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PubMed1983

Sequence of demyelination-remyelination in Guillain-Barré disease.

A detailed investigation of nerve conduction was made in a patient with Guillain-Barré disease. Conduction velocity and configuration of the compound action potential in distal (median), intermediate (tibial) and central (sciatic) nerve segments were studied serially as the patient weakened and then recovered. Demyelination was found to follow a centripetal pattern, occurring first in the most distal portion of nerve and progressing, as the patient weakened, to the spinal root level. Motor and sensory fibres were equally affected although clinically motor weakness predominated. During recovery, central conduction was the first to improve. The pattern of demyelination-remyelination in Guillain-Barré disease appears to be one in which clinical recovery follows remyelination at the spinal root level and in which the first nerve segments to be demyelinated are the last to be remyelinated.

Adult↗
PubMed1985

Passive transfer studies in demyelinating neuropathy with IgM monoclonal antibodies to myelin-associated glycoprotein.

Serum or IgM fraction from two patients with a demyelinating neuropathy and IgM monoclonal antibodies to myelin-associated glycoprotein were injected in three different animal species. There were no clinical, electrophysiological or morphological signs of demyelination in either chronic or acute passive transfer experiments. These results suggest that the pathogenesis of this human demyelinating neuropathy may be more complex than has been assumed.

Animals↗
PubMed1990

Cranial magnetic resonance imaging in chronic demyelinating polyneuropathy.

Twenty one patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and five patients with chronic demyelinating polyneuropathy associated with benign monoclonal paraproteinaemia none of whom had signs or symptoms of central nervous system disease, had cranial magnetic resonance imaging (MRI) on a 1.5 Tesla unit. Areas of increased white matter signal intensity were seen in one of 10 patients aged less than 50 years and in five of 16 patients aged more than 50 years. In only two of the patients (8%), neither of whom had paraproteinaemia, did the appearance strongly suggest demyelination. The only clinical variable that predicted MRI changes was age (p less than 0.01).

Adult↗
PubMed1995

Electrodiagnostic criteria for polyneuropathy and demyelination: application in 135 patients with Guillain-Barré syndrome. Dutch Guillain-Barré Study Group.

Since the development of effective but expensive therapeutic strategies for the treatment of Guillain-Barré syndrome, early confirmation of the diagnosis has become very important. Electrodiagnostic criteria were developed for the discrimination of polyneuropathy and in particular for demyelination. The sensitivity and specificity of these criteria were determined in 135 patients with Guillain-Barré syndrome in an early stage of the disease, along with 45 healthy volunteers. The algorithms used to develop our criteria consisted of sets of selected electrodiagnostic variables, each of them relevant to the detection of polyneuropathy. Each set was applied on all of three consecutive electrodiagnostic examinations within one month of disease onset. Application of the best set resulted in 85% of patients with Guillain-Barré syndrome fulfilling the criteria for polyneuropathy at the first examination (mean time interval six days of disease onset), whereas none of the healthy volunteers fulfilled the criteria (sensitivity 85%, specificity 100%). The set of criteria for the detection of demyelination was fulfilled by 60% during the first examination (by 66% and 72% during the second and third examination). Application of criteria for demyelinating polyneuropathy as defined by others resulted in substantially lowered incidence (3%-46%). It is concluded that these criteria for the electrodiagnostic delineation of polyneuropathy are the most sensitive to date, with respect to the early confirmation of the diagnosis of Guillain-Barré syndrome.

Adult↗
PubMed1996

The F wave disappears due to impaired excitability of motor neurons or proximal axons in inflammatory demyelinating neuropathies.

OBJECTIVES: Investigation of pathophysiology of F wave disappearance in demyelinating neuropathies. METHODS: The peripheral motor nerve conduction was studied by motor evoked potential (MEP) on transcranial magnetic stimulation as well as conventional nerve conduction studies before and after the treatment in 26 patients with inflammatory demyelinating neuropathies. In addition, serum antiganglioside antibodies in the acute or active stage were examined. RESULTS: The F wave was abolished in 10 patients. Seven of the 10 patients showed motor evoked potentials (MEPs) on transcranial magnetic stimulation that ranged from 1-4 mV. In six of them the F wave reappeared in the recovery stage, but the MEP size did not change. This may be caused by humoral factors, because the F wave reappeared immediately after plasma exchange or intravenous immunoglobulin treatment. A correlation of F wave disappearance with the presence of serum antiganglioside antibodies was found. CONCLUSIONS: The major pathophysiology of F wave disappearance in demyelinating neuropathies is impairment of motor neuron excitability or prolonged refractoriness of the most proximal axon for backfiring. The conventional interpretation that absent F waves suggest a conduction block at the proximal site is often inadequate.

Acute Disease↗
PubMed1997

Decreased electrical excitability of peripheral nerves in demyelinating polyneuropathies.

Not recognising the presence of decreased excitability may give rise to a seemingly low compound muscle action potential, which may lead erroneously to the conclusion of conduction block. To quantify decreased electrical excitability, stimulation-response curves and the current needed to achieve 90% of the maximal compound muscle action potential amplitude, i90, were obtained in 17 healthy controls, eight patients with Guillain-Barre syndrome, 14 with chronic inflammatory demyelinating polyneuropathy, and 10 with hereditary motor sensory neuropathy type I. Decreased electrical excitability was found in patients with chronic inflammatory demyelinating polyneuropathy and hereditary motor sensory neuropathy type I, by contrast with patients with Guillain-Barré syndrome. Recognising decreased excitability prevents the false assertion of conduction block and has electrodiagnostic importance for the differential diagnosis of demyelinating polyneuropathies.

Action Potentials↗
PubMed1998

Diagnostic value of sural nerve biopsy in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To investigate the additional diagnostic value of sural nerve biopsy of 64 patients in whom chronic inflammatory demyelinating polyneuropathy (CIDP) was considered, as sural nerve biopsy is recommended in the research criteria of an ad hoc subcommittee to diagnose CIDP. METHODS: Firstly, the additional diagnostic value of sural nerve biopsy was analysed with multivariate logistic regression. Six clinical features (remitting course, symmetric sensorimotor neuropathy in arms and legs, areflexia, raised CSF protein concentration, nerve conduction studies consistent with demyelination, and absence of comorbidity or relevant laboratory abnormalities) were entered into a logistic model. Afterwards, all significant features identified from this model, as well as the results of sural nerve biopsy were forced into a second logistic model. Secondly, the diagnostic performance of a neurologist experienced in diagnosis of peripheral nerve disorders was studied by receiver operating characteristics (ROC) curve analysis. RESULTS: The results of the first logistic analysis showed that CSF protein concentration >1 g/l (odds ratio (OR)=38.5) and neurophysiological studies consistent with demyelination (OR=51.7) were strong predictors of CIDP. When forcing the significant features and the sural nerve biopsy data into the model, an independent predictive value of sural nerve biopsy could not be found. The neurologist was able to discriminate patients with and without CIDP (area under the curve (AUC)=0.95). His diagnostic performance did not improve significantly by offering him the results of sural nerve biopsy. CONCLUSION: Any additional diagnostic value of sural nerve biopsy in the diagnosis of CIDP could not be shown.

Adolescent↗
PubMed2003

Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis.

In recent years, it has become evident that the adult mammalian CNS contains a population of neural stem cells (NSCs) described as immature, undifferentiated, multipotent cells, that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells. This article reviews recent progress in elucidating the genetic programs and dynamics of NSC and OPC proliferation, differentiation, and apoptosis, including the response to demyelination. Emerging knowledge of the molecules that may be involved in such responses may help in the design of future stem cell-based treatment of demyelinating diseases such as multiple sclerosis.

Animals↗
PubMed2006

Glutamate receptors in neuroinflammatory demyelinating disease.

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS). The condition predominantly affects young adults and is characterised by immunological and inflammatory changes in the periphery and CNS that contribute to neurovascular disruption, haemopoietic cell invasion of target tissues, and demyelination of nerve fibres which culminate in neurological deficits that relapse and remit or are progressive. The main features of MS can be reproduced in the inducible animal counterpart, experimental autoimmune encephalomyelitis (EAE). The search for new MS treatments invariably employs EAE to determine drug activity and provide a rationale for exploring clinical efficacy. The preclinical development of compounds for MS has generally followed a conventional, immunotherapeutic route. However, over the past decade, a group of compounds that suppress EAE but have no apparent immunomodulatory activity have emerged. These drugs interact with the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-isoxazolepropionic acid (AMPA)/kainate family of glutamate receptors reported to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. The review considers the importance of the glutamate receptors in EAE and MS pathogenesis. The use of receptor antagonists to control EAE is also discussed together with the possibility of therapeutic application in demyelinating disease.

Animals↗
PubMed1992

C wave of electroretinogram and visual evoked response in optic neuritis due to demyelinating diseases.

In 21 consecutive cases with unilateral optic neuritis due to demyelinating disease, ERG, C wave of ERG and VER were recorded and studied in both eyes. Also 8 cases suffering from optic atrophy due to trauma or glaucoma were included. The analysis of data shows that the C-wave is significantly diminished in both eyes, namely the affected and the sound, in the cases of optic neuritis. Also in comparison to VER, C wave has a comparative probability in diagnosing optic neuritis due to demyelinating disease. The C wave of ERG is normal in the cases of optic atrophy. The mechanism of C wave involvement during the course of demyelinating disease may be related with an abnormality of the ionic homeostasis of the subretinal space.

Adolescent↗
PubMed1996

Macrophage/microglial-mediated primary demyelination and motor disease induced by the central nervous system production of interleukin-3 in transgenic mice.

Activated macrophage/microglia may mediate tissue injury in a variety of CNS disorders. To examine this, transgenic mice were developed in which the expression of a macrophage/microglia activation cytokine, interleukin-3 (IL-3), was targeted to astrocytes using a murine glial fibrillary acidic protein fusion gene. Transgenic mice with low levels of IL-3 expression developed from 5 mo of age, a progressive motor disorder characterized at onset by impaired rota-rod performance. In symptomatic transgenic mice, multi-focal, plaque-like white matter lesions were present in cerebellum and brain stem. Lesions showed extensive primary demyelination and remyelination in association with the accumulation of large numbers of proliferating and activated foamy macrophage/microglial cells. Many of these cells also contained intracisternal crystalline pole-like inclusions similar to those seen in human patients with multiple sclerosis. Mast cells were also identified while lymphocytes were rarely, if at all present. Thus, chronic CNS production of low levels of IL-3 promotes the recruitment, proliferation and activation of macrophage/microglial cells in white matter regions with consequent primary demyelination and motor disease. This transgenic model exhibits many of the features of human inflammatory demyelinating diseases including multiple sclerosis and HIV leukoencephalopathy.

Animals↗
PubMed1996

Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency.

Individuals deficient in hepatic methionine adenosyltransferase (MAT) activity (MAT I/III deficiency) have been demonstrated to contain mutations in the gene (MATA1) that encodes the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and, in some cases, unusual breath odor. Most individuals with isolated hypermethioninemia have been free of major clinical difficulties. Therefore a definitive diagnosis of MAT I/III deficiency, which requires hepatic biopsy, is not routinely made. However, two individuals with isolated hypermethioninemia have developed abnormal neurological problems, including brain demyelination, suggesting that MAT I/III deficiency can be deleterious. In the present study we have examined the MATA1 gene of eight hypermethioninemic individuals, including the two with demyelination of the brain. Mutations that abolish or reduce the MAT activity were detected in the MATA1 gene of all eight individuals. Both patients with demyelination are homozygous for mutations that alter the reading frame of the encoded protein such that the predicted MATalpha1 subunits are truncated and enzymatically inactive. The product of MAT, S-adenosylmethionine (AdoMet), is the major methyl donor for a large number of biologically important compounds including the two major myelin phospholipids, phosphatidylcholine and sphingomyelin. Both are synthesized primarily in the liver. Our findings demonstrate that isolated persistent hypermethioninemia is a marker of MAT I/III deficiency, and that complete lack of MAT I/III activity can lead to neurological abnormalities. Therefore, a DNA-based diagnosis should be performed for individuals with isolated hypermethioninemia to assess if therapy aimed at the prevention of neurological manifestations is warranted.

Adolescent↗
PubMed1975

Old dog encephalitis and demyelinating diseases in man.

Pathologic findings in mature dogs with old dog encephalitis were compared with the findings in multiple sclerosis, subacute sclerosing panencephalitis and neuromyelitis optica in man. Fluorescent antibody studies in animal and human tissues were compared. Optic neuritis in dogs with chronic distemper shows changes similar to those in the optic tract of human patients with severe demyelinating disease. The pathologic changes in multiple sclerosis, such as perivascular infiltration with lymphocytes, plasma cells and demyelination are similar to those seen in old dog encephalitis. Demyelination in old dog encephalitis is usually diffuse. The findings strongly support a possible relationship of old dog encephalitis to multiple sclerosis, subacute sclerosing panencephalitis, and neuromyelitis optica.

Animals↗
PubMed1982

Swine cerebrospinal angiopathy and demyelination and malacia.

In 15 pigs affected with cerebrospinal angiopathy accompanied by demyelination and malacia, the main symptoms were diarrhea and subsequent circling, spasms, sudden forward movements, ataxia, and inability to hold the head straight. Escherichia coli was isolated in a pure culture from the small intestine of pigs with diarrhea. The only gross change was a slight increase in cerebrospinal fluid. Histologic examination showed vascular lesions, demyelination, and malacia, most commonly located in the medulla oblongata, pons, and midbrain. The vascular lesions were degenerative and there were necrotic changes of the vessel walls and formation of periodic acid-Schiff positive perivascular eosinophilic droplets. Ultrastructurally, the swollen astrocytes around the vessels had many osmiophilic bodies in their cytoplasm with no limiting membrane. Demyelination and malacia, as well as vascular lesions, were considered to be the characteristic changes of cerebrospinal angiopathy. Our study suggests that E. coli may be a cause of cerebrospinal angiopathy.

Animals↗
PubMed2002

Childhood-onset chronic inflammatory demyelinating polyradiculoneuropathy with cranial nerve involvement.

A 17-year-old male presented with chronic diplopia and generalized motor weakness. He was previously diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and acute disseminated encephalomyelitis in childhood. Cranial magnetic resonance imaging (MRI) revealed a rarely reported finding of thickening and enhancement of multiple cranial nerves. Nerve conduction studies and electromyography showed peripheral nerve demyelination with axonal involvement. There was improvement in the clinical examination, MRI, and electrophysiologic studies after combined corticosteroid and plasma exchange therapy. We review the clinical presentation, course, and response to therapy among children with chronic inflammatory demyelinating polyradiculoneuropathy, with specific emphasis on the frequency and pattern of cranial nerve involvement.

Adolescent↗
PubMed2001

Clinical, radiological, immunological and pathological findings in inflammatory CNS demyelination--possible markers for an antibody-mediated process.

The present report describes immunopathological, radiologcal and serological characteristics of antibody-mediated demyelination in a multiple sclerosis (MS) case with the main findings: (1) immunoglobulin and complement deposits in areas of active demyelination accompanied by massive macrophage activation; (2) ring-enhancing lesions in T1-weighted MRI after gadolinium application; (3) high titers of serum anti-myelin antibodies; and (4) signs of macrophage activation in the serum. Plasmapheresis may be a successful treatment for the type of inflammatory demyelination shown in the present case.

Autoantibodies↗
PubMed1998

A gene therapy approach to treat demyelinating diseases using non-replicative herpetic vectors engineered to produce cytokines.

A successful gene therapy approach in organ-specific autoimmune diseases, such as multiple sclerosis (MS), encompasses the inhibition of the autoreactive T cells or the modification of the target organ cells by the introduction of exogenous 'protective' genes. In MS, an autoimmune disease of the central nervous system (CNS), the inciting autoantigen is still unknown and therefore the isolation of autoreactive T cells may only be inferential. At present, gene therapy approaches in MS should therefore aim to the modification of the target organ. Possible candidate genes to be transferred within the CNS of MS patients are those coding for anti-inflammatory cytokines (i.e. interleukin-4, interleukin-10, transforming growth factor beta) which have been shown to ameliorate demyelinating diseases at least in experimental models. However, a limiting factor for this therapy is the difficulty to reach the CNS. A gene therapy approach using viral vectors able to infect post-mitotic cells, such as those present within the CNS, without inducing toxic reactions, may overcome this limitation. We propose to use non-replicative herpetic vectors, which represent a viable gene-transfer alternative to the classical retroviral and adenoviral vectors. Key advantages are their size, able to accommodate multiple foreign genes, and their ability to infect post-mitotic cells such as those present within the CNS. We first transferred a gene coding for interleukin-4 within the CNS of mice undergoing experimental allergic encephalomyelitis, an animal model for MS, using non-replicative Herpes Simplex Virus type 1-derived vectors. We found that this approach ameliorates the disease course and delays the disease onset. The establishment of this technique to deliver anti-inflammatory cytokines within the CNS using herpetic vectors should clarify the role of individual cytokines in the demyelinating process and allow assessment of whether gene therapy using herpetic vectors is a feasible and safe approach to treat human demyelinating disorders.

Animals↗
PubMed2002

Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination.

Treatment with paclitaxel by four intraperitoneal injections (20 mg/kg) 1 week apart attenuated clinical signs in a spontaneously demyelinating model, if given with onset of clinical signs. If given at 2 months of age (1 month prior to clinical signs), disease was almost completely prevented The astrogliosis, prominent in our model, was reversed by paditaxel as determined by astrocyte counts and quantitation of GFAP. Electron microscopic examination of affected regions at 2.5 months demonstrated that the myelin was generally normal. By 4 months of age, demyelination was common in the superior cerebellar peduncle, maximal at 6 months, but continued to 8 months. In addition to myelin vacuolation and nude axons, the presence of many thin myelin sheaths suggested remyelination or partial demyelination. Although no evidence of oligodendrocyte loss was seen, nuclear changes were observed. To substantiate that remyelination was occurring, we measured MBP (18.5 kDa), MBP-exon II, Golli-MBP, TP8, Golli-MBP-J37, platelet-derived growth factor alpha (PDGFR alpha) and sonic hedgehog (SHH). Of these TP8, PDGFR alpha and SHH were up-regulated in the untreated transgenic. After paditaxel treatment, MBP-Exon II, TP8, PDGFR alpha and SHH were further up-regulated. We concluded that some of the effects of paditaxel were to stimulate proteins involved in early myelinating events possibly via a signal transduction mechanism.

Animals↗