Diagnostic contribution of multi-frequency vibrometry to detection of peripheral neuropathy in type 1 diabetes mellitus compared with nerve conduction studies.

AIM: The aim was to assess the use of multi-frequency vibrometry (MFV) in detecting diabetic peripheral neuropathy (DPN) in type 1 diabetes in comparison to nerve conduction studies (NCS) and neurothesiometer (NT). Our objectives were to examine how VPTs correlated with NCS parameters, evaluate the efficacy of MFV in distinguishing DPN as well as to investigate whether MFV procedure could be based on fewer frequencies. METHODS: Adults with type 1 diabetes with previous MFV examinations were recruited at Skåne University Hospital in Malmö, Sweden, between 2018 and 2020. Participants were examined regarding nerve function in the lower limbs through MFV, NT and NCS. RESULTS: A total of 66 participants (28 women and 38 men) with a median age of 50 (39 to 64) years were included in the study. Through NCS assessment, 33 participants (50%) were diagnosed with DPN. We found negative correlations between VPTs and all NCS parameters, where the strongest correlation was found between sural nerve amplitude and the 125 Hz frequency of MFV. A combination of four frequencies, two low (4 and 8 Hz) and two high (125 and 250 Hz), showed the highest classification efficacy (AUC 0.83, 95% CI 0.73-0.93). CONCLUSION: We conclude that a strong correlation exists between the sural nerve amplitude and the VPTs at 125 Hz and that VPT testing with MFV can be focused on only four frequencies instead of seven, thus shortening test time, to distinguish DPN in the lower limb.

Comparison of Novel Wide-Field In Vivo Corneal Confocal Microscopy With Skin Biopsy for Assessing Peripheral Neuropathy in Type 2 Diabetes.

Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepidermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct comparisons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnostic modalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same participants, and at the same time point, no correlation between IENFD and corneal nerve density was found. Corneal nerve density did not correlate with clinical measures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN. ARTICLE HIGHLIGHTS: Comparison of intraepidermal nerve fiber density with automated wide-field corneal nerve fiber density in participants with type 2 diabetes revealed no correlation between these parameters. Intraepidermal and corneal nerve fibers both detected neurodegeneration in type 2 diabetes, but only intraepidermal nerve fibers were associated with clinical measures of diabetic peripheral neuropathy. A lack of association of corneal nerves with peripheral neuropathy measures suggests that corneal nerve fibers may be a poor biomarker for diabetic peripheral neuropathy.

Diabetic Neuropathy Assessed with Multifrequency Vibrometry Develops Earlier than Nephropathy but Later than Retinopathy.

BACKGROUND: Diabetes is associated with systemic complications. Prevalence of diabetic nephropathy, and retinopathy, in type 1 diabetes mellitus (T1DM) is declining, but it is not known if this is true also for diabetic neuropathy. AIM: To investigate the relationship between large fibre diabetic neuropathy and other diabetic complications. MATERIALS AND METHODS: Neuropathy, defined here as large fibre neuropathy, was assessed by measuring vibration perception thresholds at four different frequencies on the sole of the foot, using a standard VibroSense Meter and/or neuropathic symptoms, in 599 individuals with T1DM. Retinopathy status was graded using the International Clinical Disease Severity Scale. Grade of albuminuria and previous history of any macrovascular complications were registered. RESULTS: Diabetic individuals without retinopathy had similar vibration thresholds as age- and gender-matched control participants without diabetes, whereas those without microalbuminuria had higher thresholds than controls. Two individuals out of 599 (0.3%) had microalbuminuria, but not retinopathy or neuropathy, and 12/134 (9%) without retinopathy had signs of neuropathy. Totally 119/536 (22%) of the patients without microalbuminuria had neuropathy. Vibration thresholds increased with the rising severity of retinopathy and grade of albuminuria. In a multinomial logistic regression analysis, neuropathy was associated with retinopathy (OR 2.96 [1.35-6.49], p=0.007), nephropathy (OR 6.25 [3.21-12.15]; p=6.7×10-8) and macrovascular disease (OR 2.72 [1.50-4.93], p=0.001). CONCLUSIONS: Despite recent changes in the incidence of diabetic complications, the onset of large fibre neuropathy follows that of retinopathy but precedes the onset of nephropathy in T1DM.

Cold sensitivity and its association to functional disability following a major nerve trunk injury in the upper extremity-A national registry-based study.

AIMS: To investigate self-reported cold sensitivity and functional disability after a repaired major nerve trunk injury in the upper extremity. METHODS: We identified 735 individuals with a major nerve trunk injury in the upper extremity, surgically treated with direct nerve repair or reconstructed with nerve autografts, in the Swedish national quality registry for hand surgery (HAKIR). Patient-reported symptoms, including cold sensitivity, and perceived disability were collected using two questionnaires (HQ-8 and QuickDASH) preoperatively, and at three and 12 months postoperatively. RESULTS: We included 281 individuals, who had responded the questionnaires, where 197 (70%) were men (median age 34 [interquartile range 25-52] years) and 84 (30%) were women (median age 41 [25-55]). Cold sensitivity (scored 0-100) was the most prominent symptom 12 months postoperatively after an injured and repaired/reconstructed median (p<0.001) or ulnar (p<0.001) nerve, while individuals with a radial nerve injury showed milder symptoms. Concomitant injuries did not affect cold sensitivity scores. Individuals with ulnar nerve injuries scored higher in stiffness (p = 0.019), weakness (p<0.001) and ability to perform daily activities (p = 0.003) at 12 months postoperatively than median nerve injuries. Individuals with a median, ulnar or radial nerve injury with severe (>70) cold sensitivity had 25, 37 and 30 points higher QuickDASH scores, respectively (p<0.001), at 12 months postoperatively than individuals with mild (<30) cold sensitivity. There were no differences in QuickDASH score or cold sensitivity score at 12 months postoperatively between direct nerve repair or nerve reconstruction with nerve autografts. Neither age, nor sex, affected QuickDASH score at 12 months postoperatively. CONCLUSION: Cold sensitivity after surgery for a major nerve trunk injury in the upper extremity can be substantial with impaired ability to perform daily activities, where an ulnar nerve injury may have a worse outcome.

Cold sensitivity, functional disability and predicting factors after a repaired digital nerve injury.

To investigate self-reported cold sensitivity and functional disability after a repaired digital nerve injury. We identified 3204 individuals operated with digital nerve repair in the Swedish national quality registry for hand surgery (HAKIR). Patient-reported symptoms, including cold sensitivity and perceived disability, were examined using two questionnaires (HQ-8 and QuickDASH), three and 12 months postoperatively. Patients with diabetes (n = 48; 3%) were identified in the Swedish National Diabetes Register (NDR). Cold sensitivity (scored 0-100) was the most prominent symptom among 1553 included individuals (998 men, 555 women; median age 41 [IQR 27-54] years). In the regression analysis, flexor tendon injury, hand fracture and injury to multiple structures predicted worsened cold sensitivity (6.9, 15.5 and 25.0 points; p = 0.005, 0.046 and < 0.001) at 12 months. Individuals with moderate (30-70) and severe (> 70) cold sensitivity had higher QuickDASH scores at three and 12 months postoperatively than individuals with mild cold sensitivity (6.0 and 5.5; 19.8 and 21.0 points; p = 0.001). Flexor tendon injury, injuries to multiple structures and diabetes had significant effect on QuickDASH scores at three, but not at 12, months postoperatively. Cold sensitivity is common after a digital nerve repair and impacts self-reported disability. A concomitant injury, particularly multiple injuries, predicts postoperative cold sensitivity.

Vibrotactile sense might improve over time in paediatric subjects with type 1 diabetes-A mid-term follow-up using multifrequency vibrometry.

AIM: Impaired vibrotactile sense, mirroring diabetic peripheral neuropathy, is present among children and adolescents with type 1 diabetes. This study aims to re-examine the vibrotactile sense of paediatric type 1 diabetes subjects in order to evaluate any alterations in the vibrotactile sense over time. METHODS: A VibroSense Meter I device was used to determine the vibrotactile perception thresholds (VPTs) for seven frequencies from the pulp of index and little fingers and for five frequencies from metatarsal heads one and five on the sole of the foot, of 37 children and adolescents with type 1 diabetes, previously examined in a larger cohort. Subjects were followed up after a median time of 30 months. Z-scores of VPTs were calculated using previously collected normative data. RESULTS: Vibrotactile perception thresholds improved over time at low frequencies (especially 16 Hz) on the foot, while not being statistically significant different on the rest of the frequencies, either on hand or foot. VPTs were not correlated with HbA1c. CONCLUSION: A mid-term follow-up of vibrotactile sense in paediatric subjects with type 1 diabetes shows a conceivable normalization of previously impaired vibrotactile sense on some frequencies on the foot, indicating that vibrotactile sense might fluctuate over time.

Temporal trend of small nerve fibre degeneration in people with and without type 2 diabetes mellitus.

AIMS: We investigated the long-term temporal trend of intraepidermal nerve fibre density (IENFD) and the association between changes in IENFD and metabolic factors in individuals with and without type 2 diabetes. METHODS: A total of 66 participants were enrolled in this longitudinal population-based study, at baseline consisting of 35 individuals (median 61 years) without diabetes and 31 individuals with type 2 diabetes mellitus. Participants underwent clinical and electrophysiological examinations, as well as a skin biopsy both at baseline and at the follow-up visit (mean 8.1 ± 0.5 years). IENFD was assessed in thin sections of 5 µm, stained with the protein gene product 9.5-antibody and compared between the groups. RESULTS: IENFD decreased during the period in both groups, with a greater decline in the group without diabetes than in type 2 diabetes (-2.3 and -0.6 fibres/mm respectively; p < 0.001). While IENFD at baseline was significantly reduced in type 2 diabetes relative to people without (p < 0.001), no difference in IENFD was found between groups at the follow-up (p = 0.183). Linear mixed model analysis indicated that age, weight and HbA1c were associated with decrease in IENFD in the total population (p < 0.007). IENFD also decreased with increasing age and weight, but not with HbA1c , in the separate groups (p < 0.049). CONCLUSIONS: Despite lower IENFD levels at baseline in type 2 diabetes, IENFD was equal between the groups at follow-up. A decrease in IENFD is to a limited extent affected by body weight, and HbA1c , but age seems to be the long-term determinant of IENFD in an elderly population.

Normative values of the vibration perception thresholds at finger pulps and metatarsal heads in healthy adults.

AIMS: To establish normative values of vibration perception thresholds (VPTs), using multi-frequency vibrometry at finger pulps and at metatarsal heads of the foot in healthy adults. We also aimed to investigate factors that could potentially affect VPTs such as age, sex, height, weight, foot- or handedness and skin temperature. METHODS: VPTs were examined in 924 healthy and randomly selected subjects in the southern Sweden (mean 46 years; 628 women and 296 men). Inclusion criterias were adult subjects (>18 years) in considerable health without diabetes mellitus or other nerve affecting disorders. VPTs were measured at the finger pulps of index and little finger, as well as the first and fifth metatarsal heads of the foot, through multi-frequency vibrometry using the VibroSense Meter® I device. Patient characteristics were recorded and skin temperature was measured before assessment of VPTs. RESULTS: We present normative values of VPTs for a large population of both male and female subjects in various ages. VPTs detoriated as age increased (0.09-0.59 dB per year; p<0.001), i.e. progressing with normal aging. Increasing skin temperature affected VPTs in finger pulps, but not at metatarsal heads, with -0.2 to -1.6 dB, i.e. vibration perception improved with higher temperatures. Height was only found to affect the VPTs of metatarsal heads (250 Hz: 0.42 dB per cm). Sex, weight and handedness did not affect the VPTs. CONCLUSION: We investigated the normative values of VPTs and presented affecting factors as age, skin temperature and height. With these results, VPT testing through multi-frequency vibrometry is enabled to be used in a clinical practice as a diagnostic tool when investigating neuropathy and other neurological disorders.

Evaluation of small nerve fiber dysfunction in type 2 diabetes.

OBJECTIVES: To assess potential correlations between intraepidermal nerve fiber densities (IENFD), graded with light microscopy, and clinical measures of peripheral neuropathy in elderly male subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM), respectively. MATERIALS AND METHODS: IENFD was assessed in thin sections of skin biopsies from distal leg in 86 men (71-77 years); 24 NGT, 15 IGT, and 47 T2DM. Biopsies were immunohistochemically stained for protein gene product (PGP) 9.5, and intraepidermal nerve fibers (IENF) were quantified manually by light microscopy. IENFD was compared between groups with different glucose tolerance and related to neurophysiological tests, including nerve conduction study (NCS; sural and peroneal nerve), quantitative sensory testing (QST), and clinical examination (Total Neuropathy Score; Neuropathy Symptom Score and Neuropathy Disability Score). RESULTS: Absent IENF was seen in subjects with T2DM (n = 10; 21%) and IGT (n = 1; 7%) but not in NGT. IENFD correlated weakly negatively with HbA1c (r = -.268, P = .013) and Total Neuropathy Score (r = -.219, P = .042). Positive correlations were found between IENFD and sural nerve amplitude (r = .371, P = .001) as well as conduction velocity of both the sural (r = .241, P = .029) and peroneal nerve (r = .258, P = .018). Proportions of abnormal sural nerve amplitude became significantly higher with decreasing IENFD. No correlation was found with QST. Inter-rater reliability of IENFD assessment was good (ICC = 0.887). CONCLUSIONS: Signs of neuropathy are becoming more prevalent with decreasing IENFD. IENFD can be meaningfully evaluated in thin histopathological sections using the presented technique to detect neuropathy.

Improved metabolic control using glucose monitoring systems leads to improvement in vibration perception thresholds in type 1 diabetes patients.

AIMS: Few studies have examined how improved metabolic control might influence vibration perception thresholds (VPTs). The aim of this study was to evaluate if improved HbA1c can influence vibration thresholds in adults with type 1 diabetes (T1DM). METHODS: VPTs were investigated at six frequencies (4-125 Hz) using VibroSense Meter in the sole of the foot at two occasions in 159 T1DM patients, at the heads of the first and fifth metatarsal bones, i.e. MTH1 and MTH5, respectively. The participants were divided into three groups: group A: HbA1c improved by more than 1 mmol/mol (n = 95), group B: HbA1c deteriorated by more than 1 mmol/mol (n = 48) and group C: HbA1c unchanged (± 1 mmol/mol) (n = 16) compared to baseline. RESULTS: In group A, the mean z-score, reflecting the combined effect of all VPTs, improved being lower at the follow-up than at the baseline [0.2 (- 0.3 to 1.2) vs. -0.1 (- 0.7 to 0.8), p = 0.00002]. VPTs improved at 4 and 64 Hz at both MTH1 (metatarsal head 1) and MTH5. The VPTs at 125 Hz frequency improved at MTH5, but not at MTH1. No significant differences were seen in group B or group C. CONCLUSIONS: Lower HbA1c and lower VPTs in T1DM patients were associated with improved VPT, suggesting a reversible effect on nerve function by improved metabolic control.

Examining practice effects in repeated measurements of vibration perception thresholds on finger pulps of healthy individuals - Is it possible to improve your results over a clinically relevant test interval?

AIMS: To investigate practice effects in a test-retest situation, where vibration perception thresholds (VPT) were measured in healthy subjects using a multi-frequency test method. METHODS: In eight consecutive tests, VPTs were tested in the pulps of the index and little fingers at seven frequencies (8, 16, 32, 64, 125, 250 and 500 Hz). Subjects were twenty healthy adults aged 26 to 65 years (mean 46.0 ± 11.1 years; 10 male and 10 female). The subjects were examined at six tests with intervals of one month (mean 33 ± 6; time 0 to month 5) and at two additional tests with prolonged intervals (month 12 and 18). Linear mixed model analysis was performed to investigate differences over the subsequent test occasions. To examine where potential practice effects occurred, a pairwise comparison with Bonferroni correction was made. RESULTS: Small decreases in VPTs were found in 8 out of the 14 frequencies (index finger: 8, 16, 32, 250 and 500 Hz; little finger: 16, 250 and 500 Hz) within the test period from time 0 to month 5. In tests at 12 and 18 months, VPTs were increased compared to month 5, but lowered in comparison with time 0. Hence, minor significant decreases were found in three frequencies for the index finger (125, 250 and 500 Hz) and one frequency for the little finger (250 Hz) when examining VPTs with prolonged time intervals. CONCLUSIONS: When evaluating vibration perception thresholds in a clinically relevant time period of once or twice a year, no consideration of practice effects is necessary when interpreting the results.