Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DEMYELINATION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,135 records · Page 63Linked to original sources

[Pseudotumor forms of demyelinating diseases. Report of three cases and review of the literature].

INTRODUCTION AND CLINICAL CASES: We present three patients with unusual clinical findings studied in our hospital, after a period of follow-up of at least two years from the time of diagnosis of their demyelinating condition. We discuss the clinical onset, CT and magnetic resonance findings, neuropathological studies and posterior clinical course. Anatomopathological studies were done in two of the cases, since the diagnoses were not clear and the other paraclinical investigations did not clarify things. DISCUSSION: The presence of large space-occupying lesions or ring-like outlines in myelinating disorders may make it difficult to make a differential diagnosis from other conditions such as neoplasias and abscesses. This may lead to an erroneous initial diagnosis and even to the use of unsuitable, aggressive treatments. CONCLUSIONS: In young patients in whom radiological imaging suggests space-occupying lesions (single or multiple) one should consider the possibility of a primary demyelinating disease of the central nervous system with the appearance of a pseudo-tumour. In certain cases, stereotaxic biopsy should be considered if the diagnosis remains in doubt, rather than begin unsuitable treatment. The fundamental reason for the presentation of our cases is to emphasize that these pseudo-tumoral forms of demyelinating diseases should be considered in diagnosis.

Adolescent↗

Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis.

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.

Adjuvants, Immunologic↗

Insulin-like growth factor-I treatment reduces immune cell responses in acute non-demyelinative experimental autoimmune encephalomyelitis.

To test the effects of insulin-like growth factor-I (IGF-I) on clinical deficits, lesion severity, and immune cell response in acute, non-demyelinative experimental autoimmune encephalomyelitis (EAE), we induced EAE in Lewis rats by passive transfer of an MBP-reactive T lymphocyte line. Four days after receiving 5 x 10(5) MBPL-1 T cells intravenously, ten pairs of rats had the same mild degree of tail and hind limb weakness. Ten were given 300 micrograms IGF-I i.v. twice daily for 6 days, and the other 10 received the same volume of 0.89% NaCl. Pairs of rats were sacrificed after 4 days and 6 days of IGF-I and placebo treatment and spinal cord sections were processed for immunostaining, in situ hybridization, and morphological examination. IGF-I treatment decreased clinical deficits, lesion numbers, and lesion areas significantly. Numbers of CD4-positive T cells, alpha/beta TCR-positive cells, and ED-1-positive macrophages were also significantly reduced by IGF-I treatment. Similar reductions were found in our second trial, when 11 days of placebo and IGF-I injections began the day after transfer. No demyelination was observed in either toluidine blue-stained semithin sections or sections immunostained with an antibody raised against myelin basic protein (MBP). We conclude that IGF-I-induced reductions in immune cell responses can occur in the absence of demyelination and are of major importance in decreasing clinical deficits and lesion severity in EAE. If IGF-I has similar effects in multiple sclerosis, we think that it will be useful therapeutically.

Animals↗

Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1.

The individual role of tumor necrosis factor receptor 1 (TNFR1) and TNFR2 signaling in experimental autoimmune encephalomeylitis (EAE) was investigated using mice lacking TNFR1 (TNFR1-/-), TNFR2 (TNFR2-/-) as well as double receptor (TNFR1/2-/-) and double ligand (TNF/LT alpha-/-) knockout mice. In wild-type (wt) mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 the clinical course is characterized by an acute disease onset with peak disease scores and a consecutive chronic phase lasting up to 60 days. Compared to control mice, TNF/LT alpha-deficient mice showed a significant delay in disease onset and a remarkable reduction in demyelination which was, however, associated with increased inflammation. In TNFR1-/- and TNFR1/2-/- mice, the disease course was comparable to TNF/LT alpha-deficient mice but rather monophasic and less severe at late time points. Likewise only minimal spinal cord demyelination became apparent. In contrast, the course of EAE in TNFR2-/- mice was severe and associated with remarkable demyelination. Taken together these findings define TNFR1 as crucial mediator in MOG-induced EAE and suggest a protective role for TNFR2 signaling in the clinical course of EAE.

Animals↗

Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination.

Fibroblast growth factor 2 (FGF2) is an excellent candidate to regulate remyelination based on its proposed actions in oligodendrocyte lineage cell development in conjunction with its involvement in CNS regeneration. To assess the potential for FGF2 to play a role in remyelination, we examined the expression pattern of FGF2 and FGF receptors (FGFRs) in an experimental demyelinating disease with extensive remyelination. Adult mice were intracranially injected with murine hepatitis virus strain A-59 (MHV-A59) to induce focally demyelinated spinal cord lesions that spontaneously remyelinate, with corresponding recovery of motor function. Using kinetic RT-PCR analysis of spinal cord RNA, we found significantly increased levels of FGF2 mRNA transcripts, which peaked during the initial stage of remyelination. Analysis of tissue sections demonstrated that increased levels of FGF2 mRNA and protein were localized within demyelinated regions of white matter, including high FGF2 expression associated with astrocytes. The expression of corresponding FGF receptors was significantly increased in lesion areas during the initial stage of remyelination. In normal and lesioned white matter, oligodendrocyte lineage cells, including progenitors and mature cells, were found to express multiple FGFR types (FGFR1, FGFR2, and/or FGFR3). In addition, in lesion areas, astrocytes expressed FGFR1, FGFR2, and FGFR3. These findings indicate that, during remyelination, FGF2 may play a role in directly regulating oligodendrocyte lineage cell responses and may also act through paracrine or autocrine effects on astrocytes, which are known to synthesize other growth factors and immunoregulatory molecules that influence oligodendrocyte lineage cells.

Animals↗

Ectopic impulse generation in demyelinated axons: effects of PaCO2, pH, and disodium edetate.

Demyelinating lesions in the trigeminal root were produced by chronic implantation of chromic suture in 12 cats. Two types of abnormal repetitive action potential generation were recorded from demyelinated fibers: reflected spikes and afterdischarge. Both types of abnormal impulse generation were increased by hypocalcemia induced by disodium edetate infusion, hypocapnia produced by hyperventilation, and, to a lesser extent, alkalosis secondary to sodium bicarbonate administration. This hyperexcitability of fibers could be inhibited by hypoventilation with elevation of PaCO2 or by calcium chloride administration. These results may help explain the pathophysiological basis of paroxysmal symptoms in multiple sclerosis and other disorders in which demyelination is a prominent feature.

Acid-Base Equilibrium↗

Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection.

Nine patients with inflammatory demyelinating polyneuropathies (IDP) were found to have human T-cell lymphotropic virus type III (HTLV-III) infection. The 8 men, 6 of whom were homosexual, and 1 woman, a former intravenous drug user, presented with progressive weakness. Two had lymphadenopathy but all were otherwise asymptomatic. Six had chronic IDP and 3 had Guillain-Barré syndrome. In addition to an elevated cerebrospinal fluid (CSF) protein level (mean, 193 mg/dl), most patients had cerebrospinal fluid pleocytosis (mean, 23 cells/mm3), a distinctive feature. All had reduced T4:T8 T-cell ratios. Results of nerve conduction studies were characteristic of demyelination. Nerve biopsies revealed intense inflammatory cell infiltrates and macrophage-mediated demyelination. The patients recovered either spontaneously or following treatment with corticosteroids or plasmapheresis. During a mean interval of 20 months after presentation, only 1 patient had developed acquired immune deficiency syndrome. Patients with HTLV-III infection have disordered immune function, and the mechanism of the development of the IDP is likely to be immunopathogenic. As a result of our experience, we suggest that all patients with IDP be tested for evidence of HTLV-III infection. We also found, although in uncontrolled trials, that treatment with either prednisone or plasmapheresis was followed by clinical improvement; since plasmapheresis is not likely to further depress cell-mediated immunity, we suggest that it be the initial therapy.

Acquired Immunodeficiency Syndrome↗

Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains.

The amount of messenger RNA encoding human inducible nitric oxide synthase and the presence and distribution of NADPH diaphorase were determined in tissue sections from multiple sclerosis (MS) and control brains. Levels of human nitric oxide synthase messenger RNA were markedly elevated in MS brains when compared to normal control brains. NADPH diaphorase activity, a histochemical stain reflecting nitric oxide synthase catalytic activity, was detected in reactive astrocytes in active demyelinating MS lesions and at the edge of chronic active demyelinating lesions. Control brains did not contain NADPH diaphorase-positive astrocytes. These results implicate the free radical nitric oxide in the pathogenesis of demyelinating MS lesions.

Adult↗

Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). EAE and MS are characterized by significant inflammation, demyelination, neuroglial damage, and cell death. Metallothionein-I and -II (MT-I + II) are antiinflammatory and neuroprotective proteins that are expressed during EAE and MS. We have shown recently that exogenous administration of Zn-MT-II to Lewis rats with EAE significantly reduced clinical symptoms and the inflammatory response, oxidative stress, and apoptosis of the infiltrated central nervous system areas. We show for the first time that Zn-MT-II treatment during EAE significantly prevents demyelination and axonal damage and transection, and stimulates oligodendroglial regeneration from precursor cells, as well as the expression of the growth factors basic fibroblast growth factor (bFGF), transforming growth factor (TGF)beta, neurotrophin-3 (NT-3), NT-4/5, and nerve growth factor (NGF). These beneficial effects of Zn-MT-II treatment could not be attributable to its zinc content per se. The present results support further the use of Zn-MT-II as a safe and successful therapy for multiple sclerosis.

Animals↗

Inflammatory demyelination in a patient with CMT1A.

We report a case of Charcot-Marie-Tooth disease (CMT), with identified PMP22 gene duplication (CMT type 1A), and with evidence of an inflammatory demyelinating process superimposed on the course of the chronic genetic disease. Macrophage-associated demyelination was observed on the peripheral nerve biopsy. This observation supports some experimental data from the literature and shows that there may be a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds.

Aged↗

Primary segmental demyelination in the sural nerve in Cockayne's syndrome.

In a typical case of Cockayne's syndrome, morphometric histopathologic findings of the sural nerve were described and compared with data on two controls. The main pathologic changes of myelinated fibers were segmental demyelination and remyelination with onion bulb formation and a moderate decrease of myelinated fibers. There was no evidence of axonal atrophy in relation to myelin spiral length. In addition, no evidence of the clustered occurrence of demyelinated and remyelinated internodes was obtained on the statistical evaluation of the distribution of such internodes. Although the presence or absence of hypomyelination of a mild degree and maldevelopment of axons to be myelinated has not been clarified, our morphometric data do suggest the presence of primary segmental demyelination of the biopsied sural nerve.

Biopsy↗

Role of Cytokines in Demyelinating Disease Studied in Transgenic Mice

The pathogenesis of inflammatory demyelinating diseases of the central nervous system (CNS) is complex and in part reflects the contribution of multiple cellular and molecular factors. Determining whether these factors are primary or secondary to lesion development or are pathogenic versus protective or reparative represents a major research challenge and will be critical in the development of effective therapeutic strategies. The recent development of experimental procedures that permit the stable germline transmission in mice (so-called transgenic mice) of specific genes with expression targeted to the intact CNS offers a powerful new approach for tackling this problem. In this paper we discuss our experience in the application of genetic engineering to develop transgenic mice with the astrocyte-targeted expression of the key mediators of the host response, the cytokines. Cytokines are a large family of pluripotent mediators with specific classes of these molecules being incriminated in the pathogenesis of inflammatory demyelinating diseases. Transgenic mice were developed in which the expression of the cytokines interleukin-6 or interleukin-3 was targeted to astrocytes using a glial fibrillary acidic protein genomic expression vector. Depending on which cytokine was expressed, these animals developed white matter disease with distinct patterns of demyelination associated with different pathologic features. Here we will describe the procedural details associated with the development of these transgenic models, focusing on three general themes: (i) production of transgenic animals, (ii) analysis of transgene expression, and (iii) characterization of the transgenic mouse phenotype.

Journal Article↗

Monitoring demyelination in multiple sclerosis with multi-flash campimetry.

Multi-flash campimetry is a computer-implemented psychophysical technique that allows a rapid and extensive assessment of visual flicker sensitivity. Multi-flash field maps generated from the data typically reveal the presence of 'islands' of degraded temporal resolution in multiple sclerosis (MS) patients, but not in normal control observers. These distinct 'islands' presumably reflect the influence of demyelination as well as a variety of other possible transient factors, such as edema and inflammation of the optic nerve. The question addressed in the present study concerned a means of distinguishing among such influences. The strategy employed was to test MS patients more than once over a period of several months. Under the assumption that there is little or no significant remyelination in the central nervous system, it was argued that 'islands' that remain present over time should be those that principally reflect demyelination. Transient changes that appear in the fields of MS patients probably reflect the influence of other mediating factors. Examples of multi-flash field maps are presented to illustrate this point and to serve as an initial assessment of the reliability of the technique. It is concluded that multi-flash campimetry may prove to be an effective aid in documenting the degree of progressive visual involvement in MS, and provide a means of monitoring the clinical course of demyelination in the visual system.

Adult↗

Detection of demyelinated plaques with xenon-enhanced computed tomography.

Studies of xenon-enhanced CT for detecting cerebral demyelination have produced conflicting results. Therefore, we studied the effect of xenon inhalation on the CT appearance of five demyelinated plaques. The plaques and the surrounding white matter increased commensurately in attenuation during xenon inhalation. Therefore, xenon enhancement does not generally increase the sensitivity of CT for detecting cerebral demyelination.

Brain↗

Chronic relapsing demyelinating encephalomyelitis associated with persistent spontaneous canine distemper virus infection.

This is the first report of spontaneous canine distemper virus (CDV) infection in a dog associated with chronic progressive multiphasic neurological disease. Initial neurological deficits in the pelvic limbs progressed rapidly to paraplegia with almost complete remission after 9 weeks. Then another acute episode occurred with severe thoracic limb deficits and cerebellar dysfunction and progressive neurological deterioration over 3 months with rising serum neutralizing (SN) anti-CDV titers in the serum and cerebrospinal fluid (CSF). Three neuropathologically distinct lesions of spinal cystic necrosis, chronic demyelinating foci in the cerebellum and acute demyelinating encephalitis in the pons were identified. Persistent CDV antigen was demonstrated immunocytochemically only in acute lesions and atypically restricted to neurons. However, the immunological mechanism associated with the distinct remissions and exacerbations and CDV antigen clearance from chronic demyelinating lesions but persistence in acute lesions, despite a vigorous anti-CDV serologic response, was not defined.

Animals↗

Peptide determinants of myelin proteolipid protein (PLP) in autoimmune demyelinating disease: a review.

This article reviews recent advances in understanding the role of myelin proteolipid protein (PLP) in autoimmune demyelination. It is drawn largely from work published within the last ten years and discusses the immunology of PLP in the historical context of what has been learned from extensive studies on the immune response to myelin basic protein (MBP). Despite the fact that PLP is the major protein constituent of mammalian myelin, its role in autoimmune demyelination has not been widely recognized. The lack of understanding about the immunology of PLP is a direct result of the biochemical characteristics of the protein. PLP is a highly hydrophobic membrane protein with limited aqueous solubility. The hydrophobicity of PLP has thwarted immunologic studies of the intact protein. Recent work has circumvented the technical obstacles of studying the intact protein by using soluble synthetic PLP peptides. This approach has rapidly resulted in a more definitive understanding of the immune response to PLP. Presently, the data indicate that: i) PLP is a major central nervous system (CNS) specific encephalitogen; ii) CD4+ T cell reactivity to discrete PLP peptide determinants can mediate the development of acute, chronic relapsing, and chronic progressive experimental autoimmune encephalomyelitis (EAE); and iii) T cell reactivity to multiple PLP determinants occurs in patients with multiple sclerosis (MS), the major human CNS demyelinating disease.

Amino Acid Sequence↗

Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin.

Local injections of lysolecithin are commonly used to produce areas of demyelination in the CNS. For the mouse, the demyelinating initial phase of lesion development has been described previously but the spontaneous repair which follows has not. In this study we describe the morphological sequelae which result from the injection of 2 microliters of 1% lysolecithin into the spinal cord of adult mice. Lesion length was variable, extending 8 mm or more in 33% of lesioned animals. By 7 days after injection very little extracellular myelin debris was detected and remyelination had commenced. Remyelination progressed rapidly so that almost all axons were invested by myelin sheaths by 23 days. Remyelination was accompanied by a prominent astrocytosis. The long lesion length and the rapidity of repair has important implications for studies designed to assess the ability of transplanted myelinogenic cells to migrate towards demyelinating lesions.

Animals↗

Return of axonal and glial membrane specializations during remyelination after tellurium-induced demyelination.

We have studied remyelination of rat peripheral nerves after tellurium-induced demyelination using thin section and freeze-fracture techniques. In rats fed a 1% tellurium diet, regions of demyelination were readily identified by myelin debris and the presence of large denuded axons. Remyelination occurred despite continued tellurium ingestion. However, the demyelinated axons underwent a more rapid remyelination if tellurium was removed from the diet. Remyelination proceeded as described for myelination in the normal developing animal. Sites destined to become nodes of Ranvier were identified as patches of intramembranous particles in the axonal E-face. Early terminal loops of the remyelinating Schwann cell were found adjacent to these particle patches. As wrapping proceeded, terminal loops of myelin, along with associated rows of dimeric-particles characteristic of the axonal P-face, were wound into a paranodal location. This winding of the membrane specializations and associated terminal loops resulted in the reformation of morphologically normal paranodes. The size of the nodal E-face particle patch increased in concordance with increases in the number of paranodal loops until an annulus of particles was obtained as seen in the normal node. The thin section and freeze-fracture morphology of remyelinated fibres was indistinguishable from the morphology of control fibres. These observations are discussed with respect to proposed functions of membrane specializations in myelination and nerve conduction.

Animals↗