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PubMed2006

Chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired neuropathy, presumably of immunological origin. Its clinical presentation and course are extremely variable. CIDP is one of the few peripheral neuropathies amenable to treatment. Typical cases associate progressive or relapsing-remitting motor and sensory deficit with increased CSF protein content and electrophysiological features of demyelination. In other instances the neuropathy is predominantly or exclusively motor or sensory, CSF normal and electrophysiological studies fail to show evidence of demyelination. In such cases conventional diagnostic criteria are not filled yet the patient may respond to immunomodulatory treatments. In this paper we review the diagnostic pitfalls and clinical variants of CIDP to illustrate the problems that may arise. The different therapeutic options are reviewed. Axon loss associated with demyelination is the most important factor of disability and resistance to treatment.

Adolescent↗
PubMed2003

Acute occipital demyelinating lesion appearing as an infarct on diffusion magnetic resonance imaging.

PURPOSE: To report a case of a 27-year-old woman who presented with an acute right homonymous visual field deficit due to demyelination diagnosed by postprocessing analysis of the magnetic resonance imaging (MRI). DESIGN: Observational case report. METHODS: Magnetic resonance imaging analysis with an exponential diffusion-weighted imaging. RESULTS: On MRI, a left occipital lesion with mild enhancement after gadolinium infusion on the T1-weighted image, bright signal with some mass effect on the T2-weighted image, and the diffusion-weighted imaging suggested a diagnosis of an acute infarct. With the use of the exponential image technique, the T2 hyperintense signal present on the diffusion study was almost completely eliminated, changing the diagnosis and treatment plan. Subsequent examinations and MRI confirmed the diagnosis of demyelinating disease. CONCLUSIONS: In diseases such as cerebral ischemia and demyelination, MRI diffusion is often abnormal because such diseases modify the integrity of central nervous system structures. A technique that subtracts the T2 contribution to the diffusion-weighted imaging analysis supported a diagnosis of an acute demyelinating episode that was subsequently confirmed.

Acute Disease↗
PubMed2004

Bystander CD8 T-cell-mediated demyelination is interferon-gamma-dependent in a coronavirus model of multiple sclerosis.

Mice infected with the coronavirus mouse hepatitis virus, strain JHM (JHM) develop a disease that shares many histological characteristics with multiple sclerosis. We previously demonstrated that JHM-infected mice that only have CD8 T cells specific for an epitope not in the virus develop demyelination on specific activation of these cells. Herein we show that this process of bystander T-cell-mediated demyelination is interferon-gamma (IFN-gamma)-dependent. The absence of IFN-gamma abrogated demyelination but did not change T-cell infiltration or expression levels of inflammatory cytokines or chemokines in the spinal cord. These results are consistent with models in which IFN-gamma contributes to CD8 T-cell-mediated demyelination by activation of macrophages/microglia, the final effector cells in the disease process.

Animals↗
PubMed2000

Quantitative ultrastructural analysis of a single spinal cord demyelinated lesion predicts total lesion load, axonal loss, and neurological dysfunction in a murine model of multiple sclerosis.

Infection of susceptible mice with Theiler's murine encephalomyelitis virus results in neurological dysfunction from progressive central nervous system demyelination that is pathologically similar to the human disease, multiple sclerosis. We hypothesized that the development of neuropathology proceeds down a final common pathway that can be accurately quantified within a single spinal cord lesion. To test this hypothesis, we conducted quantitative ultrastructural analyses of individual demyelinated spinal cord lesions from chronically infected mice to determine whether pathological variables assessed within a single lesion accurately predicted global assessments of morphological and functional disease course. Within lesions we assessed by electron microscopy the frequencies of normally myelinated, remyelinated, and demyelinated axons, as well as degenerating axons and intra-axonal mitochondria. The frequency of medium and large remyelinated fibers within a single lesion served as a powerful indicator of axonal preservation and correlated with preserved neurological function. The number of degenerating axons and increased intra-axonal mitochondria also correlated strongly with global measures of disease course, such as total lesion load, spinal cord atrophy, and neurological function. This is the first study to demonstrate that functional severity of disease course is evident within a single demyelinated lesion analyzed morphometrically at the ultrastructural level.

Animals↗
PubMed2000

Assessment of hindlimb gait as a powerful indicator of axonal loss in a murine model of progressive CNS demyelination.

Identifying the role of axonal injury in the development of permanent, irreversible neurologic disability is important to the study of central nervous system (CNS) demyelinating diseases. Our understanding of neurologic dysfunction in demyelinating diseases and the ability to assess therapeutic interventions depends on the development of objective functional assays that can non-invasively measure axonal loss. In this study, we demonstrate in a murine model of progressive CNS demyelination that assessment of the hindlimb width of stride provides a powerful indicator of axonal loss and can dissociate between deficits induced by demyelination versus axonal loss.

Animals↗
PubMed1999

Dexamethasone regulation of interleukin-1-receptors in the hippocampus of Theiler's virus-infected mice: effects on virus-mediated demyelination.

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Interleukin-1 receptors are expressed in the brain of mice, in particular in the hippocampus, and have been implicated in neuroimmunoendocrine interactions. In the present study we investigated the regulation of interleukin-1 receptors in the hippocampus of a susceptible (SJL/J) and a resistant (BALB/c) strain of mice infected with TMEV, at different time intervals of the disease. Our results show that interleukin-1 receptors in the hippocampus were decreased in TMEV-infected mice at early times post-infection (10 and 14 days p.i.). The reduction in interleukin-1 receptors only occurred in the susceptible strain of mice (SJL/J), whereas interleukin-1 binding in the hippocampus of TMEV-infected resistant mice (BALB/c) showed values similar to those in control animals. The TMEV-induced down-regulation of interleukin-1 receptors was secondary to a marked decrease in the affinity of the receptor (control: Kd = 10.5 pM; TMEV: Kd = 1.30 pM) accompanied by a decrease in receptor number (control: Bmax = 2.189 fmol/mg protein; TMEV: B max = 0.84 fmol/mg protein). We also investigated the effects of glucocorticoid treatment on the regulation of hippocampal interleukin-1 receptors of TMEV-infected mice. Dexamethasone treatment in the early phase (500 microg/kg or 1 mg/kg during days 5-10 p.i.) of the disease significantly reversed the deficits in hippocampal interleukin-1 receptors observed at 10 days p.i. in SJL/J mice, and suppressed neurological signs of demyelination. These results suggest that: (i) the reduction of interleukin-1 receptors may be a consequence, at least in part, of local production of interleukin-1 at early times during TMEV infection; (ii) interleukin-1 seems to be a critical factor for the susceptibility to TMEV-induced demyelination and (iii) the protective effect of dexamethasone appears to be related to its ability to reverse the reduction in interleukin-1 receptors during the early disease. These results suggest that interleukin-1 is a pivotal mediator in TMEV-induced demyelination.

Animals↗
PubMed1991

Viral expression in experimental canine distemper demyelinating encephalitis.

We have characterized the relationship between the expression of canine distemper virus (CDV) and demyelinating lesions in the white matter of the cerebellum of experimentally infected dogs. In animals which had demyelinating lesions, CDV proteins (N, P, F and H) were expressed and infectious virus could be recovered from brain tissue. Viral proteins (N, P, F and H) were detected by monoclonal antibodies and immunocytochemistry within demyelinating lesions as well as in scattered glial cells in areas of the white matter which lacked detectable lesions. Many cell types, including astrocytes, neurons, ependymal cells, choroid plexus cells, meningeal cells and perivascular inflammatory cells were labelled for viral antigen. We conclude from our results that the mechanism of demyelination in canine distemper virus-induced encephalitis involves expression of viral gene products at the lesion site.

Animals↗
PubMed1999

Identification of CD4+ and CD8+ T cell subsets and B cells in the brain of dogs with spontaneous acute, subacute-, and chronic-demyelinating distemper encephalitis.

CD4 and CD8 antigen expression of T cells as well as B cell and canine distemper virus (CDV) antigen distribution were immunohistologically examined in the cerebellum of dogs with spontaneous distemper encephalitis. Cellular and viral antigen expression were evaluated at intralesional and extralesional sites and in the perivascular space. Histologically, acute and subacute non-inflammatory encephalitis and subacute inflammatory and chronic plaques were distinguished. Demyelination was a feature of all subacute and chronic lesions, although the majority of plaques exhibited no or only a low level of active demyelination as demonstrated by single macrophages with luxol fast blue positive material in their cytoplasm. CDV antigen expression, observed in all distemper brains, was reduced in chronic plaques. CD4+, CD8+, and B cells were absent in controls and in some brains with acute encephalitis. A mild infiltration of CD8+ cells was noticed in the neuropil of the remaining brains with acute and all brains with subacute non-inflammatory encephalitis. Single CD4+ cells were found in two brains with acute and in all brains with subacute non-inflammatory encephalitis. Numerous CD8+ and CD4+ cells and few B cells, with a preponderance of CD8+ cells, were detected in subacute inflammatory and chronic lesions. In contrast, in perivascular infiltrates (PVI) of subacute and chronic lesions a dominance of CD4+ cells was detected. The dominating CD8+ cells in acute and subacute non-inflammatory encephalitis might be involved in viral clearance or contribute as antibody-independent cytotoxic T cells to early lesion development. In subacute inflammatory and chronic lesions CD8+ cells may function as cytotoxic effector cells and CD4+ cells by initiating a delayed-type hypersensitivity reaction. The simultaneous occurrence of perivascular B and CD4+ cells indicated that an antibody-mediated cytotoxicity could synergistically enhance demyelination. Summarized, temporal and spatial distribution of CD4+, CD8+ and B cells and virus antigen in early and late lesions support the hypothesis of a heterogeneous in part immune-mediated plaque pathogenesis in distemper demyelination.

Animals↗
PubMed2003

Semliki Forest virus-induced demyelination and remyelination--involvement of B cells and anti-myelin antibodies.

Semliki Forest virus (SFV) infection induces a demyelinating encephalomyelitis in the central nervous system (CNS) of mice and serves as a model for multiple sclerosis (MS). This study investigated CNS immune responses at different stages of infection and during SFV-induced demyelination and remyelination. Following the initial CNS inflammation, pathology and viral clearance on days 6-10 post-infection (pi), primary demyelination was observed in cerebellar, brainstem and corpus collosal white matter by days 15-21 pi, with plasma cells and microglia as main participants, and this was followed by remyelination. By day 35 pi, the tissue appeared almost normal. Fluorescent antibody cell sorter (FACS) analysis showed that brain CD8(+) T cells increased during the initial inflammatory response and gradually decreased thereafter. Brain B cell (B220(+)CD19(+)) numbers did not change significantly during the course of infection; however, from days 14 to 35 pi, they matured and produced antibodies to viral and myelin proteins (and peptides) during the period of demyelination and remyelination. The proportion of CD3(-)B220(-)CD11b(+) cells also progressively increased throughout the periods of de- and remyelination. Our results suggest that CD8(+) T cells are involved in the initial destruction of CNS tissue during the first weeks of SFV infection, while B cells, antibodies and microglia may contribute to the myelin pathology seen after recovery.

Alphavirus Infections↗
PubMed1985

Acute canine idiopathic polyneuropathy (ACIP) serum demyelinates peripheral nerve in vivo.

We examined the in vivo demyelinating activity of serum from dogs with acute canine idiopathic polyneuropathy (ACIP), a Guillain-Barré syndrome (GBS)-like illness. Sera from 6 ACIP cases demyelinated rat sciatic nerves more intensely than 11 control sera. Serum activity increased after guinea pig serum (gps) was added, although gps alone had little effect. ACIP sera did not bind more to whole nerve cross sections or Schwann cells in vitro than control sera, and did not contain elevated antigalactocerebroside titers. We do not as yet know the pathogenic importance of the demyelinating factor in ACIP and control dog serum, or understand its relationship to the demyelinating constituent in serum from humans with GBS.

Animals↗
PubMed1999

Early onset of demyelination after N-methyl-D-aspartate lesions of the lateral hypothalamus.

The function of neurons residing in a particular brain area is often assessed by injecting glutamatergic excitotoxins into that area and determining the consequences for the behavior of interest. However, injections of excitotoxins into the central nervous system not only kill local neurons but also demyelinate fibers of passage. Previous studies suggest that the myelin damage is triggered by a delayed inflammatory response to cell death mediated by monocytes of peripheral origin. If so, demyelination should commence only after recruitment of monocytes, their passage through the blood-brain barrier, and their metamorphosis into macrophages. This process is estimated to require at least 48 h. Using a hematoxylin (Weil) stain and immunohistochemistry for myelin basic protein, we looked for signs of demyelination at various times after injections of N-methyl-D-aspartate into the lateral hypothalamus. Demyelination was seen within 24 h after the lesion, sooner than predicted by the monocytic infiltration hypothesis. This finding has implications for interpreting effects of excitotoxic lesions and for developing means of improving their specificity.

Animals↗
PubMed2000

Increased c-Jun expression in neurons affected by lysolecithin-induced demyelination in rats.

The objective of this study was to investigate whether the expression of c-Jun is involved in the neuronal response to experimental demyelination. Lysolecithin-induced demyelination was generated in two distinct neural systems in rats: in the pontocerebellar and the septohippocampal pathways. Six days after the stereotaxic injections of lysolecithin, expression of the immediate early gene c-Jun was visualized by immunohistochemistry. Lesion-specific expression of the Jun protein was observed in neurons whose axons transverse the demyelinated area. Unlike the neural response to axotomy, lysolecithin treatment did not alter the expression of the neuropeptide galanin in the septohippocampal pathway. These results suggest that c-Jun protein expression might represent one step in the neuronal response to demyelination and that this response might be distinct in its downstream events from axotomy.

Animals↗
PubMed1992

Demyelinating peripheral neuropathy in Cockayne syndrome: a histopathologic and morphometric study.

The clinical and histopathological features of Cockayne syndrome in a 2-year-old girl are reported. Sural nerve biopsy revealed segmental demyelination and remyelination. The density of myelinated fibers, especially small ones, was decreased in comparison with an age-matched control. Although the total number of unmyelinated fibers showed no difference from that in the control, the number of small unmyelinated fibers was slightly increased. A study of teased fibers from the patient's nerve revealed that 1% of the fibers had segmental demyelination, and 7% showed remyelination. Ultrastructurally, demyelinated fibers were present sporadically. No degeneration of axons was evident. Our pathological and morphometric data for the sural nerve suggest the presence of primary demyelination in early childhood.

Child, Preschool↗
PubMed1997

Differentiation of dys- and demyelination using diffusional anisotropy.

We attempted differential diagnosis of dysmyelination and demyelination in childhood using magnetic resonance diffusion weighted imaging. Pelizaeus-Merzbacher disease, one of the dysmyelination disorders, demonstrated diffuse high intensity of the cerebral white matter on T2-weighted images, which demonstrated diffusional anisotropy on diffusion weighted images. On the other hand, high intensity lesions on T2-weighted images in Krabbe disease, one of the demyelination disorders, lost diffusional anisotropy. Another demyelination disorder, Alexander disease-related disorder, also lost its diffusional anisotropy. In contrast to relatively high signal of the lesions on diffusion-weighted images in Krabbe disease (high signal type), the lesions in Alexander disease-related disorder showed low signal on diffusion-weighted images (low signal type). These results suggest that diffusion-weighted images will be clinically useful to differentiate dysmyelination from demyelination; both of them demonstrate similar high intensity lesions of the white matter on T2-weighted images.

Adult↗
PubMed1997

Endogenous progenitors remyelinate demyelinated axons in the adult CNS.

Remyelination occurs in demyelinated CNS regions in diseases such as multiple sclerosis. Identification of the cell type(s) responsible for this remyelination, however, has been elusive. Here, we examine one potential source of remyelinating oligodendrocytes-immature, cycling cells endogenous to adult white matter-and demonstrate that this population responds to demyelination by differentiating into myelinating oligodendrocytes. Dividing cells in subcortical white matter of adult rats were labeled by stereotactic injection of a replication-deficient lacZ-encoding retrovirus (BAG). Following a focal demyelination induced with lysolecithin, many of the BAG-labeled cells differentiated into myelinating oligodendrocytes engaging in repair of the lesion. Identification of endogenous cells capable of remyelination provides a target for the study of CNS repair processes in demyelinating diseases.

Animals↗
PubMed2003

Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production.

Multiple sclerosis is characterized by multiple lesions with selective loss of myelin and oligodendrocytes, leading to deficits of sensation and movement, as well as cognitive disabilities. Consequently, a major research endeavor is to identify strategies to enhance oligodendrocyte regeneration and remyelination. FGF-2 is a potent mitogen for OPCs, and it is induced in astrocytes in animal models of demyelinating diseases in conjunction with successful remyelination. However, the factors responsible for inducing FGF-2 after demyelination in astrocytes are unknown. Here we show that CNTF mRNA and protein increase coincident with spinal cord remyelination in mice recovering from MHV-induced demyelination. We identify CNTF within astrocytes surrounding and within remyelinating lesions, and show that CNTF increases FGF-2 ligand and receptor mRNAs in spinal cord after direct application. Furthermore, we show that CNTF increases FGF-2 mRNA approximately 2.5-fold in cultured mouse spinal cord astrocytes. Altogether, these results strongly implicate CNTF as an important cytokine in demyelinating disease and as an upstream regulator of FGF-2 production in astrocytes during early remyelination.

Adrenergic Uptake Inhibitors↗
PubMed1998

Demyelination of retinal myelinated nerve fibers in Behcet's disease.

A 39 year-old Behcet's patient had demyelination of retinal myelinated nerve fibers after recurrent papillitis and vitritis. Oral Prednisolone, cyclosporine, and later periocular corticosteroids and oral colchicine were used but demyelination continued over a 5 year-period. A pseudobulbar palsy with urinary incontinence and pyramidal tract signs developed and azathioprine and corticosteroids were used. Demyelination of retinal nerve fibers stopped and while treatment was underway, the central nervous system (CNS) signs were stable. While the ocular pathology of Behcet's can mirror the CNS signs, indeed optic nerve ischemic demyelination may signal the potential for CNS involvement; azathioprine with prednisone may be more effective in the long-term for optic nerve and CNS involvement than cyclosporine with prednisone.

Adult↗
PubMed2001

Remyelination of the adult demyelinated mouse brain by grafted oligodendrocyte progenitors and the effect of B-104 cografts.

The 4e transgenic mouse is characterized by overexpression of the PLP gene. Heterozygous littermates containing three PLP gene copies develop and myelinate normally. However, a progressive CNS demyelination begins at 3-4 months of age. Despite focal demyelination, these animals survive for one year with hind limb paralysis. We used this CNS demyelination model to determine if grafts of CG4 oligodendrocyte progenitors would survive and myelinate the adult CNS. Either CG4 cells, or co-grafts of CG4/B 104 cells 11:1 ratio respectively) were performed. Grafted cells survived and migrated in the normal and transgenic brain. Non-treated transgenic animals revealed extensive lack of myelin. Three months post-transplant hosts with CG4 or co-transplants displayed a near normal myelin pattern. Double immunofluorescence for neurofilament and myelin basic protein revealed the presence of many naked axons in non-grafted transgenic animals. Those grafted with progenitor CG4 cells or cografts displayed a clear increase in remyelination. This data provides a new direction for the development of cell replacement therapies in demyelinating diseases.

Animals↗