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PubMed2006

Molecular reconstruction of nodes of Ranvier after remyelination by transplanted olfactory ensheathing cells in the demyelinated spinal cord.

Myelin-forming glial cells transplanted into the demyelinated spinal cord can form compact myelin and improve conduction properties. However, little is known of the expression and organization of voltage-gated ion channels in the remyelinated central axons or whether the exogenous cells provide appropriate signaling for the maturation of nodes of Ranvier. Here, we transplanted olfactory ensheathing cells from green fluorescent protein (GFP)-expressing donor rats [GFP-olfactory ensheathing cells (OECs)] into a region of spinal cord demyelination and found extensive remyelination, which included the development of mature nodal, paranodal, and juxtaparanodal domains, as assessed by ultrastructural, immunocytochemical, and electrophysiological analyses. In remyelinated axons, Nav1.6 was clustered at nodes, whereas Kv1.2 was aggregated in juxtaparanodal regions, recapitulating the distribution of these channels within mature nodes of uninjured axons. Moreover, the recruitment of Nav and Kv channels to specific membrane domains at remyelinated nodes persisted for at least 8 weeks after GFP-OEC transplantation. In vivo electrophysiological recordings demonstrated enhanced conduction along the GFP-OEC-remyelinated axons. These findings indicate that, in addition to forming myelin, engrafted GFP-OECs provide an environment that supports the development and maturation of nodes of Ranvier and the restoration of impulse conduction in central demyelinated axons.

Animals↗

PubMed2006

Predicting treatment response in chronic, acquired demyelinating neuropathies.

Chronic inflammatory demyelinating polyradiculopathy is an immune-mediated neuropathy that was first described approximately 30 years ago. Since that time an increasingly wide spectrum of chronic acquired demyelinating polyneuropathies exhibiting different phenotypes, clinical course and treatment responses to immunomodulatory treatment have been described. Several new therapeutic agents have been prescribed for such conditions, some with promising results. This review summarizes what is presently known about the clinical courses, treatment responses and predictors of response of the chronic inflammatory demyelinating polyradiculopathy subgroups.

Chronic Disease↗

PubMed1997

[Demyelination and remyelination after multiple intramedullary injections of ethidium bromide in Wistar rats].

The ethidium bromide model of demyelination has been employed to study the central nervous system response to several episodes of demyelination. Twenty-seven Wistar rats received 2 to 4 intraspinal injections of 1 microliter of either 0.1% ethidium bromide in normal saline (19 rats) or saline 0.9% (8 rats) in different anatomical locations. The intervals between the injections ranged from 28 to 42 days. Ten days after the last injection all the rats were perfused with 2.5% glutaraldehyde. The spinal sections were evaluated macroscopically and by light and transmission electron microscopy. The lesions were typical of focal primary demyelination with preserved vascular structures and followed by remyelinization and varied in size and histological aspects. After multiple sequential ethidium bromide injections, the central nervous system seems to modify its response capacity to an inflammatory challenge although there is no change in its pattern of remyelination.

Animals↗

PubMed1997

[Chronic inflammatory demyelinating polyradiculoneuropathy. Study of 18 cases].

This is a prospective study that describes 18 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic type. The patients have been followed for a period of 4 to 127 months. We evaluated the clinical characteristics, the evolution, and therapeutic response. Male patients outnumbered female patients in a proportion of 1.25:1. Symptoms first appeared at an age ranging from 6 to 85. Most of the patients denied the occurrence of preceding events and a progressive evolution prevailed over relapsing evolution. All patients had both motor and sensory dysfunction associated with loss of tendon reflexes, and only three patients (16.7%) had cranial nerve involvement. The cerebrospinal fluid protein levels were increased in 88.9% of the patients and mean level was 203.4 mg/dl. Electrophysiological studies revealed demyelination in all patients and axonal damage in 94.4%. Preponderant characteristics in the sural nerve biopsy of seven patients showed demyelination and remyelination, and changes indicative of axonal damage were often present. The anti-HLA Dr antibodies were found in the sural nerve of one patient and anti-CD3 antibodies in the sural nerve of two. All patients were first treated with prednisone. The drug was maintained in reduced doses and given in alternate days to 72.2% of the patients with success. Two patients (11.1%) are asymptomatic even after the withdrawal of all medication. We administered azathioprine, associated or not with corticoid, to the four patients who had not had a satisfactory response to the prednisone treatment. By the time of the last evaluation 16 patients (88.9%) had functional improvement.

Adult↗

PubMed2001

Behaviour of oligodendrocytes and Schwann cells in an experimental model of toxic demyelination of the central nervous system.

Oligodendrocytes and Schwann cells are engaged in myelin production, maintenance and repairing respectively in the central nervous system (CNS) and the peripheral nervous system (PNS). Whereas oligodendrocytes act only within the CNS, Schwann cells are able to invade the CNS in order to make new myelin sheaths around demyelinated axons. Both cells have some limitations in their activities, i.e. oligodendrocytes are post-mitotic cells and Schwann cells only get into the CNS in the absence of astrocytes. Ethidium bromide (EB) is a gliotoxic chemical that when injected locally within the CNS, induce demyelination. In the EB model of demyelination, glial cells are destroyed early after intoxication and Schwann cells are free to approach the naked central axons. In normal Wistar rats, regeneration of lost myelin sheaths can be achieved as early as thirteen days after intoxication; in Wistar rats immunosuppressed with cyclophosphamide the process is delayed and in rats administered cyclosporine it may be accelerated. Aiming the enlightening of those complex processes, all events concerning the myelinating cells in an experimental model are herein presented and discussed.

Animals↗

PubMed2006

[Evaluation of locomotor activity after a local induction of toxic demyelination in the brainstem of Wistar rats].

Ethidium-bromide (EB)-induced lesions have been used to investigate the incomplete remyelination in the central nervous system, as well as to evaluate therapeutic strategies to accelerate the reconstruction of the lost myelin sheaths. Although many electrophysiologic studies were performed in situations of experimental demyelination and remyelination, their behavioural effects have not been properly analyzed. In this study, we investigated ultrastructurally the EB - demyelinating lesions as well as the locomotor activity of rats during the beam walking test after a focal induction of demyelination using the EB model in the ventral surface of the brainstem. It was observed the occurrence of locomotor deficits until 31 days post-injection, as well as that subsequent remyelination was related to the return of the lost function.

Animals↗

PubMed2002

Ethidium bromide-induced demyelination of the sciatic nerve of adult Wistar rats.

Peripheral nerve ultrastructure was assessed after single or multiple local injections of the intercalating dye ethidium bromide. Thirty-four adult Wistar rats of both sexes were divided into five groups and maintained in a controlled environment with rat chow and water ad libitum throughout the experiment. The experimental animals were injected with 1 microl of 0.1% ethidium bromide in 0.9% saline into the central third of the left sciatic nerve 1 (group 1), 2 (group 2), 4 (group 3), 6 (group 4) or 8 (group 5) times. In groups 2 to 5 the injections were made at 28-day intervals. Control animals received the same amount of 0.9% saline. The animals were killed at different times after injection: group 1 at 7 days (2 rats) and 15 days (2 rats); for groups 2, 3, 4 and 5, all rats were killed 10 days after the last injection and the lesions were investigated by light and transmission electron microscopy. In the acute lesions, intoxicated Schwann cells showed a vacuolated cytoplasm and separation of the sheaths from the axon. Myelin sheaths underwent progressive vesiculation and subsequent segmental demyelination. Myelin debris were withdrawn by macrophages and remyelination by Schwann cells was prominent. With the increase in the number of injections collagen fibers also increased in number and progressively enveloped smaller numbers of remyelinated axons composing new fascicles. Wallerian degeneration of fibers apparently not affected by ethidium bromide was more intense in the nerves from groups 4 and 5. The peripheral nerve repairs itself after demyelinating challenges with a profusion of collagen fibers and new fasciculations. This experimental model is valid to mimic recurrent demyelinating neuropathies.

Animals↗

PubMed2005

Exacerbation of chronic inflammatory demyelinating polyradiculoneuropathy during interferonbeta-1b therapy in a patient with childhood-onset multiple sclerosis.

Interferonbeta-1b (IFNbeta-1b) is commonly used for relapsing-remitting multiple sclerosis (MS). We report a 23-year-old woman with childhood onset relapsing-remitting MS treated with IFNbeta-1b who developed overt chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) immediately after therapy. A baseline conduction study before IFNbeta-1b therapy revealed decreased motor conduction velocities and prolonged F wave latencies in several nerves, but there was no neurological sign indicating neuropathy. The existence of subclinical demyelinating neuropathy before IFNbeta-1b treatment was suggested, although the clinical criteria for CIDP were unfulfilled. Following two months of IFNbeta-1b therapy, numbness of her right upper and lower limbs progressively worsened and all tendon reflexes were depressed. Electrophysiologically, F waves were not evoked in any limbs except for the left ulnar and tibial nerves, which showed marked prolongation of F wave latencies. Moreover, subclinical hyperthyroidism developed in association with high titers of anti-thyroglobulin and antithyroid peroxydase antibodies, which were negative before IFNbeta-1b therapy. These findings indicated that peripheral demyelination worsened at the nerve roots after IFNbeta-1b therapy. In addition to the development of autoimmune thyroid disease, the patient now fulfilled the criteria for probable CIDP. Along with the results of a previous report demonstrating IFNbeta-induced CIDP development in patients with childhood MS, this case underscores IFNbeta as a potential risk factor for CIDP in patients with childhood onset MS.

Adult↗

PubMed1985

Perivascular demyelinization of cochlear neurons in two neonates.

Localized perivascular demyelinization of the peripheral processes of cochlear neurons was observed in surface preparations of the osseous spiral lamina in two neonates, one a premature infant with erythroblastosis fetalis, the other a full-term infant with cyanotic congenital heart disease. In both cases the cause of the demyelinization was unknown. Both infants had severe edema as a result of congestive heart failure and anoxia. The serum bilirubin level in the erythroblastotic child appeared too low to have caused injury to the nerve fibers. The demyelinization was most striking in the lower half of the basal turn. It was observed only in the immediate vicinity of meandering stretches of capillaries as they crossed the nerve fibers. In the premature infant there was hair cell loss throughout the cochlea; in the other there was no hair cell loss, but a malformed labyrinth of the Mondini type.

Cochlear Nerve↗

PubMed2000

Attenuation of experimental autoimmune demyelination in complement-deficient mice.

The exact mechanisms leading to CNS inflammation and myelin destruction in multiple sclerosis and in its animal model, experimental allergic encephalomyelitis (EAE) remain equivocal. In both multiple sclerosis and EAE, complement activation is thought to play a pivotal role by recruiting inflammatory cells, increasing myelin phagocytosis by macrophages, and exerting direct cytotoxic effects through the deposition of the membrane attack complex on oligodendrocytes. Despite this assumption, attempts to evaluate complement's contribution to autoimmune demyelination in vivo have been limited by the lack of nontoxic and/or nonimmunogenic complement inhibitors. In this report, we used mice deficient in either C3 or factor B to clarify the role of the complement system in an Ab-independent model of EAE. Both types of complement-deficient mice presented with a markedly reduced disease severity. Although induction of EAE led to inflammatory changes in the meninges and perivascular spaces of both wild-type and complement-deficient animals, in both C3(-/-) and factor B(-/-) mice there was little infiltration of the parenchyma by macrophages and T cells. In addition, compared with their wild-type littermates, the CNS of both C3(-/-) and factor B(-/-) mice induced for EAE are protected from demyelination. These results suggest that complement might be a target for the therapeutic treatment of inflammatory demyelinating diseases of the CNS.

Animals↗

PubMed2006

Mechanisms of immunopathology in murine models of central nervous system demyelinating disease.

Many disorders of the CNS, such as multiple sclerosis (MS), are characterized by the loss of the myelin sheath surrounding nerve axons. MS is associated with infiltration of inflammatory cells into the brain and spinal cord, which may be the primary cause of demyelination or which may be induced secondary to axonal damage. Both the innate and adaptive arms of the immune system have been reported to play important roles in myelin destruction. Numerous murine demyelinating models, both virus-induced and/or autoimmune, are available, which reflect the clinical and pathological variability seen in human disease. This review will discuss the immunopathologic mechanisms involved in these demyelinating disease models.

Alphavirus↗

PubMed1999

Potential role of CD4+ T cell-mediated apoptosis of activated astrocytes in Theiler's virus-induced demyelination.

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains results in a chronic, immune-mediated demyelinating disease similar to human multiple sclerosis. Here, we examined the role of astrocytes as an APC population in TMEV-induced demyelination and assessed the potential consequences of T cell activation following Ag presentation. IFN-gamma-pretreated astrocytes were able to process and present all the predominant T cell epitopes of TMEV to virus-specific T cell hybridomas, clones, as well as bulk T cells. Despite low levels of proliferation of T cells due to prostaglandins produced by astrocytes, such Ag presentation by activated astrocytes induced the production of IFN-gamma, a representative proinflammatory cytokine, in TMEV-specific Th cell clones derived from the CNS of virus-infected mice. Furthermore, these Th cell clones mediate lysis of the astrocytes in vitro in a Fas-dependent mechanism. TUNEL staining of CNS tissue demonstrates the presence of apoptotic GFAP+ cells in the white matter of TMEV-infected mice. These results strongly suggest that astrocytes could play an important role in the pathogenesis of TMEV-induced demyelination by activating T cells, subsequently leading to T cell-mediated apoptosis of astrocytes and thereby compromising the blood-brain barrier.

Amino Acid Sequence↗

PubMed1999

[The immunosorption of the cerebrospinal fluid in the treatment of inflammatory demyelinating polyneuropathies].

Immunosorption of cerebrospinal fluid with updated "Pall" immunofilters (Germany) was successfully performed in 3 patients with progressing hormone-resistant Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. It was proved that clinical improvement in the patients' state correlated with a decrease in the contents of both total protein and immunoglobulins G, A, M in cerebrospinal fluid. It was suggested that the removal of these humoral factors had decreased a degree of inflammatory and demyelinating processes in inflammatory demyelinating polyneuropathies and had improved, thereby, the results of the treatment.

Adult↗

PubMed2000

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 Disease↗

PubMed1999

[Chronic inflammatory demyelinating polyneuropathy. Findings in 30 patients].

Chronic demyelinating inflammatory polineuropathy (CIDP) is a disease which was recognized several years ago. However, the mechanism underlying its pathogenesis remains poorly understood. Nevertheless, there are some clues which strongly suggest that it constitutes an autoimmune disease. Since 1992 we have studied 30 cases. All them were clinically assessed and submitted to laboratory investigations encompassing nerve conduction studies, sera proteins immunoelectrophoresis, spinal fluid analysis and sural nerve biopsies. Upon clinical examination the usual findings were weakness, muscle atrophy, absence or diminished tendon jerks, paresthesias and hyposthesias. Electrophysiological studies disclosed marked slowing of the nerve conduction velocities, suggesting demyelination. Sera immunoelectrophoresis detected monoclonal gammopathy in 17% of the studied patients, which was not associated with lymphoproliferative illnesses. Of the patients 79% had increased levels of spinal fluid proteins. Seventeen patients gave their consent for performing a sural nerve biopsy; all the samples showed demyelination. In conclusion, we think that CDIP is a disease which can be recognized when the clinical assessment, the nerve conduction studies and the spinal fluid findings suggest the diagnosis. Although nerve biopsy may be strongly supporting, we believe that it has to be performed only if doubts arise from the clinical, electrophysiological or spinal fluid observations. It is worth noting that its early detection may benefit the patient through the administration of the right therapy precluding the eventual sequelae of the disease.

Adolescent↗

PubMed2000

[Acquired demyelinating neuropathies].

The acquired demyelinating polyneuropathies with either acute or chronic clinical presentation are considered autoimmune disorders. The Guillain-Barré syndrome is viewed as an acutely reactive and self-limited autoimmune disease, triggered by preceding bacterial or viral infections. There is a particularly strong association with the gastroenteric pathogen, Campylobacter jejuni, and with Cytomegalovirus and Epstein-Barr virus. It is likely that immune response directed towards the infecting organisms are involved in the pathogenesis of Guillain-Barré syndrome by cross-reaction with neural tissues. In the susceptible individual, the infecting organism induces humoral and cellular immune responses that, because of the sharing of homologous epitopes (molecular mimicry), cross-react with ganglioside surface components of peripheral nerve. Immune reactions against target epitopes in the Schwann cell surface membrane or myelin result in acute inflammatory demyelinating neuropathy (90% of cases); reactions against epitopes contained in the axonal membrane cause the acute axonal forms of Guillain-Barré syndrome. Immunomodulation with infusions of IgG or plasma exchange treatments effectively foreshorten the disease course. The immunopathogenesis of the chronic disease forms, chronic inflammatory demyelinating peripheral neuropathy and multifocal motor neuropathy are less well-known. Immunomodulatory treatments with corticosteroid or cytotoxic drug treatments, infusion of Ig or therapeutic plasma exchanges are variably effective. The article outlines the principles and practices of an individualized approach to therapy.

Adrenal Cortex Hormones↗

PubMed1996

Chronic inflammatory demyelinating polyneuropathy in dogs and cats.

Over the past several years, we have accumulated data on a spontaneous demyelinating peripheral neuropathy that is not well identified in domestic animals. This disorder occurs in dogs and cats of either sex and does not appear breed-related. Onset of signs is usually insidious and the course is typically chronic, sometimes relapsing, and often slowly progressive. Mature animals of any age may be affected. Clinical signs include tetraparesis, sometimes progressing to tetraplegia, stumbling gait, and hyporeflexia. Motor nerve conduction velocities are decreased. Pathologically, changes in teased single fibers from peripheral nerves are dominated by multifocal paranodal demyelination. Scattered, thinly myelinated fibers are seen on semithin sections. Ultrastructural studies reveal macrophages within myelinated fibers stripping the myelin sheaths, naked and remyelinating axons, and focal/multifocal endoneurial mononuclear cells. Indirect immunofluorescence revealed positive IgG staining in peripheral nerve myelin sheaths from two dogs. The course of the disease, clinical signs, electrophysiology, and pathology have similarities to chronic inflammatory demyelinating polyneuropathy in people.

Age Factors↗

PubMed2000

Pathogenesis and treatment of inflammatory demyelinating polyradiculoneuropathy.

Inflammatory demyelinating polyradiculoneuropathy causes a spectrum of conditions ranging from acute (Guillain-Barré syndrome), through subacute to chronic forms. The pathogenesis of acute forms is related to antibody responses against glycolipid epitopes which mimic bacterial, especially Campylobacter jejuni, structures but T cells are also involved. The pathogenesis of chronic forms is poorly understood. Different forms differ in their responses to steroids. Chronic inflammatory demyelinating polyradiculoneuropathy responds to steroids but a variant multifocal motor neuropathy and the acute forms of inflammatory demyelinating polyradiculoneuropathy do not. Acute and chronic forms respond to plasma exchange and intravenous immunoglobulin.

Gangliosides↗