Development and validity testing of the neuropathy total symptom score-6: Questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy

Bastyr, Edward J.; Price, Karen; Bril, Vera

doi:10.1016/j.clinthera.2005.08.002

Cited by 171 publications

(122 citation statements)

References 46 publications

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“…Tactile allodynia is observed in a considerable proportion (30%-47%) of human subjects with diabetes mellitus. 10,85 A similar phenomenon is observed in STZ-diabetic rats, in which the light touch (Ͻ15 g) of von Frey filaments or the light stroking of a paw induces a withdrawal response from the stimulus. 86 In diabetic mouse models, the findings on tactile sensitivity are contradictory.…”

Section: Diabetes-associated Tactile Allodyniamentioning

confidence: 55%

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

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Summary:Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin-and leptin-receptor-deficient, and highfat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADPribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. Key Words: Animal models, diabetic insensate neuropathy, diabetic painful neuropathy, formalin-induced hyperalgesia, mechanical hyper-and hypoalgesia, pathogenetic treatments of diabetic neuropathic pain and sensory loss, symptomatic treatments of diabetic pain, tactile allodynia, thermal hyper-and hypoalgesia.

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Section: Diabetes-associated Tactile Allodyniamentioning

confidence: 55%

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

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“…In addition, ob/ob mice clearly developed manifest tactile allodynia, a condition in which a light touch is perceived as painful. This phenomenon is observed in a considerable proportion (from 30% [31] to 47% [26]) of human subjects with diabetes and, so far, has not been described in mouse models of PDN. The severity of allodynia as determined by reduction in threshold of response to light touch with flexible von Frey filaments is quite comparable in 11-week-old ob/ob mice and rats with an 8-week duration of streptozotocin-induced diabetes (30).…”

Section: Discussionmentioning

confidence: 99%

The Leptin-Deficient (ob/ob) Mouse

et al. 2006

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Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocininduced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice (ϳ11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (ϳ78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg ⅐ kg ؊1 ⅐ d ؊1 ), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestattreated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes. Diabetes 55: 3335-3343, 2006 P eripheral diabetic neuropathy (PDN) is a devastating complication of diabetes and a leading cause of foot amputation (1,2). Clinical indications of PDN include increased vibration and thermal perception thresholds that progress to sensory loss, occurring in conjunction with degeneration of all fiber types in the peripheral nerve. A proportion of patients with PDN also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain that sometimes coexist with loss of normal sensory function (3). Functional, metabolic, neurotrophic, and morphological abnormalities of PDN have extensively been explored in animal models of type 1 diabetes and, in particular, in streptozotocin-induced diabetic rats (4 -8) and mice (9,10). In contrast, manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models remain remarkably understudied despite the fact that the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes.The epidemic of obesity in the developed countries is driving a ...

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“…Sensory symptoms were measured using two questionnaires: the NTSS-6, which quantifies frequency and intensity of aching, burning, prickling and lancinating pain, numbness, and allodynia in patients' feet and legs (13), and the Neuropathy Symptom Score (NSS), which quantifies symptoms of motor, sensory, and autonomic deficits (19).…”

Section: Efficacy Measurementsmentioning

confidence: 99%

A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-β Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

et al. 2007

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OBJECTIVE -Diabetes leads to protein kinase C (PKC)-␤ overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-␤ inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN.RESEARCH DESIGN AND METHODS -Endothelium-dependent and C fibermediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo-and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged Ն18 years; with type 1 or type 2 diabetes and A1C Յ11%) during a randomized, doublemasked, single-site, 6-month study.RESULTS -Endothelium-dependent (ϩ78.2%, P Ͻ 0.03) and C fiber-mediated (ϩ56.4%, P Ͻ 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months Ϫ48.3%, P ϭ 0.01; end point Ϫ66.0%, P Ͻ 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point Ϫ41.2%, P ϭ 0.01, and Ϫ41.0, P ϭ 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo Ϫ13.1%; ruboxistaurin Ϫ66.0%, P Ͻ 0.03) and the Norfolk QOL-DN symptom subscore (placebo Ϫ4.0%; ruboxistaurin Ϫ41.2%, P ϭ 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies.CONCLUSIONS -In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated. Diabetes Care 30:896 -902, 2007

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Development and validity testing of the neuropathy total symptom score-6: Questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy

Cited by 171 publications

References 46 publications

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

The Leptin-Deficient (ob/ob) Mouse

A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-β Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

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