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PubMed1999

Minimal and asymptomatic chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: Show the chronic inflammatory demyelinating polyneuropathy (CIDP) is not only clinically heterogeneous but extremely variable in severity. METHODS: Three patients were referred for mild distal paresthesiae lasting more than 6 months and one for inguinal and thigh pain later ascribed to coxarthrosis. Strength was normal in all patients and tactile sensation reduced distally only in one. Tendon jerks were absent, except the knee jerks in one patient, reduced in lower limbs in two and normal in one. RESULTS: Electrophysiology showed a demyelinating neuropathy without motor conduction block. CSF protein content was increased in all patients. Nerve biopsies showed de-remyelination with varying degrees of axonal loss. Genetic studies excluded a demyelinating neuropathy associated with duplication or deletion of the 17p.11.2 segment. CONCLUSIONS: CIDP patients with pure sensory clinical presentation have been described but are generally more severely impaired. However, because of the mildness of symptoms and the unequivocal electrophysiological involvement of motor fibers, we think that in these cases the term minimal CIDP is more appropriate than sensory CIDP. These cases represent the most benign end of the CIDP spectrum. In our series minimal or even asymptomatic CIDP encompasses 8% of cases.

Adolescent↗
PubMed2001

Remyelination in vitro following protein kinase C activator-induced demyelination.

In previous work we found that mezerein, a C kinase activator, as well as basic fibroblast growth factor (FGF-2) induce demyelination and partial oligodendrocyte dedifferentiation in highly differentiated aggregating brain cell cultures. Here we show that following protein kinase C activator-induced demyelination, effective remyelination occurs. We found that mezerein or FGF-2 caused a transient increase in DNA synthesis following a pronounced decrease of the myelin markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphohydrolase. Both oligodendrocytes and astrocytes were involved in this mitogenic response. Within 17 days after demyelination, myelin was restored to the level of the untreated controls. Transient mitotic activity was indispensable for remyelination. The present results suggest that myelinating oligodendrocytes retain the capacity to reenter the cell cycle, and that this plasticity is important for the regeneration of the oligodendrocyte lineage and remyelination. Although it cannot be excluded that a quiescent population of oligodendrocyte precursor cells was present in the aggregates and able to proliferate, differentiate and remyelinate, we could not find evidence supporting this view.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1997

Schwann cells responding to primary demyelination in vivo express p75NTR and c-erbB receptors: a light and electron immunohistochemical study.

We have used quantitative and qualitative light microscope immunohistochemistry to examine the expression of p75NTR and c-erbB receptors in Schwann cells in a demyelinating lesion induced by the intraneural injection of lysophosphatidyl choline (LPC). We report that levels of p75NTR, c-erbB2 and c-erbB4, as assessed using image analysis of immuno-peroxidase labelled sections, and c-erbB3, as assessed by eye, increased within each lesion site soon after the initiation of myelinolysis, peaked between 5 and 8 days after induction of demyelination and fell to undetectable levels at the onset of remyelination. Pre-embedding immunoelectron microscopy confirmed that Schwann cells ensheathing demyelinated axons were p75NTR positive. Immunolabel decorated overlapping processes of neighbouring Schwann cells, suggesting that in this context p75NTR could play a role in juxtacrine signalling between reacting cells. We conclude that upregulation of p75NTR and c-erbB receptors is a constitutive Schwann cell response to an acute disruption of the axon-Schwann cell relationship.

Animals↗
PubMed2003

Antibody-mediated CNS demyelination II. Focal spinal cord lesions induced by implantation of an IgM antisulfatide-secreting hybridoma.

We showed previously that spinal cord implants of hybridoma cells (O1) that secrete an IgM antigalactocerebroside cause focal multiple-sclerosis-like plaques of demyelination followed by remyelination to form "shadow plaques" (Rosenbluth et al., 1999). The antibody in that case was directed against a glycolipid present in mature oligodendrocytes and myelin but not in precursor cells. We now report the effects of implanting a different hybridoma (O4) that secretes IgM antibodies directed against sulfatide, a constituent not only of mature myelin and oligodendrocytes but also of late precursor cells, in order to determine whether this hybridoma too would generate focal demyelination and would, in addition, block remyelination. Our results show that focal plaques of demyelination indeed appear after O4 implantation, and that remyelination does occur, but only in cases where the hybridoma cells have degenerated, probably through host rejection. The occurrence of remyelination suggests that oligodendrocyte precursor cells are capable of migrating in rapidly from adjacent areas or that early precursors, not yet expressing sulfatide, remain undamaged within the lesions. In cases where intact hybridoma cells persist at lesion sites, remyelination does not occur. Failure of remyelination in this model thus appears to result from the continuing presence of antimyelin antibodies rather than from depletion of oligodendrocyte precursors.

Animals↗
PubMed1993

Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells.

The transplantation of well defined populations of precursor cells offers a means of repairing damaged tissue and of delivering therapeutic compounds to sites of injury or degeneration. For example, a functional immune system can be reconstituted by transplantation of purified haematopoietic stem cells, and transplanted skeletal myoblasts and keratinocytes can participate in the formation of normal tissue in host animals. Cell transplantation in the central nervous system (CNS) has been proposed as a means of correcting neuronal dysfunction in diseases associated with neuronal loss; it might also rectify glial cell dysfunction, with transplanted oligodendrocyte precursor cells eventually allowing repair of demyelinating damage in the CNS. Here we use co-operating growth factors to expand purified populations of oligodendrocyte type-2 astrocyte (O-2A) progenitor cells for several weeks in vitro. When injected into demyelinating lesions in spinal cords of adult rats, created in such a way as to preclude host-mediated remyelination, these expanded populations are capable of producing extensive remyelination. In addition, transplantation of O-2A progenitor cells genetically modified to express the bacterial beta-galactosidase gene gives rise to beta-galactosidase-positive oligodendrocytes which remyelinate demyelinated axons within the lesion. These results offer a viable strategy for the manipulation of neural precursor cells which is compatible with attempts to repair damaged CNS tissue by precursor transplantation.

Animals↗
PubMed2004

Deficiency of the complement regulator CD59a enhances disease severity, demyelination and axonal injury in murine acute experimental allergic encephalomyelitis.

There is a growing body of evidence implicating complement and, in particular, the terminal pathway (membrane attack complex; MAC) in inducing demyelination in multiple sclerosis and experimental allergic encephalomyelitis. In this paper, we examined the disease course and pathological changes in mice deficient in the major regulator of MAC assembly, CD59a, during the course of acute experimental allergic encephalomyelitis induced by immunisation with recombinant myelin oligodendrocyte glycoprotein. Disease incidence and severity were significantly increased in CD59a-deficient mice. The extent of inflammation, demyelination and axonal injury were assessed in spinal cord cross-sections from CD59a-deficient and control mice, and all these parameters were enhanced in the absence of CD59a. Areas of myelin loss and axonal damage in CD59a-deficient mice were associated with deposits of MAC, firmly implicating MAC as a cause of the observed injury. These findings are relevant to some types of human demyelination, where abundant deposits of MAC are found in association with pathology.

Animals↗
PubMed2000

Demyelination but no cognitive, motor or behavioral deficits after adenovirus-mediated gene transfer into the brain.

Adenovirus-mediated gene transfer of interferon gamma (AdIFN) elicits rejection of intracerebral Lewis lung carcinoma. In this system, gene transfer into brain parenchymal cells is both necessary and sufficient to generate the antitumor response. Despite persistent parenchymal inflammation and demyelination, wild-type mice injected intracerebrally with either AdIFN or beta-galactosidase adenovirus (AdBGAL) perform as well as non-injected animals in behavioral, memory, and motor tests. Both AdIFN and AdBGAL elicit demyelination whose incidence rises sharply when the lowest effective dose of AdIFN is exceeded. Therefore, transfer of interferon gamma into brain parenchyma does not seem to elicit detectable cognitive, behavioral or motor deficits. Furthermore, gene transfer into the brain, by adenoviral vectors currently in clinical trials, is associated with a narrow therapeutic window where the incidence of demyelination rises sharply soon after the effective dose is achieved. Gene Therapy (2000) 7, 2094-2098.

Adenoviridae↗
PubMed1998

Investigation of the role of delayed-type-hypersensitivity responses to myelin in the pathogenesis of Theiler's virus-induced demyelinating disease.

The contribution of autoimmune responses to the pathogenesis of Theiler's virus-induced demyelinating disease was investigated. Delayed-type hypersensitivity responses to myelin were examined in both symptomatic and asymptomatic mice at different times post-infection, in order to determine whether autoreactivity correlates with the development of demyelination. The results indicate that although autoimmune responses probably do not play a major role in the initiation of demyelination at early times post-infection, autoreactivity to myelin antigens dose eventually develop in symptomatic animals, perhaps through the mechanism of epitope spreading. Autoimmunity to myelin components is therefore an additional factor that may contribute to lesion progression in chronically diseased animals.

Animals↗
PubMed2000

Porcine neural progenitors require commitment to the oligodendrocyte lineage prior to transplantation in order to achieve significant remyelination of demyelinated lesions in the adult CNS.

Glial cell transplantation is a potential therapy for human demyelinating disease, though obtaining large numbers of oligodendrocyte precursors from nonrodent species is currently problematic. Culturing of multipotent neural progenitors may provide a solution to this problem, because these cells can be expanded in vitro whilst retaining the ability to differentiate into both neurons and glial cells. In order to investigate the myelinating capability of multipotent neural progenitors, we isolated cells from the porcine subventricular zone, a region rich in neural progenitors, and transplanted them into areas of persistent demyelination in the spinal cord of immunosuppressed rats, created by the injection of ethidium bromide and subsequent exposure to 40 Gy X-irradiation. Porcine SVZ cells were transplanted either within 12 h of isolation or after 7 days in B104-conditioned medium. Freshly isolated cells did not mature into myelinating oligodendrocytes following transplantation and instead remained as clusters of undifferentiated progenitors. However, cells exposed to B104-conditioned medium prior to transplantation were able to effect complete remyelination of the demyelinated axons. This suggests that neural progenitors must be manipulated in vitro for commitment to the oligodendrocyte lineage prior to transplantation if significant remyelination is to be achieved.

Age Factors↗
PubMed2003

Increasing local levels of neuregulin (glial growth factor-2) by direct infusion into areas of demyelination does not alter remyelination in the rat CNS.

Glial growth factor-2 (GGF-2) is a neuronally derived isoform of neuregulin shown in vitro to promote proliferation and survival of oligodendrocytes, the myelinating cells of the CNS. Enhanced remyelination has been demonstrated in vivo following systemic delivery of human recombinant GGF-2 (rhGGF-2) in experimental autoimmune encephalomyelitis (EAE). However, it is uncertain whether this is the result of direct effects of rhGGF-2 on cells of the oligodendrocyte lineage or due to modulation of the immune or inflammatory response. If this enhanced remyelination was due to direct effects of rhGGF-2 on cells of the oligodendrocyte lineage then one would expect rhGGF-2 to induce a similar proremyelinating response in nonimmune, gliotoxin models of demyelination. Using a gliotoxin model of demyelination we were therefore able to ascertain the in vivo effect of rhGGF-2 following local CNS delivery in a model that is not confounded by the concurrent presence of an immune-mediated process. No significant alteration in the rate or character of remyelination was evident following local delivery as compared to controls, and indeed nor following systemic delivery in the gliotoxin model. The results of this study therefore indicate that both direct infusion and systemic delivery of rhGGF-2 do not alter remyelination in a nonimmune, gliotoxin model of demyelination. This suggests that the proremyelinating effects of systemically delivered rhGGF-2 in EAE are unlikely to be due to direct effects on the oligodendrocyte lineage, but may be mediated by rhGGF-2 inducing an environment more favourable to remyelination, possibly through modulation of the immune response.

Animals↗
PubMed2002

Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination.

Exposure of mice to the copper chelator, cuprizone, results in CNS demyelination. There is remyelination after removal of the metabolic insult. We present brain regional studies identifying corpus callosum as particularly severely affected; 65% of cerebroside is lost after 6 weeks of exposure. We examined recovery of cerebroside and ability to synthesize cerebroside and cholesterol following removal of the toxicant. The temporal pattern for concentration of myelin basic protein resembled that of cerebroside. We applied Affymetrix GeneChip technology to corpus callosum to identify temporal changes in levels of mRNAs during demyelination and remyelination. Genes coding for myelin structural components were greatly down-regulated during demyelination and up-regulated during remyelination. Genes related to microglia/macrophages appeared in a time-course (peaking at 6 weeks) correlating with phagocytosis of myelin and repair of lesions. mRNAs coding for many cytokines had peak expression at 4 weeks, compatible with intercellular signaling roles. Of interest were other genes with temporal patterns correlating with one of the three above patterns, but of function not obviously related to demyelination/remyelination. The ability to correlate gene expression with known pathophysiological events should help in elucidating further function of such genes as related to demyelination/remyelination.

Animals↗
PubMed1999

Chronic inflammatory demyelinating polyneuropathy presenting with headache and papilledema.

Chronic inflammatory demyelinating polyneuropathy is a disorder typified clinically by motor and sensory neuropathy of at least 2 months' duration and pathologically by multifocal inflammatory demyelination. Its usual presentation is with features reflecting the polyneuropathy, namely limb weakness with hyporeflexia or areflexia and sensory symptoms of glove and stocking distribution. In this report, we detail the course of a 53-year-old man who presented to our neurological service with a severe headache in association with papilledema. The initial diagnosis considered was of possible primary intracranial pathology. Two months later, he developed limb weakness and sensory symptoms typical of chronic inflammatory demyelinating polyneuropathy. His headache, papilledema, and limb symptoms responded to oral corticosteroid therapy, the standard treatment for this type of neuropathy. We hypothesize that his headache and papilledema were due to the elevated cerebrospinal fluid protein level as a result of the polyneuropathy. To our knowledge, this is the first report of headache being a prominent and early symptom of this disorder.

Adrenal Cortex Hormones↗
PubMed2000

Chronic inflammatory demyelinating polyneuropathy caused by HIV infection in a patient with asymptomatic CMT 1A.

It is well known that patients with Charcot-Marie-Tooth (CMT) disease are liable to present with episodes of cortisone-responsive demyelination, and a superimposed inflammatory component has been suggested. We report a patient who presented with a chronic inflammatory demyelinating polyneuropathy due to a recent HIV infection, which revealed a previously asymptomatic CMT 1A disease documented by identification of the characteristic duplication on the p11.2 region of chromosome 17. The inflammatory process was characterized by pathologic findings on a superficial peroneal nerve biopsy, and the patient improved significantly after corticotherapy. This report gives support to the hypothesis of a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds.

Adult↗
PubMed2005

Increased risk for demyelinating diseases in patients with inflammatory bowel disease.

BACKGROUND & AIMS: Reports of multiple sclerosis (MS), demyelination, and optic neuritis (ON) associated with anti-tumor necrosis factor alpha therapy resulted in warnings on prescribing instructions for infliximab, etanercept, and adalimumab. However, the underlying relationship between IBD and these neurologic conditions has not been established. METHODS: We performed a retrospective cohort study and a retrospective cross-sectional study using 1988 to 1997 data from the General Practice Research Database. A total of 7988 Crohn's disease and 12,185 ulcerative colitis patients were matched for age, sex, and primary care practice to 80,666 randomly selected controls. In the cohort study, incident cases of MS, demyelination, and/or ON (MS/D/ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD. In the cross-sectional study, the diagnosis of MS/D/ON could either precede or follow the IBD diagnosis. RESULTS: In the cohort study, the incidence of MS/D/ON was higher in patients with Crohn's disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis (ulcerative colitis incidence rate ratio [IRR], 2.63; 95% confidence interval, 1.29-5.15; Crohn's disease IRR, 2.12; 95% confidence interval, .94-4.50). In the cross-sectional study, MS/D/ON was more prevalent in patients with Crohn's disease and ulcerative colitis compared with their matched controls (Crohn's disease odds ratio, 1.54; 95% confidence interval, 1.03-2.32; ulcerative colitis odds ratio, 1.75; 95% confidence interval, 1.28-2.39). CONCLUSIONS: Demyelinating diseases occur more commonly among patients with IBD than among non-IBD patients. Future studies should clarify whether treatment with tumor necrosis factor alpha blockers results in further increased incidence of MS/D/ON among IBD patients.

Adult↗
PubMed2003

Demyelinating focal motor neuropathy of the ulnar nerve masquerading as compression in Guyon's canal: a case report.

Ulnar nerve-innervated intrinsic muscle weakness, in the absence of sensory complaints or deficits, usually is the result of compression at the ulnar nerve in zone II of Guyon's canal. In rare instances the problem is not caused by a compressive neuropathy but by a demyelinating focal motor neuropathy. Demyelinating neuropathies have been well documented in the neurologic literature but they have received little attention in the hand surgery literature. We report on one such case and the importance of differentiating the 2 neuropathies. Although surgery often is necessary for a compressive neuropathy it is contraindicated for a demyelinating neuropathy.

Adult↗
PubMed2000

Chronic inflammatory demyelinating polyradiculoneuropathy and severe peripheral oedema: a renal explanation.

Inflammatory demyelinating neuropathies have been associated with membranous and focal sclerosing glomerulonephritis. Here we describe a 58 year old man with a clinical history, physical examination and laboratory investigations consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), who also had severe lower limb and sacral oedema resistant to medical therapy. Mild proteinuria was present and a renal biopsy showed features consistent with focal sclerosing glomerulonephritis (FSGN). The patient's weakness and oedema did not respond to i.v. immunoglobulin or plasmapheresis but responded to high dose oral prednisone. The oedema was not explained by immobility, hypoproteinaemia or local factors. The occurrence of the oedema in a person with CIDP and FSGN and its improvement with prednisone, together with improvement in CIDP and FSGN, suggests that it was immune mediated, possibly due to increased capillary permeability. The presence of renal disease in patients with inflammatory demyelinating neuropathies may be more common than currently realised.

Anti-Inflammatory Agents↗
PubMed2004

Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease.

Chronic disabilities in multiple sclerosis are believed to be due to neuron damage and degeneration, which follow remyelination failure. Due to the presence of numerous oligodendrocyte precursors inside demyelination plaques, one reason for demyelination failure could be the inability of oligodendrocyte precursor cells to turn into myelinating oligodendrocytes. In this study, we show that thyroid hormone enhances and accelerates remyelination in an experimental model of chronic demyelination, i.e., experimental allergic encephalomyelitis in congenic female Dark Agouti rats immunized with complete guinea pig spinal cord. Thyroid hormone, when administered during the acute phase of the disease, increases expression of platelet-derived growth factor alpha receptor, restores normal levels of myelin basic protein mRNA and protein, and allows an early and morphologically competent reassembly of myelin sheaths. Moreover, thyroid hormone exerts a neuroprotective effect with respect to axonal pathology.

Animals↗
PubMed2006

Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination.

Enhancement of oligodendrocyte survival through activation of leukemia inhibitory factor receptor (LIFR) signaling is a candidate therapeutic strategy for demyelinating disease. However, in other cell types, LIFR signaling is under tight negative regulation by the intracellular protein suppressor of cytokine signaling 3 (SOCS3). We, therefore, postulated that deletion of the SOCS3 gene in oligodendrocytes would promote the beneficial effects of LIFR signaling in limiting demyelination. By studying wild-type and LIF-knockout mice, we established that SOCS3 expression by oligodendrocytes was induced by the demyelinative insult, that this induction depended on LIF, and that endogenously produced LIF was likely to be a key determinant of the CNS response to oligodendrocyte loss. Compared with wild-type controls, oligodendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3. Moreover, these SOCS3-deficient mice were protected against cuprizone-induced oligodendrocyte loss relative to wild-type animals. These results indicate that modulation of SOCS3 expression could facilitate the endogenous response to CNS injury.

Animals↗