Degeneration Of Unmyelinated Fibres Research Articles

Altered expression of sodium channel distribution in the dorsal root ganglion after gradual elongation of rat sciatic nerves

To elucidate the pathophysiological mechanisms underlying chronic nerve-stretch injury, we gradually lengthened rat femurs by 15 mm at the rate of 0.5 mm/day (group L, n = 13). The control groups comprised sham-operated (group S, n = 10) and naive (group N, n = 8) rats. Immediately after the lengthening, we performed a conduction study on their sciatic nerves and harvested samples. Electrophysiological and histological analyses showed mild conduction slowing and axonal degeneration of unmyelinated fibers in group L rats. Altered mRNA expression of the voltage-gated sodium channels in the dorsal root ganglion was also observed. Tetrodotoxin-resistant (TTX-R) sodium-channel Nav1.8 mRNA expression was significantly decreased and TTX-R sodium-channel Nav1.9 mRNA expression showed a tendency to decrease when compared with the mRNA expressions in the control groups. However, tetrodotoxin-sensitive (TTX-S) sodium-channel Nav1.3 mRNA expression remained unaltered. The immunohistochemical alteration of Nav1.8 protein expression was parallel to the results of the mRNA expression. Previous studies involving neuropathic states have suggested that pain/paresthesia is modulated by a subset of sodium channels, including downregulation and/or upregulation of TTX-R and TTX-S sodium channels, respectively. Our findings indicate that Nav1.8 downregulation may be one of the pathophysiological mechanisms involved in limb lengthening-induced neuropathy.

Sciatic Nerve Block with Resiniferatoxin: An Electron Microscopic Study of Unmyelinated Fibers in the Rat

Perineural administration of the naturally occurring vanilloids (capsaicin, resiniferatoxin [RTX]) produces selective nociceptive blockade. Studies using perineural vanilloids in high concentrations suggest that they can cause a degeneration of unmyelinated fibers. However, electron microscopic studies of local vanilloid toxicity produced conflicting outcomes. In the present study, we sought to determine whether RTX-induced reversible sciatic nerve block results in the degenerative changes of unmyelinated fibers. In rat experiments, RTX was administered percutaneously at the sciatic nerve. The effect of RTX was monitored by measuring the rat's response to noxious heat. The sciatic nerves were removed 48 h after the blockade initiation. Quantitative electron microscopic evaluation of the unmyelinated fibers was performed in three groups of animals: RTX 0.0001% (0.1 microg), RTX 0.001% (1 microg), and control (RTX vehicle, 0.1 mL). Cross-sections of the sciatic nerve 48 h after the initiation of RTX-induced reversible nerve blockade appeared essentially normal. One rarely observed finding was the irregularly compacted membranous deposits in the unmyelinated axons. The frequency of this finding was approximately one per thousand fibers with both concentrations of RTX. The results of the study suggest that a selective and long-lasting sciatic nerve block (up to 2 wk) can be provided by RTX without any significant damage to the unmyelinated nerve fibers.

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy

The early pathological features of human diabetic neuropathy are not clearly defined. Therefore we quantified nerve fibre and microvascular pathology in sural nerve biopsies from diabetic patients with minimal neuropathy. Twelve diabetic patients underwent detailed assessment of neuropathy and fascicular sural nerve biopsy at baseline, with repeat assessment of neuropathy 8.7+/-0.6 years later. At baseline, neuropathic symptoms, neurological deficits, quantitative sensory testing, cardiac autonomic function and peripheral nerve electrophysiology showed minimal abnormality, which deteriorated at follow-up. Myelinated fibre density, fibre and axonal area, and g-ratio were normal but teased fibre studies showed paranodal abnormalities (p<0.001), segmental demyelination (p<0.01) and remyelination (p<0.01) without axonal degeneration. Unassociated Schwann cell profile density (p<0.04) and unmyelinated axon density (p<0.001) were increased and axon diameter was decreased (p<0.007). Endoneurial capillaries demonstrated basement membrane thickening (p<0.006), endothelial cell hyperplasia (p<0.004) and a reduction in luminal area (p<0.007). The early pathological features of human diabetic neuropathy include an abnormality of the myelinated fibre Schwann cell and unmyelinated fibre degeneration with regeneration. These changes are accompanied by a significant endoneurial microangiopathy.

Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology.

Nerve fibre pathology is poorly described in diabetic patients with mild neuropathy and has not been adequately related to clinical evaluation, quantitative sensory examination and neurophysiology. Sural nerve myelinated and unmyelinated fibre pathology was morphometrically quantified and related to the presence of pain and conventional measures of neuropathic severity in 15 diabetic patients with mild neuropathy and 14 control subjects. Diabetic patients demonstrated a significant (P < 0.01) reduction in myelinated fibre density, but no change in fibre/axonal area, or g-ratio, compared to control subjects. Unmyelinated fibre degeneration was evidenced by an increase in the percentage of unassociated Schwann cell profiles (P < 0.0001) and a reduction in axon density (P < 0.0008) in diabetic patients. This was associated with a significant reduction in unmyelinated axon diameter (P < 0.001) with a shift of the size frequency distribution to the left (P < 0.02). Neurophysiology, quantitative sensory testing and nerve fibre pathology failed to differentiate diabetic patients with painful and painless neuropathy and failed to correlate with any measure of unmyelinated fibre pathology.

Differences in the axon composition of nerves supplying the rat knee joint following intra-articular injection of capsaicin

This study was used to examine the ultrastructure of articular nerves supplying the medial aspect of the rat knee joint following injection of capsaicin into the synovial cavity. One week after the intra-articular injection of 0.2 ml of 1% capsaicin solution there was significant reduction in the number of unmyelinated fibres. Two weeks post-injection this appeared to recover and by 4 weeks post-injection no further changes were observed. Myelinated fibres were unaffected by capsaicin injection. This procedure provides an effective means of producing short-term degeneration of unmyelinated fibres innervating the knee joint.

Acute and remitting painful diabetic polyneuropathy: a comparison of peripheral nerve fibre pathology

The cause of the neuropathic pain that is experienced by some patients with diabetic neuropathy remains to be established. Early neuropathological reports, based on comparisons between diabetic patients and non-diabetic control subjects, emphasised associations between pathological changes in specific classes of peripheral nerve fibre and the presence of pain. By making comparisons with more appropriate control subjects, namely diabetic patients without neuropathic pain, more recent studies have found that there are few clear morphological correlates for this type of pain. To investigate this further, we have conducted a detailed morphometric study of sural nerve biopsies from six diabetic patients, four with active acute painful neuropathy and two with recent remission from the same condition. Normal values for the neuropathological parameters were obtained from six non-diabetic control subjects. Teased fibre analysis showed that similar axonal and Schwann cell abnormalities were present in both groups of diabetic patients. Electron microscopical studies revealed that evidence of both myelinated and unmyelinated fibre degeneration and regeneration was also present in the nerves of all diabetic patients, irrespective of whether they had pain. Within the constraints of interpreting results from small numbers of patients, our observations suggested that remission from pain might be associated with a less abnormal axon/Schwann cell calibre ratio, more successful myelinated fibre regeneration and less active unmyelinated fibre regeneration. However, the inescapable finding of this study was, in fact, the similarity in the nerve fibre pathology in diabetic patients with active and remitting painful neuropathy. We conclude that the occurrence of nerve fibre degeneration and regeneration is in itself unlikely to be sufficient to account fully for diabetic neuropathic pain. However, it is conceivable that events occurring during certain stages in the pathological cycle of degeneration and regeneration create the necessary circumstances which lead to pain.

Hypoxic neuropathy: relevance to human diabetic neuropathy

Clinical and neurophysiological studies were conducted in 47 patients with chronic obstructive airways disease and compared with 46 age-matched control subjects. Symptomatic neuropathy was reported in 13% and ankle jerks were absent in 45% of hypoxic patients. Peroneal and median nerve conduction velocities and median and sural sensory nerve amplitudes were significantly reduced in hypoxic patients (p less than 0.01). Six hypoxic patients underwent biopsy of the sural nerve, soleus muscle and overlying skin. Nerve glucose, sorbitol, fructose and myo-inositol concentrations were normal. Detailed light and electronmicroscopy revealed both nerve fibre and microvascular pathology. Segmental demyelination (32%) and unmyelinated fibre degeneration were found to be prominent lesions. The sural nerve perineurium was thickened due to an increase in the number of perineurial lamellae and an increase in intraperineurial space. Basement membrane thickening was observed in capillaries of nerve, muscle and skin. Endothelial cell hyperplasia and hypertrophy were observed in nerve and muscle capillaries but not in skin capillaries. In conclusion, this study has provided neurological, neurophysiological and neuropathological evidence of a neuropathy in hypoxic patients with chronic obstructive airways disease. These findings may be of relevance to some aspects of the aetiology of human diabetic neuropathy.

Comparison between electrophysiologic and morphologic changes in lead induced peripheral neuropathy in rats

Compound nerve action potential (CNAP) of the mixed peripheral nerve is composed of A alpha beta, A delta, and C potentials. All components of CNAPs in the sciatic nerve were recorded by stimulating the tibial nerve of both control and lead-poisoned rats. Marked decrease of nerve conduction velocity and prolonged duration were found in A alpha beta and A delta fibers especially in large myelinated A alpha beta fibers. The amplitude decreased in A alpha beta potential, but the area did not change. In C potential produced by activation of unmyelinated fibers, nerve conduction velocity slightly decreased, but the amplitude and area did not significantly change. Pathologic correlates revealed prominent segmental demyelination with significant decrease of large myelinated fiber densities. Minimal axonal degeneration of unmyelinated fibers was present. We can conclude that electrophysiologic changes in the lead-poisoned rats correlate with pathologic changes in them.

Disulfiram neuropathy: A morphometric study of sural nerve

This report describes peripheral nerve morphology in 3 patients whose acute polyneuropathy followed disulfiram therapy. In all patients a combination of axonal degeneration with segmental demyelination and remyelination was seen, suggesting a varying degree of toxicity to both cytons and Schwann cells. The observed randomness of abnormal internodes argued against primary axonal atrophy and secondary demyelination. While large myelinated fibres were preferentially lost, ultrastructural studies also suggested degeneration of unmyelinated fibres. Because of high chloral consumption at the onset of peripheral nerve disease in 2 patients, the possibility of disulfiram-chloral interaction was considered. Present evidence suggests that the combined use of chloral or its derivatives with disulfiram is best avoided.

Somatic unmyelinated fibre degeneration in rabbits with granulomatous hypersensitivity produced by a non-myelin antigen in sensory peripheral nerve

Rabbits previously sensitised by injection of human sensory peripheral nerve showed degeneration of somatic unmyelinated fibres at skin test sites when challenged by sensory nerve or certain non-myelin fractions prepared from human sensory nerve. Epithelioid cells were found in the endoneurium and may mediate the nerve damage. The degeneration was consistently found and lasted for at least 58 days. Phagocytosing macrophages were absent. Differences in the pattern of nerve damage to that of EAN and EAE are discussed.