Multicomponent T2 analysis of dithiocarbamate-mediated peripheral nerve demyelination

Standard light microscope histological evaluation of peripheral nerve lesions has been used routinely to assess peripheral nerve demyelination; however, the development of magnetic resonance (MR) methodology for assessing peripheral nerve may provide complementary information, with less expense and in less time than nerve histology methods. In this study, the utility of multicomponent NMR T(2) relaxation analysis for assessing myelin injury in toxicology studies was examined using two dithiocarbamates, N,N-diethyldithiocarbamate (DEDC) and pyrrolidine dithiocarbamate (PDTC), known to produce myelin injury and elevate copper in the nervous system. T(2) analysis was used in conjunction with standard histological methods to assess myelin injury and determine if dithiocarbamate-mediated copper accumulation in peripheral nerve was associated with more severe myelin lesions. Male Sprague-Dawley rats were administered i.p. DEDC for 8 weeks and maintained on either a diet containing normal (13 ppm) or elevated (200 ppm) copper. Another group of male Sprague-Dawley rats was administered oral PDTC and a 200 ppm copper diet, with controls given only the 200 ppm copper diet, for 47 weeks. Following exposures, the morphology of sciatic nerve was evaluated using light microscopy and multicomponent T(2) analysis of excised fixed nerves; and copper levels in sciatic nerve were determined using ICP-AES. Light microscopy demonstrated the presence of a primary myelinopathy in dithiocarbamate-exposed rats characterized by intramyelinic edema, demyelination, and secondary axonal degeneration. Both the nerve copper level and number of degenerated axons, as ascertained by ICP-AES and microscopy, respectively, were augmented by dietary copper supplementation in conjunction with administration of DEDC or PDTC. T(2) analysis revealed a decreased contribution from the shortest T(2) component in multicomponent T(2) spectra obtained from animals administered DEDC or PDTC, consistent with decreased myelin content; and the decrease of the myelin water component was inversely correlated to the levels of nerve copper and myelin lesion counts. Also, the T(2) analysis showed reduced variability compared to histological assessment. These studies support multicomponent T(2) analysis as a complementary method to light microscopic evaluations that may also be applicable to in vivo assessments.     

Assesment criteria for experimental demyelination induced in frog peripheral nerve

In ideal conditions the area under compound action potential may be used as an index for the number of activated fibers in a nerve trunk whereas peak amplitude, maximum time derivative, and duration may be used as an indicator for the rate of contribution to compound action potential and the degree of velocity dispersion. In this study, the time domain effect of demyelination on compound action potential has been investigated in experimentally demyelinated frog sciatic nerve. The results were analyzed in order to suggest criteria for demyelination. The results suggest that the changes in peak amplitude and maximum time derivative of compound action potential that is made up by the contribution of the active fibers may be more useful in the assessment of early phase of demyelination. Therefore, it may be concluded that these two parameters, intrinsically, carry augmented information on the velocity dispersion originated from larger-diameter fibers.     

Acute conduction block associated with experimental antiserum-mediated demyelination of peripheral nerve

Intraneural injection of antisera from rabbits with high antigalactocerebroside antibody levels into rat sciatic nerve produced acute nerve conduction block. This was first apparent in some motor axons between 30 and 60 minutes after injection and progressed to completion within 2 to 4 hours. Concurrent morphological evidence of demyelination was present, but structural changes at the time of onset of block were mild and were restricted to the myelin and Schwann cell, particularly at the paranodal areas and Schmidt-Lanterman clefts. It is suggested that paranodal lesions could account for the observed conduction block.     

Combined central and peripheral acute demyelination

We describe a patient with multiple sclerosis who had a bout of central demyelination associated with an acute inflammatory demyelinating polyneuropathy. The contemporary involvement of central and peripheral nervous system due to a demyelinating disease has been reported anecdotically in humans, and can be induced experimentally in animals. It may be sustained by a common pathogenetic factor.

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Sommario In una paziente portatrice di sclerosi multipla una poussée di demielinizzazione centrale si associa ad una polineuropatia demielinizzante infiammatoria acuta. Il contemporaneo coinvolgimento del sistema nervoso centrale e periferico da parte di una malattia demielinizzante è stato riportato sporadicamente nell'uomo, ma può essere sperimentalmente indotto nell'animale e può essere sostenuto da un fattore patogenetico comune.

     

Combined peripheral nerve and central nervous system demyelination in a patient with chronic inflammatory demyelinating polyneuropathy

We report the case of a 49-year-old woman suffering combined central and peripheral demyelination, with serial magnetic resonance images scans illustrating the development of central demyelination in a patient with established chronic inflammatory demyelinating polyneuropathy. This is the sixth patient with this rare overlap syndrome reported to date. We review the available literature and argue that an inherited predisposition to both diseases is the most likely explanation for its occurrence.     

Peripheral nerve demyelination in multiple sclerosis

OBJECTIVE: To elucidate the frequency of peripheral nerve demyelination in multiple sclerosis (MS). There are a number of case reports describing MS patients associated with demyelinating neuropathy, but its frequency in a whole MS population is unknown. METHODS: Extensive nerve conduction studies were prospectively performed in 60 consecutive patients with relapsing-remitting MS. Multiple excitability measurements using threshold tracking were also performed in median motor axons and superficial radial sensory axons. RESULTS: Nerve conduction abnormalities suggestive of demyelination were found for 3 (5%) of the patients. Two of them developed clinically evident neuropathy, whereas the remaining one had only generalized areflexia in addition to MS symptoms/signs. In all the three, MS preceded demyelinating neuropathy by several years. Excitability testing showed that supernormality and threshold electrotonus at the tested sites (median motor axons at the wrist, and radial sensory axons at the mid-forearm) were similar in the normal and MS groups. CONCLUSIONS: MS patients do not generally have peripheral nerve demyelination, but approximately 5% of patients develop demyelinating neuropathy. The association could result from a common pathogenesis possibly due to epitope spreading during the long course of MS. SIGNIFICANCE: Association of chronic inflammatory demyelinating polyneuropathy with MS is not frequent, but needs to be recognized as a treatable condition.     

Double-stranded RNA induces iNOS gene expression in Schwann cells, sensory neuronal death, and peripheral nerve demyelination

Inflammation in the peripheral nervous system (PNS) is one of the characteristics of virus-induced peripheral neuropathy. In this inflammatory response, Schwann cells are actively involved. Previously, toll-like receptor 3 (TLR3) was reported as a receptor for double-stranded RNA (dsRNA) that induces antiviral and inflammatory responses in cells of the innate immune system. In this study, we investigated the expression and putative role of TLR3 in Schwann cells. TLR3 was constitutively expressed in Schwann cells. Stimulation with polyinosinic-polycytidylic acid, a synthetic dsRNA analogue, induced the expression of inducible nitric oxide synthase (iNOS) gene in Schwann cells. Studies on the intracellular signal transduction pathways using iSC, an immortalized Schwann cell line, revealed that dsRNA induces the activation of NF-kappaB, p38, and c-Jun N-terminal kinase (JNK). The activation of NF-kappaB, p38, JNK, and dsRNA-dependent protein kinase is required for dsRNA-mediated iNOS gene expression. However, the activation of PI3 kinase and GSK-3beta inhibited iNOS gene induction, a process mediated by their inhibitory effects on NF-kappaB and p38 activation. dsRNA-induced NO production caused neuronal cell death in cultured dorsal root ganglion. Finally, the introduction of dsRNA into the rat sciatic nerve induced iNOS gene expression and peripheral nerve demyelination in vivo. Taken together, these data suggest that viral RNA may induce inflammatory Schwann cell activation via TLR3 and peripheral nerve damage in the PNS.     

Acute inflammatory demyelination in reperfusion nerve injury

We investigated the pathological appearance of acute inflammation and its role in the development of demyelination in reperfused rat sciatic, tibial, and peroneal nerves after a 5-hour period of near-complete ischemia. Polymorphonuclear neutrophil migration was seen early in the endoneurial lesion. After 18 hours of reperfusion, there was maximal intercellular adhesion molecule-1 expression on endoneurial vessels, and polymorphonuclear neutrophil accumulation was then prominent, reaching a peak 24 hours after reperfusion. Endoneurial mononuclear macrophages increased nearly fourfold after 48 to 72 hours of reperfusion. Macrophages were observed invading Schwann cells and myelin lamellae with associated demyelination. Thus, this study provides evidence of macrophage-associated demyelination after reperfusion similar to that seen in inflammatory neuropathies.     

Acute central and peripheral demyelination associated with Mycoplasma pneumoniae

A 7-year-old female presented with Mycoplasma pneumoniae pneumonitis and a progressive ascending limb paralysis. She developed severe respiratory distress, requiring ventilation, and became apparently unresponsive with fixed dilated pupils. Peripheral nerves were inexcitable in nerve-conduction studies. Magnetic resonance imaging of the brain revealed evidence of extensive demyelination. Anti-GM1 immunoglobulin M antibody titers were raised. She improved after a second course of intravenous immunoglobulin and eventually made a full recovery.     

Associated central and peripheral demyelination: an electrophysiological study

Summary A case is reported in which retrobulbar neuritis preceded Guillain-Barré syndrome by 4 weeks. The visual evoked potential latencies were prolonged. After peripheral nervous system signs had cleared, median and peroneal somatosensory evoked potentials showed prolonged cervical N13, scalp N20 and L3-scalp conduction times.     

Patterns and significance of concomitant central and peripheral inflammatory demyelination

Inflammatory demyelinating diseases comprise a spectrum of disorders that affect central nervous system (CNS) and peripheral nervous system (PNS) myelin. Most individuals have demyelinating disease restricted to one or the other compartment but patients with concomitant CNS and PNS inflammatory inflammatory demyelinating processes have been reported not infrequently. In most such patients, involvement of either the CNS or the PNS predominates the clinical picture. Involvement of the other compartment is usually mild or subclinical with unclear prognostic and therapeutic implications. Similarly, while experimentally induced demyelinating disease in animal models is usually CNS or PNS predominant, varying degrees of pathology in the other system can occur depending on the species, type of immunogen, and genetic background of the immunized animal. When CNS and PNS demyelinating diseases occur concurrently, effective treatment for CNS disease can be safely combined with effective treatment for PNS disease.     

Galactocerebroside antiserum causes demyelination of cat optic nerve

A model of immune-mediated optic nerve demyelination is described. Micro-injection of small volumes (< 5 μl) of high titer polyclonal anti-Gal-C serum into the cat optic nerve resulted in a focal, highly selective demyelinative lesion followed by remyelination. Demyelination appears to be due to a dual effect of myelin and on oligadendrocytes. The numbers of these cels within the lesion were initially reduced but subsequently increased as remyelination occured.     

Conduction block without demyelination following acute nerve infarction

Incomplete infarction of the tibial nerve was produced in 37 rats by injecting arachidonic acid into the femoral artery. Sciatic-tibial motor nerve conduction studies were performed 1, 2, 3 and 7 days later. In all animals the evoked motor responses were of low amplitude and morphological examination showed axonal degeneration. In 20 rats the response elicited by proximal stimulation was of lower amplitude than the distal response indicating focal conduction block in a proportion of those axons which had survived the ischemia and were not degenerating distally. The conduction block resolved over several days and in all but one rat had disappeared by 7 days. Morphological examination of semithin sections and single teased myelinated axons revealed no evidence of segmental demyelination. The rapid resolution of conduction block and the lack of significant segmental demyelination suggest that it has a metabolic basis. We suggest that hypoperfusion of the subperineurial region of the proximal tibial nerve, the region surrounding the infarct through which surviving axons pass, may be sufficient to temporarily block impulse transmission in these surviving axons without producing morphological changes.