Axonal atrophy in the painful peripheral neuropathy in AIDS

Summary Two patients with lymphoproliferative disorders developed peripheral neuropathy and neoplastic lymphocytic nerve infiltrates. One of these patients, with B cell small lymphocytic lymphoma, presented with a chronic axonal neuropathy. CD22⁺, CD5^– cells were identified in the epineurium. The other patient with chronic lymphocytic leukemia of 3 years duration developed a mixed axonal and demyelinating neuropathy. CD22⁺ and CD5⁺ cells were observed in the endoneurium. While the cause of the neuropathy in these two cases is unknown, intraneural or systemic autoantibody production may have led to the development of disease.Supported by center grants from the NIH (NINCDS-NS117661) and the Muscular Dystrophy Association to Columbia University, by a grant from the Aaron Diamond Foundation, and by NIH grants CA48236 and EY06337 to Dr. Knowles. Dr. Thomas is a fellow of the Charles A. Dana Foundation and of the Muscular Dystrophy Association     

Axonal transport disturbances in vincristine-induced peripheral neuropathy.

Fast axoplasmic transport of labeled proteins as well as the ultrastructure was studied in the vagus nerves of cats treated chronically with vincristine sulfate (VCR) and in normal nerves exposed in vitro to vincristine. Transport was partially blocked in nerves of some neuropathic cats, and nerves of all neuropathic animals showed a small accelerated transport peak, probably reflecting a reactive or regenerative proces. In vitro, vincristine induced a dose-related partial blockage of fast axoplasmic transport, with concurrent disappearance of microtubules and appearance of paracrystals.     

Axonal transport in mdx mouse sciatic nerve

Anterograde and retrograde flows of acetylcholinesterase (AChE) in sciatic nerves of adult mdx mice were compared with those of normal mice. Specific molecular forms of AChE were resolved by high-performance liquid chromatography such that slow anterograde (G1 + G2), fast anterograde and fast retrograde (G4 and A12) flows could be simultaneously studied. Although we found no difference in the total AChE activity and the molecular forms in non-ligated nerves between mdx and the normal mice, ligated nerves showed significant differences. The total AChE activity accumulated at the proximal segment of ligated nerve was higher in mdx mice than in normal mice after 24 h ligation. The G1 + G2 molecular forms were accumulated more in the proximal segment of mdx than the normal. A12, on the other hand, was more abundant in both segments of mdx mice than the normal. No statistically significant difference in the accumulated amount of G4 molecular form was present between mdx and the normal mice at either proximal or distal segment. These results indicated that axonal flow in sciatic nerve likely plays a role in muscle regeneration, and that the transport machinery in dystrophin-deficient mdx neuron is probably normal.     

Hypoglycaemic neuropathy: microvascular changes due to recurrent hypoglycaemic episodes in rat sciatic nerve

Intensive diabetes treatment causes a considerable increase in the number of severe hypoglycaemic episodes which could aggravate the progression of diabetic neuropathy. However, the effect of repeated hypoglycaemic episodes on nerve morphology has never been previously investigated. The aims of the present study were: (i) to establish a rat model of recurrent episodes of severe hypoglycaemia, and (ii) to assess morphological changes after repeated hypoglycaemic episodes in rat sciatic nerves. We induced hypoglycaemic episodes, blood glucose level <3.0 mmol/l for 3 h, by injecting regular insulin intravenously on 4 consecutive days. We found endothelial swelling of endoneurial microvessels at the thigh level of sciatic and tibial nerves 24 h after four daily episodes of hypoglycaemia. Endothelial swelling was confirmed by vascular morphometry which showed significantly increased endothelial and pericyte areas. No obvious abnormalities were seen on nerve fibres. In conclusion, recurrent hypoglycaemic episodes cause early vascular anomalies in endoneurial microvessels in rat sciatic nerves without any observable changes in nerve fibres.     

Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy

Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1–2 days after and 3–4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.     

Axonal elongation into peripheral nerve grafts between thalamus and somatosensory cortex of the rat. An experimental model

After destruction of the thalamocortical projections of one side in 12 adult rats, the ipsilateral thalamic ventrobasal nucleus was connected with the contralateral somatosensory cortex through an autologous peripheral nerve graft. Three months after the implanting procedure, horseradish peroxidase was applied to the transected nerve. Retrograde labeling of cells occurred in all examined animals. Evidence of newly formed thalamocortical connections provides the experimental basis to a model suitable for functional evaluations.     

HIV neuropathy: insights in the pathology of HIV peripheral nerve disease

HIV-associated neuropathies (HIV-N) have become the most frequent neurological disorder associated with HIV infection. The most common forms of HIV-N are the distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathies (ATN), disorders characterized mostly by sensory symptoms that include spontaneous or evoked pain that follow a subacute or chronic course. The main pathological features that characterize DSP and ATN include "dying back" axonal degeneration of long axons in distal regions, loss of unmyelinated fibers, and variable degree of macrophage infiltration in peripheral nerves and dorsal root ganglia. Marked activation of macrophages as well as the effect of pro-inflammatory cytokines appear to be the main immunopathogenic factors in DSP. Interference with DNA synthesis and mitochondrial abnormalities produced by nucleoside antiretrovirals have been hypothesized as pathogenic factors involved in ATN. The use of skin biopsy has become a useful tool in the evaluation of HIV-N. Reduction in fiber density, increased frequency of fiber varicosities and fiber fragmentation are prominent features of skin biopsies from patients with HIV-N. Other forms of HIV-N include acute or chronic inflammatory polyneuropathies, uncommon disorders that may ocur during seroconversion or early stages of HIV infection. Opportunisitic infections, mostly associated with cytomegalovirus or herpes zoster virus infection occur in late stages of AIDS and produce characteristic clinical features such as mononeuritis multiple or radiculopathies.     

Ischemia-reperfusion injury of peripheral nerve in experimental diabetic neuropathy

The pathogenesis of human diabetic neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative stress. Mild-moderate ischemia-reperfusion to streptozotocin (STZ)-induced diabetes results in florid fiber degeneration in diabetic but not in normal nerves. Uncertainty exists as to the influence of duration of diabetes on this susceptibility. We therefore studied diabetic tibial and sciatic nerves using a rat ischemia-reperfusion (IR) model after 1 month and 4 months of diabetes utilizing electrophysiological, behavioral, and neuropathological methods. Electrophysiological abnormalities were present in 1-month diabetic rats (D) and persisted over 4 months. Behavioral scores were decreased markedly at 4 months (p<0.05). Endoneurial edema and ischemia fiber degeneration (IFD) were observed at both the 1-month (p<0.01 and p<0.001) and 4-month (p<0.001) durations in diabetic nerves, whereas only mild or no damage was observed in age-matched control nerves. These findings demonstrate that STZ-induced diabetes exacerbates the morphological and electrophysiological pathology in peripheral nerve to IR injury both in the early timepoint of 1 month and late timepoint of 4 months, although there was a gradation of injury, which is more severe at the later timepoint. Reperfusion exaggerated morphological pathology in 1-month STZ-induced diabetic peripheral nerve.     

糖尿病周围神经病动物模型的建立、病理观察及巴曲酶保护作用研究

目的建立稳定、可靠的糖尿病周围神经病（DPN）动物模型，观察坐骨神经的病理改变及检测周围神经传导速度和血液流变性等指标，观察巴曲酶是否对DPN有保护作用。方法将大鼠腹腔注射链脲佐菌素制作实验性糖尿病模型，再分别于成模后2个月和3个月时腹腔注射巴曲酶进行干预。电镜、光镜下观察坐骨神经的病理改变，同时检测周围神经传导速度和血液流变件等指标。结果糖尿病大鼠自造模后2个月开始，周围神经传导速度明显减慢，血液粘度及血浆粘度明显升高，用巴曲酶治疗后均得以明显改善，但神经传导速度仍低于正常。血液流变学中仅低切速血液粘度随病程延长而增加，其它指标与病程无关。光镜下可见糖尿病大鼠坐骨神经纤维髓鞘密度不均匀，有斑块状密度减低区。电镜下可见糖尿病大鼠髓鞘局部增厚及板层分离，治疗后上述改变均减轻，细小神经纤维明显增生。结论腹腔注射链脲佐菌素法可建立可靠的实验性DPN动物模型，巴曲酶干预后血液流变性得以改善，周围神经病理改变得以减轻，说明巴曲酶对DPN有保护作用。     

Sciatica due to malignant nerve sheath tumour of sciatic nerve in the thigh.

Malignant peripheral nerve sheath tumour (MPNST) is a rare malignant neoplasm arising from the supportive non-neural component of the peripheral nerves. An unusual case of pain and weakness of the foot and calf muscles due to a giant MPNST of the sciatic nerve in the posterior compartment of the thigh is presented. The patient was already investigated as a case of sciatica due to a lumbar disc disease with a negative magnetic resonance imaging and then unsuccessfully operated elsewhere twice, with a misdiagnosis of tarsal tunnel syndrome. Neurosurgical referral prompted a diagnostic magnetic resonance study of the thigh, revealing the lesion, which was completely excised microsurgically with total relief in the pain and partial improvement in the weakness and sensations in the sole of the foot.     

Axonal neuropathy due to myelin protein zero mutation misdiagnosed as amyloid neuropathy

In up to 50% of chronic idiopathic axonal neuropathies, an underlying diagnosis may be identified, including hereditary neuropathy. Charcot-Marie-Tooth disease (CMT) is clinically and genetically heterogeneous. Several mutations in the myelin protein zero (MPZ) gene have been associated with different CMT phenotypes, including classical demyelinating CMT1B and the axonal form of the disease. Primary amyloidosis, a rare disease where the amyloid is formed by the N-terminal portion of a monoclonal immunoglobulin light chain, may be complicated by polyneuropathy. We report a patient who was incorrectly diagnosed with amyloid neuropathy, but was found to have axonal CMT1B only after sural nerve biopsy ruled out an acquired amyloid neuropathy.     

Axonal autophagy during regeneration of the rat sciatic nerve**★

BACKGROUND: The removal of degenerated axonal debris during Wallerian degeneration is very important for nerve regeneration. However, the mechanism by which debris is removed is not been completely understood. Considerable controversy remains as to the clearance pathway and cells that are involved. OBJECTIVE: To investigate axonal autophagy during removal of degenerated axonal debris by transecting the sciatic nerve in a rat Wallerian degeneration model.DESIGN, TIME AND SETTING: Experimental neuropathological analysis. The experiment was conducted at the Laboratory Animal Service Center of the Southern Medical University between January and June 2005. MATERIALS: Fifty-four adult, Wistar rats of either sex, weighing 180-250 g, were obtained from the Laboratory Animal Service Center of the Southern Medical University. Animals were randomly divided into nine groups of six rats. METHODS: Wallerian degeneration was induced by transecting the rat sciatic nerve, and tissue samples from the distal stump were obtained 0.2, 0.4, 1, 2, 3, 4, 7, 10, and 15 days post-transection. Ultrathin sections were prepared for electron microscopy to study ultrastructure and enzyme cytochemistry staining. MAIN OUTCOME MEASURES: Ultrastructure (axon body, autophagic body, and cystoskeleton) of axons and myelin sheaths observed with electron microscopy; acidic phosphatase activity detected by Gomori staining using electron microscopy. RESULTS: The major changes of degenerating axons after transection were axoplasm swelling and separation of axons from their myelin sheath between five hours and two days post-transection. At four days post-transection, the axoplasm condensed and axons were completely separated from the myelin sheath, forming dissociative axon bodies. Vacuoles of different sizes formed in axons during the early phase after lesion. Larger dissociative axon bodies were formed when the axons were completely separated from the myelin sheath during a late phase. The axolemma surrounding the axon body was derived from the neuronal cell membrane; the condensed axoplasm contained many autophagic vacuoles at all levels. A large number of neurofilaments, microtubules, and microfilaments were arranged in a criss-cross pattern. The autophagic vacuoles exhibited acidic phosphatase activity. Axonal bodies were absorbed after degradation from day 7 onwards, and macrophages were observed rarely in the formative cavity. CONCLUSION: The degenerating axons were cleared mainly by axonal autophagy and Schwann cell phagocytosis during regeneration of the rat sciatic nerve, and macrophages exhibited only an assisting function.     

Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.     

Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy

The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.