Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction

Caselli, Antonella

doi:10.1136/jnnp.2005.069609

Cited by 49 publications

(32 citation statements)

References 33 publications

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“…However, hypoalgesia at 5 and 250 Hz were observed in the STZinduced diabetic rats, and transplantation of MSCs improved this abnormality. These results are consistent with clinical findings that an impairment of small fibers occurs as an earlier event than that of large fibers in the natural history of DPN (52)(53)(54). However, STZ-induced diabetic rats did not show hyperalgesia at 4 weeks of diabetes, in contrast with previous reports that evaluated small fiber functions of STZ-induced diabetic rats using conventional testing methods, such as a thermal plantar test.…”

Section: Discussionsupporting

confidence: 91%

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

et al. 2008

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OBJECTIVE-Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.RESEARCH DESIGN AND METHODS-MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number-to-muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.RESULTS-VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number-to-muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. D iabetic polyneuropathy (DPN) is the most common complication of diabetes. It is estimated that ϳ20 -30% of diabetic patients are affected by symptomatic DPN (1). Generally, DPN develops symmetrically in a length-dependent fashion, with dying back or dropout of the longest nerve fibers; both myelinated and unmyelinated, large and small are affected. Diabetic patients suffer from various symptoms of DPN, such as spontaneous pain, hyperalgesia, and diminished sensation (2). It has been shown that tight glycemic control is effective in slowing the progression of DPN but cannot completely prevent it (3). Therefore, additional therapeutic strategies are required. CONCLUSIONS-TheseNeural cell degeneration and decreased nerve blood flow (NBF) have been recognized as pathophysiologically characteristic features of DPN (4). Therefore, therapeutic agents that could act as both neurotrophic and angiogenic factors would be useful for the treatment of DPN even at an advanced stage. We previously demonstrated that local administration of basic fibroblast growth factor (bFGF) by intramusclar injection with crosslinked gelatin hydrogel improved the impaired nerve functions of streptozotocin (STZ)-induced diabetic rats, including amelioration of decreased NBF, hypoalgesia, and the delayed motor nerve conduction velocity (MNCV) on the treated side of sciatictibial nerves and that these effects were maintained for at least 30 days (5). Schratzberger et al. (6) showed that vascular endothelial growth factor (VEGF) gene transfer significantly increased the NCV and NBF as well as the vascular densities in muscle and peripheral nerv...

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Section: Discussionsupporting

confidence: 91%

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

et al. 2008

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“…Uranyl acetate and lead citrate. Bar: 1 μm tion with nerve-axon reflex also showed that small-fibre impairment was an early event in the natural history of diabetic neuropathy [5,33]. In a series of selected IDDM patients, foot thermal threshold was more frequently altered than vibration thresholds [13].…”

Section: Discussionmentioning

confidence: 96%

Sensory loss, pains, motor deficit and axonal regeneration in length-dependent diabetic polyneuropathy

Saïd¹,

Baudoin²,

Toyooka³

2008

J Neurol

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In order to learn more on the occurrence of pains and motor deficit in severe diabetic polyneuropathy we reviewed the data of a series of 30 diabetic patients with an uncommonly severe length-dependent diabetic polyneuropathy (LDDP). Extensive sensory loss predominated with pains and temperature sensations and affected all four limb extremities, anterior trunk in all, plus the top of the scalp in 9 patients and the cauda equina territory in 2. Twenty patients had neuropathic pains. Symptomatic autonomic dysfunction was present in 28/30 patients, mild distal motor deficit in 12 patients, severe in only one. Vibratory sensation was impaired in the lower limbs in 18 patients; position sense in 8. In the 10 nerve biopsy specimens, the density of myelinated axons was reduced to 23 % and that of unmyelinated axons to 8.5 % of control values. Regenerating axons accounted for 32.4 +/- 19.8 % of the myelinated fibres. On teased fibre preparations 13.9 % of fibres were undergoing axonal degeneration, while 29.4 % of fibres showed focal abnormalities of the myelin sheath.We conclude that distal motor deficit occurs only after major loss of sensory fibres in LDDP; the unmyelinated axons are predominantly affected; absence of clinical improvement contrasts with the high proportion of regenerating axons; detection of alteration of pain and temperature sensation in the feet seems the best method for neuropathy screening in diabetic patients.

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“…In the clinical evaluation of patients with painful DSP, the neurogenic flare was frequently observed to be impaired even in the face of normal quantitative sensory testing and normal morphology as assessed by intra-epidermal nerve fibre density [16]. In support of the attributes of the LDI FLARE area as an early DSP biomarker are numerous small correlational studies [15], [16], [19], [30], [31].…”

Section: Discussionmentioning

confidence: 97%

Diabetic Neuropathy and Axon Reflex-Mediated Neurogenic Vasodilatation in Type 1 Diabetes

et al. 2012

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ObjectiveAxon reflex-mediated neurogenic vasodilatation in response to cutaneous heating may reflect early, pre-clinical small fibre dysfunction. We aimed to evaluate the distribution of the vascular flare area measured by laser doppler imaging (“LDIFLARE area”) in type 1 diabetes and in healthy volunteers.Research and MethodsConcurrent with clinical and electrophysiological examination to classify diabetic sensorimotor polyneuropathy (DSP), LDIFLARE area (cm2) was determined in 89 type 1 diabetes subjects matched to 64 healthy volunteers. We examined the association and diagnostic performance of LDI with clinical and subclinical measures of DSP and its severity.ResultsCompared to the 64 healthy volunteers, the 56 diabetes controls without DSP had significantly lower LDIFLARE area (p = 0.006). The 33 diabetes cases with DSP had substantially lower LDIFLARE area as compared to controls without DSP (p = 0.002). There was considerable overlap in LDIFLARE area between all groups such that the ROC curve had an AUC of 0.72 and optimal sensitivity of 70% for the detection of clinical DSP. Use of a subclinical definition for DSP, according to subclinical sural nerve impairment, was associated with improved AUC of 0.75 and sensitivity of 79%. In multivariate analysis higher HbA1c and body mass index had independent associations with smaller LDIFLARE area.ConclusionsAxon reflex-mediated neurogenic vasodilatation in response to cutaneous heating is a biomarker of early nerve dysfunction in DSP. Its independent association with glycemic exposure in diabetes subjects and both glycemic exposure and BMI in healthy volunteers highlights the existence of small-fibre dysfunction in the natural history of DSP.

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Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction

Abstract: Small-fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small-fibre impairment is an early event in the natural history of diabetic neuropathy.

Cited by 49 publications

References 33 publications

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

Sensory loss, pains, motor deficit and axonal regeneration in length-dependent diabetic polyneuropathy

Diabetic Neuropathy and Axon Reflex-Mediated Neurogenic Vasodilatation in Type 1 Diabetes

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