Recent developments in the assessment of efficacy in clinical trials of diabetic neuropathy

Mojaddidi, Moaz; Quattrini, Cristian; Tavakoli, Mitra; Malik, Rayaz A.

doi:10.1007/s11892-005-0048-6

Cited by 22 publications

(18 citation statements)

References 56 publications

(47 reference statements)

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“…These observations support the view that in clinical intervention trials for diabetic neuropathy, perhaps the focus should be on assessment of small fiber damage and repair (1,8). Until recently, this could only be provided by costly, time-consuming, and, most importantly, invasive procedures such as nerve (10) and skin biopsy (11,12).…”

Section: After Transplantationsupporting

confidence: 59%

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Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

et al. 2007

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OBJECTIVE -Corneal confocal microscopy (CCM) is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber pathology. We have used it to assess the neurological benefits of pancreas transplantation in type 1 diabetic patients. RESEARCH DESIGN AND METHODS-In 20 patients with type 1 diabetes undergoing simultaneous pancreas and kidney transplantation (SPK) and 15 control subjects, corneal sensitivity was evaluated using noncontact corneal esthesiometry, and small nerve fiber morphology was assessed using CCM.RESULTS -Corneal sensitivity (1.54 Ϯ 0.28 vs. 0.77 Ϯ 0.02, P Ͻ 0.0001), nerve fiber density (NFD) (13.8 Ϯ 2.1 vs. 42 Ϯ 3.2, P Ͻ 0.0001), nerve branch density (NBD) (4.04 Ϯ 1.5 vs. 26.7 Ϯ 2.5, P Ͻ 0.0001), and nerve fiber length (NFL) (2.23 Ϯ 0.2 vs. 9.69 Ϯ 0.7, P Ͻ 0.0001) were significantly reduced, and nerve fiber tortuosity (NFT) (15.7 Ϯ 1.02 vs. 19.56 Ϯ 1.34, P ϭ 0.04) was increased in diabetic patients before pancreas transplantation. Six months after SPK, 15 patients underwent a second assessment and showed a significant improvement in NFD (18.04 Ϯ 10.48 vs. 9.25 Ϯ 1.87, P ϭ 0.001) and NFL (3.60 Ϯ 0.33 vs. 1.84 Ϯ 0.33, P ϭ 0.002) with no change in NBD (1.38 Ϯ 0.74 vs. 1.38 Ϯ 1.00, P ϭ 1.0), NFT (15.58 Ϯ 1.20 vs. 16.30 Ϯ 1.19, P ϭ 0.67), or corneal sensitivity (1.23 Ϯ 0.39 vs. 1.54 Ϯ 00.42, P ϭ 0.59).CONCLUSIONS -Despite marked nerve fiber damage in type 1 diabetic patients undergoing pancreas transplantation, small fiber repair can be detected within 6 months of pancreas transplantation using CCM. CCM is a novel noninvasive clinical technique to assess the benefits of therapeutic intervention in human diabetic neuropathy. Diabetes Care 30:2608-2612, 2007S omatic polyneuropathy is one of the most common long-term complications of diabetes and is the main initiating factor for foot ulceration and lower extremity amputation (1,2). As 80% of amputations are preceded by foot ulceration, an effective means of detecting and treating peripheral neuropathy would have a major medical, social, and economic impact. With the exception of optimal glycemic control, there are currently no licensed treatments that prevent, slow, or arrest the development of neuropathy (1). The development of new treatments is of paramount importance, but they are hampered by a lack of clinically relevant surrogate end points favored by regulatory authorities (1). We have relied on tests that quantify predominantly large nerve fiber dysfunction, which were principally developed to aid diagnosis and not to assess nerve repair and hence a therapeutic response (3). Thus, nerve conduction studies are useful but only detect an abnormality in large myelinated nerve fibers, whereas thermal and pain thresholds assess thinly myelinated (A␦) and unmyelinated (C) fiber function. Heart rate variability during respiratory stimuli indicates parasympathetic vagal efferent function, and blood pressure change during orthostatic manipulation evaluates sympathetic vasomotor efferents.Although these tests correlate with axonal los...

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Section: After Transplantationsupporting

confidence: 59%

“…Although these tests correlate with axonal loss (4 -7), there are major shortcomings when they are used to define therapeutic efficacy in clinical intervention trials (8). These tests do not target the specific fiber types that may benefit from the therapeutic intervention and demonstrate a limited ability to detect regeneration and repair.…”

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confidence: 99%

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

et al. 2007

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“…The main aim of establishing a surrogate marker is to define those at risk of developing a complication, anticipate deterioration, and assess the efficacy of new therapies. Although electrophysiology, QST, and assessment of neurological disability are advocated to define neuropathic severity (1), there is debate as to which test, if any, is appropriate in the early stages of neuropathy (25) and also whether the same tests should be used to define therapeutic efficacy in clinical intervention trials (5). Regulatory authorities favor clinically relevant surrogate end points.…”

Section: Discussionmentioning

confidence: 99%

“…Although electrophysiology, quantitative sensory testing (QST), and assessment of neurological disability are advocated to define neuropathic severity (1), they have limitations when they are used to define therapeutic efficacy in clinical intervention trials (5). Only biopsy of the sural nerve (6,7) and skin biopsy (8,9) permit a direct examination of nerve fiber damage and repair.…”

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confidence: 99%

Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy

et al. 2007

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Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fiftyfour diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy. Diabetes

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“…Although electrophysiology, quantitative sensory testing (QST), and assessment of neurological disability are advocated to define neuropathy severity, they have limitations when they are used to define therapeutic efficacy in clinical intervention trials [9,10]. Only biopsy of the sural nerve and skin biopsy allows a direct examination of nerve fiber damage and repair [11].…”

Section: Background and Aimsmentioning

confidence: 99%

Corneal Confocal Microscopy – A Novel, Noninvasive Method to Assess Diabetic Peripheral Neuropathy

Inceu

Demea²,

Vereşiu

2014

Romanian Journal of Diabetes Nutrition and Metabolic Diseases

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Recent developments in the assessment of efficacy in clinical trials of diabetic neuropathy

Cited by 22 publications

References 56 publications

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy

Corneal Confocal Microscopy – A Novel, Noninvasive Method to Assess Diabetic Peripheral Neuropathy

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