings support further research that revisits the role of CDT in early DSP detection.