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PubMedDate not supplied

Progressive multifocal neurologic deficit with disseminated subpial demyelination.

A sixty-six year-old man developed visual and gait difficulties, a deficit in recent memory and hearing, and acute urinary retention. He subsequently became blind, deaf, and quadriparetic. Terminally, weakness deepended and he lapsed into semi-coma. The cerebrospinal fluid contained increased amounts of protein with a normal electrophoretic pattern, and a moderate mononuclear pleocytosis. Gross examination of the brain revealed normal vessels and meninges. Coronal sections showed irregular areas of subpial discoloration in forebrain and brainstem. Stains for myelin revealed scattered foci of pallor in the intracortical myelinated fibers; demyelination throughout the brainstem, most severe in subpial areas; and a focus of central pontine myelin loss. The subependymal myelin was intact throughout the neuraxis. Histological examination showed axonal preservation in areas of extreme myelin loss. Demyelination was accompanied by astrocytic gliosis showing different degrees of activity, and occasional perivascular cuffing with mononuclear cells in cerebral and meningeal vessels. Electron microscopy revealed filamentous structures in cell nuclei. These were 180-220 A in diameter, had a hollow core, and, in some tangential sections, showed cross striations. The unusual clinical picture and correspondingly striking pattern of demyelination suggest that this case might represent a distinct clinical entity.

Aged↗
PubMed1980

The influence of the ground substance on the extracellular water of normal and edematous human brain: focal edema and the demyelinating diseases, including multiple sclerosis.

The presence of a ground substance in brain provides a mechanism by which edema localized to one region of the white matter might occur without spreading diffusely into the adjacent tissues. The most common such localization is the sparing of the arcuate white matter when the deeper white matter is markedly edematous. This may be related to the higher concentration of mucopolysaccharides in the former. Petechial hemorrhages in the white matter may be surrounded by a zone free of edema, although the hemorrhagic zone itself is almost certainly edematous. This, and the presence of a central zone within some of the petechiae forming a ring hemorrhage may reflect the influence of the ground substance. Focal lesions of the dorsum of the corpus callosum and similar lesions of the basal surface of the pons, these probably due to traumatization by the contiguous falx or arteries, are characterized by myelin loss and axon preservation, a characteristic of edema; the surrounding tissues are not edematous. Severe hypertension is sometimes associated with the presence of clusters of focal perivenous demyelinating lesions in the white matter, the axons being preserved. These resemble the lesions of acute disseminated encephalomyelitis and may be due to edema; they are surrounded by nonedematous white matter. It is suggested that the same concept may apply to the focal demyelinating lesions of acute disseminated encephalomyelitis, multifocal leukoencephalopathy, central pontine myelinolysis and of multiple sclerosis, i.e. the "true" demyelinating diseases, just as has already been suggested for diffuse sclerosis.

Astrocytes↗
PubMed1980

The endoneurial content of lead related to the onset and severity of segmental demyelination.

The endoneurial lead and water content was serially evaluated in the nerves of rats fed lead carbonate and related to the onset and severity of segmental demyelination and remyelination. Lead began to accumulate significantly in the endoneurium by 5 days, reached a maximum level (71 microgram/g dry weight) by 34 days, and then fell to the perineurial level (28 microgram/g dry weight) by 3 months. The water content of endoneurium did not become significantly increased until the 50th day. Extensive teased fiber grading of pathologic abnormalities carried out on the same animals showed that segmental demyelination began between the 20th and 35th days and worsened progressively. This provides the first evidence that high endoneurial lead concentration precedes segmental demyelination and nerve edema. It suggests that the random Schwann cell damage is more likely to be due to a direct toxic effect of lead rather than to a factor associated with edema or increased endoneurial pressure. Contrary to our expectations, lead content does not parallel water content, as would be expected if lead entry into the endoneurium were associated with an abrupt breakdown of the blood-nerve barrier. A further new finding is the decrease in endoneurial lead content at a time when edema and the pathologic lesions are progressing. This may suggest the development of lead removal mechanisms.

Animals↗
PubMed1997

Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions.

The cellular localization and distribution of inducible and constitutive nitric oxide synthase (iNOS/cNOS) was determined in tissue sections from multiple sclerosis (MS) and control brain and spinal cord. Immunocytochemical techniques were applied using specific iNOS- and cNOS-directed antibodies. In addition, NADPH-diaphorase histochemistry was performed. To establish the identity of iNOS-, cNOS- and NADPH-diaphorase-positive cells single and double staining was performed on tissue sections with the macrophage marker KP1 (CD68) and with the astrocyte marker glial fibrillary acidic protein (GFAP). Areas of myelin breakdown and demyelination were determined using a staining for neutral lipids, Oil Red O (ORO). Furthermore, macrophages isolated from active demyelinating MS lesions were stained for iNOS, cNOS, KP1 and ORO. In active MS lesions strong iNOS immunoreactivity was found exclusively in perivascular and parenchymal macrophages distributed within regions of active demyelination. In these active MS lesions immunoreactivity for cNOS was also found in macrophages. Macrophages isolated from active MS lesions also showed immunoreactivity for iNOS and cNOS. Moreover, these isolated macrophages produced nitric oxide (NO; >30 microM) in vitro. NADPH-diaphorase activity was detected in KP1-positive perivascular and parenchymal macrophages and in GFAP-positive reactive astrocytes in active MS lesions and in reactive astrocytes located in the hypercellular rims of chronic active MS lesions. cNOS-positive reactive astrocytes were detected in both active and chronic active MS lesions. Inside chronic active lesions some residual macrophages were weakly iNOS-positive. In control brain and spinal cord no iNOS immunoreactivity could be detected. These results suggests an important role for human macrophages capable of producing the free radical nitric oxide (NO), which may contribute to the cytotoxicity of oligodendrocytes and destruction of myelin in MS brain and spinal cord.

Aged↗
PubMed1986

Assessment of therapeutic plasmapheresis in demyelinating neurologic disorders.

Considerable controversy exists with regard to therapeutic efficacy of plasmapheresis in the immune-mediated demyelinating disorders of the peripheral and central nervous system: acute inflammatory polyneuropathy (Guillain-Barré syndrome), chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis. In an effort to establish specific situations where plasmapheresis was of therapeutic value, we reviewed the experience at Southwestern Medical School, University of Texas Health Science Center at Dallas, and that published in the literature. In acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome), plasmapheresis may prevent progression of the illness, and it significantly increases the rate of recovery. For patients with chronic inflammatory polyneuropathy, plasmapheresis has produced clinical improvement in 50% of corticosteroid-refractory patients. The use of plasmapheresis in patients with acute or chronic progressive multiple sclerosis still remains controversial.

Adolescent↗
PubMed1991

Central and peripheral nervous system demyelination after infection with Mycoplasma pneumonia: evidence of an autoimmune process.

We have reported a unique case of multiple central and peripheral nervous system abnormalities after a serologically documented infection due to Mycoplasma pneumoniae. The evidence suggests that this organism is capable of causing demyelination, probably through an autoimmune process. This case may help to provide further insight into the pathogenetic mechanisms involved in other demyelinating diseases in which the triggering exogenous agent is unknown. Certainly this case demonstrated that both central and peripheral nervous system demyelination can occur and that patients with M pneumoniae infections should be observed closely for possible development of neurologic symptoms.

Adult↗
PubMed1998

Demyelinating inflammatory neuropathies, including Guillain-Barré syndrome.

The highly complex and multiple mechanisms responsible for the development of demyelinating neuropathies are reviewed, in particular Guillain-Barré syndrome and its variant Miller Fisher syndrome, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, anti-myelin-associated glycoprotein neuropathy, as well as experimental models. Recent investigations into the role of auto antibodies against myelin proteins, or glycolipids have given insights into the pathogenesis of demyelinating inflammatory neuropathies.

Autoimmune Diseases↗
PubMed2004

Demyelination during anti-tumor necrosis factor alpha therapy with infliximab for Crohn's disease.

BACKGROUND: Inflammatory demyelinating disease of the central nervous system may be linked to anti-tumor necrosis factor alpha therapy. CASE HISTORY: A 19-year-old female with Crohn's ileocolitis developed right arm and leg numbness and right hand weakness 4 weeks after the initiation of infliximab. Neurologic examination confirmed upper and lower right extremity sensory and motor deficits. MRI examination of the head and thoracic cord showed multiple gadolinium-enhancing lesions with distribution and configuration most suggestive of multiple sclerosis or other demyelinating process. The infliximab therapy was immediately stopped and follow-up at 8 weeks revealed symptomatic improvement. CONCLUSION: This case report describes the onset of a demyelinating process after the institution of infliximab therapy in a patient with Crohn's disease.

Adult↗
PubMed2006

Leukemia inhibitory factor arrests oligodendrocyte death and demyelination in spinal cord injury.

As a consequence of secondary pathophysiological mechanisms elicited after spinal cord injury (SCI), oligodendrocytes die by waves of apoptosis. This ultimately results in demyelination of intact axons leading to a loss of their conducting properties. Preservation of as few as 5% to 10% of myelinated axons in individual tracts can confer locomotor recovery. Thus, strategies aimed at rescuing mature oligodendrocytes ensheathing viable axons are likely to be of therapeutic significance. We report that leukemia inhibitory factor (LIF) can prevent oligodendrocyte apoptosis, notably contralateral to the spinal cord lesion, through the induction of the JAK/STAT and Akt signaling pathways as well as by potentiating the expression of the antiapoptotic molecule, cIAP2. Reduced oligodendrocyte apoptosis after SCI with LIF administration resulted in a substantial decrease in demyelination shown by the preservation of lamellated myelin surrounding viable axons and deposition of the degraded myelin basic protein. The data suggest that LIF signals survival in oligodendrocytes after SCI, prevents the secondary wave of demyelination, and thereby reduces inhibitory myelin deposits.

Animals↗
PubMed2003

The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system.

PURPOSE OF REVIEW: Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. RECENT FINDINGS: Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. SUMMARY: The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.

Animals↗
PubMed2006

Fas-mediated T-cell apoptosis is impaired in patients with chronic inflammatory demyelinating polyneuropathy.

The Fas death receptor is expressed by activated lymphocytes and is involved in switching-off the immune response. Its inherited defects cause auto-immune lymphoproliferative syndrome. Impaired Fas function may also play a role in other auto-immune diseases, such as multiple sclerosis and type 1 diabetes mellitus. The aim of this work was to evaluate Fas function in T cells from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We evaluated Fas-induced apoptosis in T-cell lines from 27 patients with CIDP, 12 patients with acute inflammatory demyelinating polyneuropathy (AIDP), and 110 controls. CIDP patients displayed lower Fas function than both AIDP patients and controls, whereas no statistically significant difference was found between AIDP patients and controls. Moreover, Fas function was lower in CIDP patients with progressive course than in those with relapsing-remitting course and lower in CIDP patients with axonal damage than in those with pure demyelination. These data suggest that defective Fas function favours CIDP development and aggressive evolution.

Adult↗
PubMedDate not supplied

Partial demyelination of cat spinal cord after X-irradiation and surgical interference.

Following 4000 rad of X-irradiation and transplantation of sciatic nerve over the dorsal columns, extensive partial demyelination occurred in some animals. This dose of radiation inhibits remyelination so this phenomenon could be studied knowing that remylination was absent. Partial demyelination was characterized by translocation of myelin to form large myelin ovoids which remained associated with the remaining thinned myelin sheath: nodal widening, involvement of one paranode only, transition from thin to thick myelin along an internode, enlargement and disorientated oligodendrocyte tongues were also features of this change. It is concluded that partial demyelination results when oligodendrocytes have to function in a sub-optimal environment.

Animals↗
PubMedDate not supplied

Observations on focal demyelinating lesions in cat optic nerves.

A demyelinating perivascular condition has been observed in the optic nerves of three cats, the lesions of which included the following features: thinly myelinated and demyelinated axons, few normal oligodendrocytes, astroglial scar tissue, lymphocytes, plasma cells, mononuclear phagocytic cells and lipid-laden cells. Also present were tubular inclusion bodies which had morphological features similar to the nucleocapsids of some paramyxoviruses. These lesions are compared with some other demyelinating diseases of the central nervous system, and similarities to the lesions of multiple sclerosis are suggested.

Animals↗
PubMed1991

Inflammatory demyelinating lesions in two patients with IgM monoclonal gammopathy and polyneuropathy.

We report two patients with polyneuropathy and IgM monoclonal gammopathy in whom peripheral nerve biopsy showed the widening of myelin lamellae which is characteristic of IgM paraproteinaemic neuropathy. Moreover, certain myelinated fibres were invaded by histiocytes overloaded with myelin debris, and in some instances elongated macrophage processes could be seen peeling away the myelin lamellae. The latter ultrastructural features are characteristic of inflammatory demyelinating polyneuropathies in both human and experimental pathology. Such an association has not been reported to date in human pathology, but could explain the prevalence of inflammatory demyelinating lesions in experimental models of IgM paraproteinaemic neuropathy. These two cases seem to bridge the gap between inflammatory demyelinating polyneuropathies and polyneuropathies associated with IgM monoclonal gammopathy.

Aged↗
PubMed1991

A primary demyelinating disorder of young cattle.

The clinical signs and neuropathological changes are described in six Limousin X calves that, at about one month after birth, showed signs of blindness, nystagmus, rotation of the eyes, opisthotonos, hyperprotraction of the forelegs and, in one case, apparent seizures. Pathologically there was necrosis of the optic chiasma and focal areas of myelin sheath vacuolation or demyelination in certain areas of the brain, especially in the cerebellar peduncles. In one animal, kept alive for 7 months, there was remyelination by Schwann cells of some demyelinated axons in the focal cerebellar lesions, while other axons remained demyelinated. There was no evidence of oligodendrocyte remyelination. The cause of the condition was not determined but a genetic association is likely.

Age Factors↗
PubMed1987

Amantadine restores impulse conduction across demyelinated nerve segments.

1. Drugs can be identified that relieve clinical symptoms of demyelinating diseases such as multiple sclerosis based on their ability to alter voltage-dependent ion channels in membranes and restore conduction in demyelinated nerve. Beneficial drugs either slow inactivation of membrane Na+ channels or block K+ channels. 2. Amantadine, an antiviral drug that slows Na+ inactivation in Myxicola giant axons, restores conduction in frog and rat sciatic nerves partially demyelinated by disruption of the perineurium (the 'perineurial window') loose ligatures, or lysolecithin. 3. A positive effect of amantadine on several different animal models supports the need for clinically oriented studies of amantadine and related inactivation-blocking agents in diseases such as multiple sclerosis.

Action Potentials↗
PubMed1991

Demyelinating peripheral neuropathy in Devic disease.

This is a report of a 20-year-old man with typical features of Devic disease (neuromyelitis optica) associated with demyelinating peripheral neuropathy. A sural nerve biopsy showed markedly decreased myelinated fibers of a large diameter. Teased fiber preparations showed segmental remyelination in 50% of examined fibers, as well as a few demyelination. Demyelination of bilateral optic nerves, spinal cord, and peripheral nerves at the same time suggests a possibility of common pathogenetic mechanisms in both the central and peripheral nervous systems.

Adult↗
PubMed2006

European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.

BACKGROUND: Paraprotein-associated neuropathies have heterogeneous clinical, neurophysiological, neuropathological and haematological features. Objectives. To prepare evidence-based and consensus guidelines on the clinical management of patients with both a demyelinating neuropathy and a paraprotein (paraproteinaemic demyelinating neuropathy, PDN). METHODS: Search of MEDLINE and the Cochrane library, review of evidence and consensus agreement of an expert panel. RECOMMENDATIONS: In the absence of adequate data, evidence based recommendations were not possible but the panel agreed the following good practice points: (1) Patients with PDN should be investigated for a malignant plasma cell dyscrasia. (2) The paraprotein is more likely to be causing the neuropathy if the paraprotein is immunoglobulin (Ig)M, antibodies are present in serum or on biopsy, or the clinical phenotype is chronic distal sensory neuropathy. (3) Patients with IgM PDN usually have predominantly distal and sensory impairment, with prolonged distal motor latencies, and often anti-myelin associated glycoprotein antibodies. (4) IgM PDN sometimes responds to immune therapies. Their potential benefit should be balanced against their possible side-effects and the usually slow disease progression. (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy, clinically, electrophysiologically, and in response to treatment. (6) For POEMS syndrome, local irradiation or resection of an isolated plasmacytoma, or melphalan with or without corticosteroids, should be considered, with haemato-oncology advice.

Advisory Committees↗