Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy

Püttgen, Sonja; Bönhof, Gidon J.; Strom, Alexander; Müssig, Karsten; Szendroedi, Julia; Roden, Michael; Ziegler, Dan

doi:10.1210/jc.2019-01072

Cited by 13 publications

(15 citation statements)

References 38 publications

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“…The studies were conducted in Canada 10 , 26 , 31 , 32 , 33 , United Kingdom 4 , 8 , 9 , 21 , 24 , 25 , 28 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , Germany 27 , Denmark 12 , Australia 43 , 44 , 45 , 46 , 47 , 48 , 49 , Japan 18 , 19 , 22 , 50 , and China 23 , 51 (Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Thirty studies 4 , 8 , 9 , 12 , 18 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 31 , 32 , 33 , 34 , 35 , 37 , 38 , 40 , 41 , 43 , 44 , 45 , 46 , 50 , 51 with 3,460 (2,072 DPN + and 1,388 control) participants were included in the meta‐analysis. The CNBD (branch/mm 2 ) was significantly lower in the DPN + group compared with the controls (MD = −11.00, 95% CI −11.65 to −10.35, P < 0.00001) (CCMetrics (MD = −20.87, 95% CI −22.05 to −19.68, P < 0.00001), ACCMetrics (MD = −7.34, 95% CI −8.35 to −6.32, P < 0.00001), ImageJ (MD = −4.79, 95% CI −6.05 to −3.53, P < 0.0001), and morphometric software (MD = −21.81, 95% CI −26.61 to −17.01, P = 0.0003)).…”

Section: Resultsmentioning

confidence: 99%

“…Both CNFD and IENFD have a comparable diagnostic performance for DPN 8 , 9 , 59 , although in a study of patients with recently diagnosed type 2 diabetes there were differences in the extent of small nerve fiber damage between CCM and skin biopsy 57 . Additionally, a reduction in corneal nerve parameters is associated with incident DPN 10 , 53 , 60 and greater corneal nerve loss 41 , and augmented nerve branching 27 occurs in patients with painful diabetic neuropathy. CCM could act as a biomarker as defined by the NIH Biomarkers Definitions Working Group 61 ; it is non‐invasive, easily measured, and produces rapid results with high sensitivity 5 , 6 , 7 .…”

Section: Discussionmentioning

confidence: 99%

“…No neuropathy was classified as DPN − and mild‐severe neuropathy was classified as DPN + 23 , 24 , 25 , 26 . No differentiation was made for either painful or painless DPN and both were classified as DPN + 27 , 28 . Where the vibration perception threshold (VPT) was used, <15V was classified as DPN − and ≥15V as DPN + 4 .…”

Section: Methodsmentioning

confidence: 99%

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Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta‐analysis

Gad

Petropoulos

Khan

et al. 2021

J of Diabetes Invest

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Introduction: Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that identifies corneal nerve fiber damage. Small studies suggest that CCM could be used to assess patients with diabetic peripheral neuropathy (DPN). Aim: To undertake a systematic review and meta-analysis assessing the diagnostic utility of CCM for sub-clinical DPN (DPN -) and established DPN (DPN + ). Data sources: Databases (PubMed, Embase, Central, ProQuest) were searched for studies using CCM in patients with diabetes up to April 2020. Study selection: Studies were included if they reported on at least one CCM parameter in patients with diabetes. Data extraction: Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length (IWL) were compared between patients with diabetes with and without DPN and controls. Meta-analysis was undertaken using RevMan V.5.3. Data synthesis: Thirty-eight studies including ~4,000 participants were included in this meta-analysis. There were significant reductions in CNFD, CNBD, CNFL, and IWL in DPNvs controls (P < 0.00001), DPN + vs controls (P < 0.00001), and DPN + vs DPN -(P < 0.00001). Conclusion: This systematic review and meta-analysis shows that CCM detects small nerve fiber loss in subclinical and clinical DPN and concludes that CCM has good diagnostic utility in DPN.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta‐analysis

Gad

Petropoulos

Khan

et al. 2021

J of Diabetes Invest

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“…24 Furthermore, we recently described enhanced corneal nerve branching in individuals with painful DSPN compared with painless DSPN. 25…”

Section: Box 1 Continuedmentioning

confidence: 99%

BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy

et al. 2022

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IntroductionDiabetic sensorimotor polyneuropathy (DSPN) affects approximately 30% of people with diabetes, while around half of cases are symptomatic. Currently, there are only few pathogenetically oriented pharmacotherapies for DSPN, one of which is benfotiamine, a prodrug of thiamine with a high bioavailability and favourable safety profile. While benfotiamine has shown positive effects in preclinical and short-term clinical studies, no long-term clinical trials are available to demonstrate disease-modifying effects on DSPN using a comprehensive set of disease-related endpoints.Methods and analysisThe benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes trial is a randomised double-blind, placebo-controlled parallel group monocentric phase II clinical trial to assess the effects of treatment with benfotiamine compared with placebo in participants with type 2 diabetes and mild to moderate symptomatic DSPN. Sixty participants will be 1:1 randomised to treatment with benfotiamine 300 mg or placebo two times a day over 12 months. The primary endpoint will be the change in corneal nerve fibre length assessed by corneal confocal microscopy (CCM) after 12 months of benfotiamine treatment compared with placebo. Secondary endpoints will include other CCM measures, skin biopsy and function indices, variables from somatic and autonomic nerve function tests, clinical examination and questionnaires, general health, health-related quality of life, cost, safety and blood tests.Ethics and disseminationThe trial was approved by the competent authority and the local independent ethics committee. Trial results will be published in peer-reviewed journals, conference abstracts, and via online and print media.Trial registration numberDRKS00014832.

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Optimizing examination time and diagnostic performance of the histamine‐induced axon‐reflex flare response in diabetes

Røikjer,

Croosu,

Borbjerg

et al. 2023

Muscle and Nerve

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Introduction/AimsThe axon‐reflex flare response is a reliable method for functional assessment of small fibers in diabetic peripheral neuropathy (DPN), but broad adoption is limited by the time requirement. The aims of this study were to (1) assess diagnostic performance and optimize time required for assessing the histamine‐induced flare response and (2) associate with established parameters.MethodsA total of 60 participants with type 1 diabetes with (n = 33) or without (n = 27) DPN participated. The participants underwent quantitative sensory testing (QST), corneal confocal microscopy (CCM), and flare intensity and area size assessments by laser‐Doppler imaging (FLPI) following an epidermal skin‐prick application of histamine. The flare parameters were evaluated each minute for 15 min, and the diagnostic performance compared to QST and CCM were assessed using area under the curve (AUC). Minimum time‐requirements until differentiation and to achieve results comparable with a full examination were assessed.ResultsFlare area size had better diagnostic performance compared with CCM (AUC 0.88 vs. 0.77, p < 0.01) and QST (AUC 0.91 vs. 0.81, p = 0.02) than mean flare intensity, and could distinguish people with and without DPN after 4 min compared to after 6 min (both p < 0.01). Flare area size achieved a diagnostic performance comparable to a full examination after 6 and 7 min (CCM and QST respectively, p > 0.05), while mean flare intensity achieved it after 5 and 8 min (CCM and QST respectively, p > 0.05).DiscussionThe flare area size can be evaluated 6–7 min after histamine‐application, which increases diagnostic performance compared to mean flare intensity.

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Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy

Cited by 13 publications

References 38 publications

Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta‐analysis

Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta‐analysis

BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy

Optimizing examination time and diagnostic performance of the histamine‐induced axon‐reflex flare response in diabetes

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