Diabetic Sensorimotor Polyneuropathy Research Articles

Tarsal tunnel release restores sensations in sole for diabetic sensorimotor polyneuropathy

BackgroundDiabetic sensorimotor polyneuropathy (DSPN) is the commonest form of neuropathy. Loss of sensations in sole leads to diabetic foot ulcers (DFU) and its complications. Surgical decompression has been used in the treatment of diabetic peripheral neuropathy, however; its effectiveness has been questioned.Purpose of this study was to evaluate the sensory recovery in sole after tarsal tunnel decompression (TTD) in patients having DSPN. MethodsThirteen patients (Age28-70 years, average 35.57 years; 7 Males, 6 Females; 20 feet) with DSPN and positive Tinel's sign over the tarsal tunnel were included in the study. Pre and post-operative sensory tests performed on the sole included tests for touch, pain, temperature, pressure, vibration perception threshold (VPT) and two-point discrimination (2-PD). Results were classified as per British Medical Research Council (MRC) scoring system. Results–Sixteen feet were followed-up for 6 months. In all feet perception of touch, pain and pressure recovered. Temperature perception recovered in 75% feet. VPT came to normal range (16.81V) from 40.37 V and 2-PD came down to average of 6.0 mm from preoperative average of11.2 mm.MRC scale improved from S0 in 5 feet and S2 in 15 feet to S3+ in all 16 feet.There were no ulcers or amputation in operated limbs during follow up period of 6 months. ConclusionsTTD improves plantar sensations in diabetic neuropathy and prevents ulcers and its related complications.

Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study

Cluster analyses have proposed different diabetes phenotypes using age, BMI, glycaemia, homoeostasis model estimates, and islet autoantibodies. We tested whether comprehensive phenotyping validates and further characterises these clusters at diagnosis and whether relevant diabetes-related complications differ among these clusters, during 5-years of follow-up. Patients with newly diagnosed type 1 or type 2 diabetes in the German Diabetes Study underwent comprehensive phenotyping and assessment of laboratory variables. Insulin sensitivity was assessed using hyperinsulinaemic-euglycaemic clamps, hepatocellular lipid content using magnetic resonance spectroscopy, hepatic fibrosis using non-invasive scores, and peripheral and autonomic neuropathy using functional and clinical criteria. Patients were reassessed after 5 years. The German Diabetes Study is registered with ClinicalTrials.gov, number NCT01055093, and is ongoing. 1105 patients were classified at baseline into five clusters, with 386 (35%) assigned to mild age-related diabetes (MARD), 323 (29%) to mild obesity-related diabetes (MOD), 247 (22%) to severe autoimmune diabetes (SAID), 121 (11%) to severe insulin-resistant diabetes (SIRD), and 28 (3%) to severe insulin-deficient diabetes (SIDD). At 5-year follow-up, 367 patients were reassessed, 128 (35%) with MARD, 106 (29%) with MOD, 88 (24%) with SAID, 35 (10%) with SIRD, and ten (3%) with SIDD. Whole-body insulin sensitivity was lowest in patients with SIRD at baseline (mean 4·3 mg/kg per min [SD 2·0]) compared with those with SAID (8·4 mg/kg per min [3·2]; p<0·0001), MARD (7·5 mg/kg per min [2·5]; p<0·0001), MOD (6·6 mg/kg per min [2·6]; p=0·0011), and SIDD (5·5 mg/kg per min [2·4]; p=0·0035). The fasting adipose-tissue insulin resistance index at baseline was highest in patients with SIRD (median 15·6 [IQR 9·3-20·9]) and MOD (11·6 [7·4-17·9]) compared with those with MARD (6·0 [3·9-10·3]; both p<0·0001) and SAID (6·0 [3·0-9·5]; both p<0·0001). In patients with newly diagnosed diabetes, hepatocellular lipid content was highest at baseline in patients assigned to the SIRD cluster (median 19% [IQR 11-22]) compared with all other clusters (7% [2-15] for MOD, p=0·00052; 5% [2-11] for MARD, p<0·0001; 2% [0-13] for SIDD, p=0·0083; and 1% [0-3] for SAID, p<0·0001), even after adjustments for baseline medication. Accordingly, hepatic fibrosis at 5-year follow-up was more prevalent in patients with SIRD (n=7 [26%]) than in patients with SAID (n=5 [7%], p=0·0011), MARD (n=12 [12%], p=0·012), MOD (n=13 [15%], p=0·050), and SIDD (n=0 [0%], p value not available). Confirmed diabetic sensorimotor polyneuropathy was more prevalent at baseline in patients with SIDD (n=9 [36%]) compared with patients with SAID (n=10 [5%], p<0·0001), MARD (n=39 [15%], p=0·00066), MOD (n=26 [11%], p<0·0001), and SIRD (n=10 [17%], p<0·0001). Cluster analysis can characterise cohorts with different degrees of whole-body and adipose-tissue insulin resistance. Specific diabetes clusters show different prevalence of diabetes complications at early stages of non-alcoholic fatty liver disease and diabetic neuropathy. These findings could help improve targeted prevention and treatment and enable precision medicine for diabetes and its comorbidities. German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, Research Network SFB 1116 of the German Research Foundation, and Schmutzler Stiftung.

Relationship between diabetic neuropathy and sarcopenia

ObjectiveThe present study was designed to examine the prevalence of sarcopenia in patients who have Diabetic Neuropathy (DN); and to determine the relation between DN and sarcopenia. Material and methodsA total of 602 diabetic patients (mean age 60.2 ± 10.6 years; 40.5% male) were included in the study, which was designed as a cross-sectional study. The body composition was measured with the bioimpedance analysis method, and the muscle strength was measured by evaluating the hand grip strength. Those who showed only reduced handgrip strength were categorized in the s-presarcopenia group, whereas patients with only muscle volume loss were categorized in the v-presarcopenia group, those who had them together were defined as sarcopenia; and sarcopenia that was accompanied by obesity was defined as sarcopenic obesity. DN consisted of Diabetic Sensorimotor Polyneuropathy (DSPN) and Diabetic Autonomic Neuropathies (DAN) as two large groups. DAN consisted of its sub-groups of Cardiovascular Autonomic Neuropathy (CV-AN), Gastrointestinal Autonomic Neuropathy (GI-AN), Genitourinary Autonomic Neuropathy (GU-AN), Sudomotor Autonomic Neuropathy (SM-AN), which were identified with their own methods. Logistic regression analyzes were carried out to determine the relations of DN and its subgroups with sarcopenia and its components. ResultsThe DN prevalence was determined to be 85% in the entire patient population; and it was 80.2% in those who had normal muscle mass and strength, 84.4% in s-presarcopenic patients, 82.1% in v-presarcopenic patients, and 94.1% in sarcopenic patients. On the other hand, DN prevalence was 89.2% in non-obese sarcopenics; however, it was determined as 95,9% in sarcopenic obese patients. Similarly, the DN prevalence of non-sarcopenic patients was determined to be 76.7% in non-obese patients; and 88.5% in those who were obese. The sarcopenia incidence in patients who had DN was higher at a significant level than in those without DN (24.7%–8.9%). In the multivariate logistic regression analyzes, DN was determined to be associated with sarcopenia, independently from age and gender, even from accompanying concomitant diseases, BMI, Ha1c and GFR levels (OR: 2.38, 95% CI: 1.02–5.54). ConclusionsThe present study revealed the relation of sarcopenia with DN, especially with GI-AN and GU-AN.

Uric Acid Levels Correlate with Sensory Nerve Function in Healthy Subjects.

High levels of uric acid (UA) are associated with various peripheral neuropathies. Furthermore, uric acid levels have been found to correlate with both the clinical and electrophysiological severity of diabetic sensorimotor polyneuropathy, mainly with sensory functions. To determine whether higher UA levels are associated negatively with nerve function in healthy subjects. A total of 126 healthy subjects recruited prospectively for another study were included. We extracted demographic data, body mass index (BMI), blood pressure, Toronto Clinical Neuropathy Score (TCNS), electrophysiological findings, vibration perception thresholds (VPT), and laboratory test results including UA, hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and lipid levels. The mean age of the cohort was 56 ± 17 years with 56% females. Males had higher UA values compared with females. Univariate beta regression coefficient analysis between UA levels and demographic, clinical, electrophysiological, and laboratory findings showed significant positive correlations with male gender, components of the metabolic syndrome, and with VPT, while an inverse correlation was found with electrophysiological sensory parameters. A multivariate regression model showed positive correlations only with BMI, finger VPT, and triglycerides. Higher UA levels correlate with lower sensory nerve function in healthy subjects, expanding the evidence of possible negative influence of UA on peripheral nerves, although a causative role has not yet established.

A Waves in Diabetic Neuropathy: Pathophysiology and Neurographic Images.

To evaluate the presence of A waves in diabetic neuropathy, we designed a retrospective observational study recruiting patients with type II diabetes and chronic diabetic distal sensorimotor polyneuropathy. We recruited 238 patients of both sexes aged between 41 and 89 years. Neurography was undertaken on two bilateral upper (median and ulnar) and lower (peroneal and tibial) limb nerves. As controls, we considered that neurographs performed bilaterally on the same nerves of 40 healthy subjects. In addition to neurographic changes typical of chronic distal sensorimotor neuropathy, patients had a 32.77% incidence of A waves, mostly found in the tibial (16.38%) and peroneal (8.8%) nerves. Among controls, A waves were found only in the tibial nerve of a single subject (2.5%). Chi-square test with Yates correction to compare the two percentages (32.77% of patients and 2.5% of healthy subjects): 13.98, P = 0.0002, highly significant. We postulate that demyelination may be the site of backfiring or slowing of nerve conduction velocity, explaining the appearance of A waves in their different varieties. Implementing the search for A waves in routine neurographic examination can be a useful option for the diagnosis of neuropathy and the prediction of possible latent neuropathic processes.

Optimal Ultrasonographic Measurements for Diagnosing Carpal Tunnel Syndrome in Patients With Diabetic Sensorimotor Polyneuropathy: A Case-Control Study.

ObjectiveTo investigate the optimal sonographic method for diagnosing carpal tunnel syndrome (CTS) in patients with diabetic sensorimotor polyneuropathy (DSP).MethodsA total of 190 participants were divided into four groups based on DSP history and electrodiagnostic results of CTS. The absolute parameters were measured at baseline and the relative values were calculated: maximal cross-sectional area (CSA) of the median nerve throughout the carpal tunnel (Mmax), median nerve CSA at the forearm level (Mf), ulnar nerve CSA at the pisiform level (Upi), difference between Mmax and Mf (∆MM), and difference between Mmax and Upi (∆MU). Then, the optimal ultrasonographic parameters for diagnosing CTS, according to the presence of DSP, using absolute and relative cutoff values were analyzed.ResultsMedian and ulnar nerve CSAs were significantly larger in the DSP group than in the control group. In the DSP participants, the mean Mmax, ∆MM, and ∆MU values were significantly larger in patients with both DSP and CTS than in patients with DSP only. The Mmax thresholds of 9.5 mm2 in the control group and 11.5 mm2 in the DSP group showed the greatest sensitivity and specificity for diagnosing CTS. The ∆MM thresholds of 2.5 mm2 and ∆MU thresholds of 4.5 mm2 had the greatest sensitivity and specificity in both the DSP and control groups.ConclusionMeasurement of Mmax, ∆MM and ∆MU is an optimal ultrasonographic evaluation method for diagnosing CTS in patients with DSP.

Polyneuropathies and chronic inflammatory demyelinating polyradiculoneuropathy in multiple sclerosis

BackgroundPolyneuropathies co-occurring with multiple sclerosis (MS) may be underdiagnosed while causing additional disability burden. ObjectiveTo determine polyneuropathy presence and type in MS and compare MS with chronic inflammatory demyelinating polyradiculoneuropathy (MS-CIDP) versus MS with other non-inflammatory polyneuropathies. MethodsRetrospective chart review of Mayo Clinic cases diagnosed with MS and polyneuropathy. Serum from MS-CIDP for pan-IgG autoantibodies to neurofascin-155 were tested when available. ResultsFrom 1980–2013, 133 co-existing MS/ polyneuropathy cases were identified. Twenty-eight MS patients had inflammatory neuropathy (11 CIDP, 5 plexopathy, 2 vasculitis, 4 monoclonal gammopathy-associated, 6 other), 15 inherited neuropathy (8 axonal, 7 demyelinating), 32 diabetic sensorimotor polyneuropathy, and 58 other. 109 had neuropathy beginning simultaneous to or after MS diagnosis (82%). Compared to MS cases with other polyneuropathy subtypes, MS-CIDP cases had absent or reduced ankle reflexes (100 vs. 70%, p = 0.04), earlier age of neuropathy recognition (52 vs. 58 years, p = 0.048), worse impairment (NIS 27 vs. 22 points, p < 0.03), and more acquired demyelinating electrophysiology features (46% vs. 9%, p < 0.003). Of MS-CIDP cases with available serum, 1-in-3 had IgG4 autoantibodies to neurofascin-155. Conclusion(1) Polyneuropathies occurring in MS contribute to neurological disability. (2) Diagnosing polyneuropathies in people with MS is challenging and, likely, under-diagnosed. Recognition is important as some polyneuropathies (e.g., CIDP) are treatable. (3) The probable over-representation of inflammatory neuropathy (especially CIDP) in MS suggests a shared dysimmune pathogenesis, supported by autoantibodies to neurofascin-155.

Specifics of diagnosis and treatment of diabetic polyneuropathy in elderly patients

To study the specifics of diagnosis and treatment of diabetic polyneuropathy in elderly patients. Forty-two patients (22 men and 20 women, aged from 65 to 75 years) with diabetes mellitus type 2 and diabetic polyneuropathy were studied using the following psychometric scales: the Michigan Neuropathy Screening Instrument (MNSI), Neurological symptoms scale (NSS), Neuropathy Disability Score (NDS), the Numerical Rating Scale (NRS), Kaplan-Feinstein index (KFI), the Covi Anxiety Scale (COVI), the Recovery Locus of Control Scale (RLOC). Patients were divided into group 1 (n=24) treated with neuromultivit injections, along with standard treatment, and group 2 (n=18), which received standard treatment only. Patients were examined at baseline and one month after treatment. In elderly patients, diabetic distal symmetric sensorimotor polyneuropathy of moderate severity was comorbid mostly with cardio-vascular disease. Pain syndrome was associated with anxiety and significant direct correlation between anxiety and pain intensity was found. The level of motivation towards recovery was significantly lower and correlated with COVI scores. Injections of neuromultivit decrease the intensity of pain, improve the emotional state and increase the level of motivation towards recovery.

Prevalence of Diabetic Neuropathy in Young Adults with Type 1 Diabetes and the Association with Insulin Pump Therapy.

The aim was to investigate the prevalence of diabetic sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in a Danish population of young adults with type 1 diabetes (T1D) using both established and novel measuring modalities. Furthermore, to investigate the association between continuous subcutaneous insulin infusion (CSII) treatment and these complications. CAN was assessed by cardiovascular autonomic reflex tests. DSPN was assessed not only by perception of light touch and pain, vibration perception threshold (VPT), Brief Pain Inventory (BPI), and Michigan Neuropathy Screening Instrument questionnaires but also by novel modalities: electrochemical skin conductance (ESC), sural nerve conduction velocity (SNCV), and sural nerve amplitude potential (SNAP). The study comprised 156 young adults with a mean age of 22 years (standard deviation 1.6). The prevalence of CAN and early CAN was 9% and 28.1%, respectively. Subclinical DSPN was 55.1% and confirmed DSPN was 2.6%. Prevalence of abnormal SNAP was 23.8%, SNCV was 37.1%, ESC on the hands and feet was 4% and 8%, respectively, VPT was 1.3%, and BPI questionnaire was 1.9%. No association was found between CSII treatment and the measures of DSPN and CAN. DSPN and CAN are prevalent in young adults with T1D with no association found with CSII treatment. The use of novel measuring modalities identified a higher number of subjects with DSPN compared with established measures. Screening for diabetic neuropathy in young adults may be beneficial to detect and prevent nerve damages at early stages.

Nerve ultrasound can distinguish chronic inflammatory demyelinating polyneuropathy from demyelinating diabetic sensorimotor polyneuropathy

Diabetic patients with poor glycaemic control can demonstrate demyelinating distal sensorimotor polyneuropathy (D-DSP) on electrophysiology. Distinguishing D-DSP from chronic inflammatory demyelinating polyneuropathy (CIDP) can be challenging. In this study, we investigated the role of nerve ultrasound in differentiating the two neuropathies. Nerve ultrasound findings of D-DSP patients (fulfilling the electrophysiological but not clinical criteria for CIDP) were compared with non-diabetic CIDP patients (fulfilling both criteria). We studied 108 and 95 nerves from 9 D-DSP and 10 CIDP patients respectively. CIDP patients had significantly larger cross-sectional areas of the median nerve at the mid-arm (17.0 ± 12.5 vs 8.7 ± 2.6; p = 0.005), ulnar nerve at the wrist (7.3 ± 3.1 vs 4.1 ± 1.0; p = 0.001), mid forearm (8.8 ± 5.3 vs 5.5 ± 1.5; p = 0.002) and mid-arm (14.5 ± 14.1 vs 7.5 ± 1.9; p = 0.013), and radial nerve at mid forearm (4.1 ± 2.4 vs 1.2 ± 0.4; p < 0.001). In comparison to D-DSP, CIDP patients had markedly larger nerves at the proximal and non-entrapment sites of the upper limbs, suggesting that nerve ultrasound is useful in differentiating the two neuropathies.

High glucose concentration suppresses a SIRT2 regulated pathway that enhances neurite outgrowth in cultured adult sensory neurons

In peripheral nerve under hyperglycemic conditions high flux of d-glucose through the polyol pathway drives an aberrant redox state contributing to neurodegeneration in diabetic sensorimotor polyneuropathy (DSPN). Sirtuins, including SIRT2, detect the redox state via the NAD+/NADH ratio to regulate mitochondrial function via, in part, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). In adult dorsal root ganglia (DRG) sensory neurons mitochondrial dysfunction has been proposed as an etiological factor in dying-back neuropathy in diabetes. We tested the hypothesis that a high concentration of d-glucose depleted SIRT2 expression via enhancement of polyol pathway activity. We posited that this would lead to impaired mitochondrial function and suppression of neurite outgrowth in cultured sensory neurons. The use of dominant negative mutants or neurons from SIRT2 knockout (KO) mice to block SIRT2 signaling revealed that neurons derived from control or type 1 diabetic rodents required SIRT2 for optimal neurite outgrowth. Over-expression of WT-SIRT2 elevated neurite outgrowth in normal and diabetic cultures. SIRT2 protein isoforms 2.1 and 2.2 were reduced by 20–30% in DRG of type 1 diabetic mice (p < .05). After 72 h exposure to high d-glucose (25 mM vs 5 mM) cultured sensory neurons showed a significant 2-fold (p < .05) decrease in SIRT2 expression, P-AMPK, levels of respiratory Complexes II/III and respiratory capacity. DRG neurons expressed aldose reductase and the aforementioned deficits were prevented by treatment with aldose reductase inhibitors (lidorestat or sorbinil) or sorbitol dehydrogenase inhibitor (SDI-158). In cultures derived from type 1 diabetic rats treatment with SDI-158 elevated expression of SIRT2, P-AMPK/PGC-1α and neurite outgrowth (p < .05). SIRT2 KO neurons exhibited deficits in the LKB-1/AMPK/PGC-1α pathway and mitochondrial function. In cultured neurons the SIRT2 pathway enhances axonal outgrowth and this signaling axis encompassing activation of AMPK/PGC-1α is impaired in DSPN, in part, due to enhanced polyol pathway activity caused by hyperglycemia.

Surgical peripheral nerve decompression for the treatment of painful diabetic neuropathy of the foot – A level 1 pragmatic randomized controlled trial

AimsTo assess the efficacy of surgical decompression of lower extremity nerves for the treatment of painful diabetic peripheral sensorimotor polyneuropathy (DPN). MethodsPeople with painful diabetic neuropathy were randomized single-blind to a lower extremity decompression surgery (n = 12) or observation (n = 10) for 1 year. ResultsPain was the primary outcome assessed with 2 measures. The McGill pain visual analogue scores over time changed within the groups (p for time < 0.0001), and changed differently over time within the groups (p for group × time = 0.0138). The NeuroQoL pain sensitivity analysis significantly changed from baseline to 12 months comparing intervention to control (p = 0.0079), and the joint effect of group and time on pain scores was statistically significant (p for group × time = 0.0009). At the study end-point of 12 months, intervention group participants had over 3 times the odds of rating their pain as “better” compared to “unchanged” or “worse” in the control group (p = 0.0177). ConclusionsSurgical decompression of lower limb nerves was an effective treatment for decreasing pain in patients with DPN and superimposed nerve compressions.

Differential Association of Inflammatory Markers and Growth Factors with Type 2 Diabetes and Polyneuropathy—A Multimarker Approach

There is emerging evidence supporting a role of inflammation in the development and progression of diabetic sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes. We aimed to characterize inflammatory signatures associated with DSPN and/or type 2 diabetes using a multimarker approach. We measured 92 serum biomarkers including pro- and anti-inflammatory cytokines, chemokines, and growth factors (GF) using the Proseek Multiplex INF I assay (OLINK Proteomics) in 304 individuals with type 2 diabetes and polyneuropathy, defined by the Toronto Consensus Criteria (2011), from the PROPANE study (DSPN) as well as 158 individuals with type 2 diabetes without DSPN (T2D) and 354 individuals with normal glucose tolerance and without DSPN (CON) from the KORA F4 study (DSPN/T2D/CON [mean±SD]: age: 68±9/71±6/69±5 years; male: 76/59/41%; BMI: 30.8±5.3/30.8±4.4/26.9±3.7 kg/m²; diabetes duration: 13.5±9.6/7.6±5.8/- years; HbA1c: 7.4±1.3/6.6+1.0/5.5+0.3%). After adjustment for multiple testing and sex, age, BMI, and smoking, a biphasic pattern of serum levels (normalized protein expression values) with an increase in T2D and decrease in DSPN was observed for four GFs (e.g., transforming GF (TGF)-α: 4.51±0.51 vs. 4.63±0.56 vs. 3.91±0.51; vascular endothelial GF (VEGF): 10.9±0.5 vs. 11.0±0.5 vs. 10.8±0.6), two chemokines (e.g., C-C motif ligand 4 (CCL4): 8.18±0.57 vs. 8.4±0.6 vs. 7.93±0.68) and one cytokine (oncostatin M: 4.83±0.62 vs. 5.06±0.63 vs. 4.35±0.75). Compared to T2D, the levels of another 12 biomarkers were lower in DSPN (e.g., tumor necrosis factor (TNFSF)-14: 5.65±0.55 vs. 4.90±0.77; matrix metalloproteinase (MMP)-1: 14.4±0.7 vs. 14.1±0.9), while five were higher (e.g., CCL20: 5.2±1.1 vs. 5.79±1.23) (all P&amp;lt;0.00024). In conclusion, deficits in growth factors promoting nerve regeneration/angiogenesis and a complex cross-talk between innate and adaptive immunity may contribute to the development of DSPN in type 2 diabetes. Disclosure G.J. Bönhof: None. A. Strom: None. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S. M. Heier: None. C. Meisinger: None. A. Peters: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. B. Thorand: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. D. Ziegler: None.

The Reference Distribution of Annual Change in Corneal Nerve Fibre Length in Diabetes Mellitus

The measurement of corneal nerve fibre length (CNFL) by in vivo corneal confocal microscopy is a biomarker for the presence of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, its prevalence in T1D and T2D, and its clinical predictors. We examined longitudinal data from 94 nondiabetic controls and 297 diabetes participants (224 T1D and 73 T2D) from an ongoing multi-centre NIH-funded study of IVCCM in diabetes. Participants were included if they had at least 1-year of follow-up data and were classified as progressors with “rapid corneal nerve fibre loss” (RCNFL) if the loss of CNFL was beyond the 5th percentile (-14%/y) of the nondiabetic controls. Nondiabetic controls were 43.0±15.8 y, had a median of 2 follow-up visits over a median of 2 y, baseline CNFL of 15.4±4.2 mm/mm2, and the median annual change in CNFL was -1.7%[90% CI, -14.3 to 30.9%]. Diabetes participants were 49.6±15.5 y, had a median of 3 visits over a median of 2 y, baseline CNFL of 14.3±4.4 mm/mm2 and the median annual change in CNFL was 1.8%[90% CI, -26.1 to 25.0%]. There were 33(11.1%) cases of RCNFL in the diabetes sub-cohort, which was comparable between T1D (26(11.6%)) and T2D (7(9.6%)). Progressors did not differ from non-progressors for baseline levels of age, sex, BMI, HbA1c or CNFL levels. However, progressors were more likely to have baseline DSP (16(50%) vs. 83(32%), p=0.048), lower cooling detection threshold (21.3 C±8.5 vs. 25.3 C±7.2, p=0.048) and lower heart rate variability (26.3±13.1 vs. 38.2±25.4, p=0.036). A more rapid loss of CNFL (RCNFL) exceeding 14%/y occurs in ∼11% of diabetes patients. This more rapid of corneal nerves may identify patients at highest risk for the development or progression of DSP. Disclosure E.J.H. Lewis: Employee; Self; Nutarniq Corp. M. Tavakoli: None. L. Lovblom: None. E.M. Halpern: None. M. Jeziorska: None. D. Pacaud: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Versartis, Inc. N. Pritchard: Other Relationship; Self; JDRF, NHMRC. R.M. Shtein: None. N. Efron: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc.. R.A. Malik: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc..

Usefulness of a Point-of-Care Sural Nerve Conduction Device (DPNCheck™) for Evaluation of Diabetic Symmetric Sensorimotor Polyneuropathy in Japan

Nerve conduction study (NCS) is a reliable examination to diagnose and to evaluate diabetic symmetric sensorimotor polyneuropathy (DSPN). However, NCS is not feasible in daily medical practice, because it requires skilled laboratory technicians and an expensive equipment. A point-of-care device, DPNCheck™can measure sural nerve (SN) action potential amplitude (Amp) and conduction velocity (CV) in less than 5 minutes without special techniques. Here, we evaluated the accuracy and the usefulness of DPNCheck™ for diagnosis of DSPN in Japanese diabetic patients. We selected 207 diabetic patients. 1. We examined bilateral SN both by electromyography (EM) and DPNCheck™ and compared the differences. 2. To evaluate the reproducibility and inter-rater reliability of DPNCheck™, Amp and CV of SN were measured twice by an examiner and once by another examiner. 3. Based on the results of EM, we classified the severity of DSPN into 3 grades as follows; grade 0: Amp of SN (SNAP) 5μV or more and Amp of tibial nerve (CMAP) 5mV or more, grade 1: SNAP&amp;lt;5μV and CMAP 5mV or more, and grade 2: SNAP&amp;lt;5μV and CMAP&amp;lt;5mV. Then, a formula to predict the grades of DSPN severity by using the Amp and CV from DPNCheck™ was created. For statisticalanalyses SPSS was used. 1. The correlation coefficient (R) for CV and Amp between DPNCheck™ and EM were R=0.7663 and 0.6178, respectively. 2. The reproducibility and inter-rater reliability of DPNCheckTM were “superior” and “acceptable”, respectively. 3. The formula to predict the severity of DSPN by DPNCheck™ was as follows; “grade = 2.235+0.009xAge-0.015xCV-0.041xAmp.” The grade calculated by this formula was relatively “acceptable” compared with the real grade determined by EM (correlation coefficient: R=0.645). These results indicate that DPNCheck™ is a useful device to measure SN functions in Japanese diabetic patients and should be used more frequently in the bedside to diagnose and evaluate DSPN. Disclosure Y. Shibata: None. H. Kamiya: Other Relationship; Self; MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca, Astellas Pharma KK, Eli Lilly and Company, Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd.. T. Himeno: None. M. Motegi: None. H. Shimoda: None. M. Kato: None. Y. Yamada: None. E. Miura-Yura: None. M. Kondo: None. S. Tsunekawa: None. Y. Kato: Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., Sanofi, Takeda Pharmaceutical Company, Eli Lilly Japan. J. Nakamura: Other Relationship; Self; Astellas Pharma US, Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd., MSD K.K., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceuticals America, Inc., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly and Company, Novartis Pharma K.K., Pfizer Inc..

Validation of a simple disease-specific, quality-of-life measure for diabetic polyneuropathy: CAPPRI.

We studied the performance of a 15-item, health-related quality-of-life polyneuropathy scale in the clinic setting in patients with diabetic distal sensorimotor polyneuropathy (DSPN). Patients with DSPN from 11 academic sites completed a total of 231 Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) scales during their clinic visits. Conventional and modern psychometric analyses were performed on the completed forms. Conventional and modern analyses generally indicated excellent psychometric properties of the CAPPRI in patients with DSPN. For example, the CAPPRI demonstrated unidimensionality and performed like an interval-level scale. Attributes of the CAPPRI for DSPN include ease of use and interpretation; unidimensionality, allowing scores to be summed; adequate coverage of disease severity; and the scale's ability to address relevant life domains. Furthermore, the CAPPRI is free and in the public domain. The CAPPRI may assist the clinician and patient with DSPN in estimating disease-specific quality of life, especially in terms of pain, sleep, psychological well-being, and everyday function. The CAPPRI may be most useful in the everyday clinical setting but merits further study in this setting, as well as the clinical trial setting.

Corneal nerve fiber size adds utility to the diagnosis and assessment of therapeutic response in patients with small fiber neuropathy

Small fiber neuropathy (SFN) is a common feature of many inflammatory diseases, often presenting with pain and disability. SFN is diagnosed using symptoms, thermal threshold testing, and intra-epidermal nerve fiber quantification. Corneal confocal microscopy (CCM) is an ophthalmic imaging technique which non-invasively quantifies corneal nerve fiber (CNF) density, branch density and length, and has comparable diagnostic and superior ability to identify nerve regeneration compared to skin biopsy. CNF size (width and area) depends upon the number of fibers within each nerve, as well as pathology (e.g., swelling), and may provide additional sensitivity to diagnose SFN and identify nerve repair. We have compared the utility of the standard CCM variables employed to CNF size in patients with diabetic sensorimotor polyneuropathy or sarcoidosis-associated SFN, and in patients with SFN following cibinetide administration, an agent which promotes nerve repair. The results show that: 1) CNF width distribution and area depend upon neuropathy severity; 2) CNF area, density, branch density and length possess comparable discriminatory power for diagnosing neuropathy; 3) CNF area is related to length by a quadratic function which is predictive for both healthy subjects and those with SFN; 4) CNF area is a useful variable for quantifying change in CNF morphology.

Corneal Nerve Fractal Dimension: A Novel Corneal Nerve Metric for the Diagnosis of Diabetic Sensorimotor Polyneuropathy.

ObjectiveCorneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, is a noninvasive and objective imaging biomarker for identifying small nerve fiber damage. We have evaluated the diagnostic performance of previously established CCM parameters to a novel automated measure of corneal nerve complexity called the corneal nerve fiber fractal dimension (ACNFrD).MethodsA total of 176 subjects (84 controls and 92 patients with type 1 diabetes) with and without diabetic sensorimotor polyneuropathy (DSPN) underwent CCM. Fractal dimension analysis was performed on CCM images using purpose-built corneal nerve analysis software, and compared with previously established manual and automated corneal nerve fiber measurements.ResultsManual and automated subbasal corneal nerve fiber density (CNFD) (P < 0.0001), length (CNFL) (P < 0.0001), branch density (CNBD) (P < 0.05), and ACNFrD (P < 0.0001) were significantly reduced in patients with DSPN compared to patients without DSPN. The areas under the receiver operating characteristic curves for identifying DSPN were comparable: 0.77 for automated CNFD, 0.74 for automated CNFL, 0.69 for automated CNBD, and 0.74 for automated ACNFrD.ConclusionsACNFrD shows comparable diagnostic efficiency to identify diabetic patients with and without DSPN.

High frequency of MGUS in DSP.

Monoclonal gammopathy has been reported in several polyneuropathies. In this study, we sought to explore the frequency and characteristics of monoclonal gammopathy in patients with diabetic sensorimotor polyneuropathy (DSP). Patients with type 1 and type 2 diabetes mellitus (DM 1, DM 2) and controls without diabetes were evaluated between November 2008 and December 2013. Fifty controls, 66 patients with DM 1, and 106 patients with DM 2 were included, with average ages of 43 ± 18, 45 ± 17, and 65 ± 10 years, respectively; the frequency of monoclonal gammopathy was 0%, 8%, and 15%, respectively. In patients with DSP, the frequency of monoclonal gammopathy increased to 14% in DM 1 and 21% in DM 2; the most common monoclonal proteins were immunoglobulin (Ig) M and IgG, respectively. DSP might be associated with a high frequency of monoclonal gammopathy, with different characteristics in DM 1 and in DM 2. Muscle Nerve 57: 1018-1021, 2018.

How to diagnose neuropathy in diabetes mellitus?

Diabetic neuropathy is a common problem and can present various clinical presentations such as cranial neuropathy, radiculopathy, plexopathy, mononeuropathy, polyneuropathy and autonomic neuropathy. Clinical evaluation and use of scoring systems for the evaluation of diabetic polyneuropathy is an important step to get correct diagnosis. New informations about the diagnosis of diabetic neuropathy continue to emerge, which will lead to correct diagnosis and treatment as well. Diabetic length-dependent sensorimotor polyneuropathy (DSPN) and carpal tunnel syndrome are the most common seen problems. While acute and painful situations with motor weakness are mostly transient, sensory fibres are predominantly involved in chronic ones. Nerve conduction studies are needed to confirm diagnosis of any type of diabetic neuropathy, but they are normal in cases with small fiber involvement. The early diagnosis is crucial because it is well-known that subclinical diabetic neuropathy may be reversed or significantly improved with diabetes control. Because neuropathy at the stage in which only small fibers are affected can be reversed, it is important to diagnose DSPN in these stages. Skin biopsy taken from the dermatomal area of sural nerve, laser-doppler-imager flare technique, corneal confocal microscopy are used to assess small fibre dysfunction. The aim of the present review was to evaluate evidence-based diagnosis for any type of neuropathy seen in the patients with diabetes mellitus.