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PubMed2005

Tumefactive demyelinating lesions: conventional and advanced magnetic resonance imaging.

In rare instances, demyelinating disorders present with radiological features that mimic a brain tumour. This often leads to biopsy, which--apart from carrying significant morbidity--frequently turns out as nondiagnostic or dispensable. We therefore set out to assess the contribution of repeated conventional magnetic resonance imaging (MRI), 1H-MR spectroscopy and magnetization transfer imaging in establishing a correct diagnosis of tumefactive demyelinating lesions (TDLs). We studied two females and one male, who presented with TDLs that led to brain biopsy in two cases, for up to three years. TDLs were characterized by the following features: (a) delayed or absent response to high-dose steroids together with progressive lesion growth over several weeks; (b) late or sparse enhancement, ill-defined borders, signal inhomogeneity and considerable concomitant oedema; and (c) normalization of initial increases in lipid and lactate peaks within three to four weeks, followed by persistent, marked reductions of the neuronal marker NAA and MTR values around or below 30%. These imaging characteristics reflected the histological correlate of marked demyelination in the absence of significant inflammation. MRI techniques thus appear to have the potential to establish a correct diagnosis of this subtype of TDLs. Awareness of these possibilities might obviate the need for biopsy at least in some cases in future.

Acute Disease↗
PubMed2006

Human demyelinating disease and the polyomavirus JCV.

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies--which have a genetic basis; multiple sclerosis (MS)--where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML)--where the etiology is well-established as being viral. The human neurotropic polyomavirus--JC virus (JCV)--is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.

Demyelinating Diseases↗
PubMed2002

Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.

BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.

Age of Onset↗
PubMed1978

Prerequisites for conduction in demyelinated fibers.

Data are herein reviewed which show that there are structural differences between nodal and internodal membrane in normal myelinated fibers. It appears likely that in most normal myelinated fibers, ionic channel densities in the internodal axon membrane are lower than those at the nodes of Ranvier. Conduction through demyelinated fibers may require structural reorganization, for example, redistribution or production of new channels, in the internodal membrane. Impedance mismatch may also block conduction at sites of demyelination. Reduction in internode distance proximal to the site of demyelination provides one solution to the problem of impedance matching.

Action Potentials↗
PubMed1982

Multifocal demyelinating neuropathy with persistent conduction block.

We describe five patients with a chronic asymmetric sensorimotor neuropathy most pronounced in the upper extremities with focal involvement of individual nerves. Diagnosis was established by electrophysiologic evidence of persistent multifocal conduction block. Sural nerve biopsy in three patients showed primarily demyelinating-remyelinating changes with varying degrees of fiber loss. Two patients had acute optic neuritis, indicating that the disorder was not always restricted to the peripheral nervous system. Two patients treated with corticosteroids improved, whereas three untreated patients had static deficits or steady progression of symptoms. Chronic multifocal demyelinating neuropathy with persistent conduction block seems to be a variant of chronic acquired demyelinating polyneuropathy and may be immunologically mediated.

Adult↗
PubMed1984

Chronic demyelinating polyneuropathy in systemic lupus erythematosus.

Mononeuritis multiplex and acute demyelinating polyneuropathy (Guillain-Barré syndrome) are well known in systemic lupus erythematosus (SLE). Chronic acquired demyelinating polyneuropathy has been reported rarely in SLE. Two young women had monophasic progressive weakness, areflexia, elevated CSF protein, and slow nerve conduction velocities as the first manifestation of SLE. Sural nerve biopsy in one patient revealed mild loss of myelinated fibers and an increased number of thinly myelinated fibers. Steroid therapy led to improvement in both patients. These patients demonstrate that chronic demyelinating polyneuropathy can be an unusual presentation of SLE, even preceding characteristic systemic disease by months.

Adult↗
PubMed1984

Experimental demyelination produced by the A59 strain of mouse hepatitis virus.

Intracerebral inoculation of 4- to 6-week-old C57BL/6 mice with the A59 strain of mouse hepatitis virus (MHV), a murine coronavirus, produced biphasic disease. Acute hepatitis and mild meningoencephalitis were followed by subacute spastic paralysis with demyelinating lesions in the brain and spinal cord as determined by Epon-embedded toluidine-blue-stained sections and by electronmicroscopy. MHV-A59 was cultured by plaque assay from the blood, brain, spinal cord, and liver of infected mice during the acute phase, but not in the chronic stage. MHV-A59 antigen was detected by immunofluorescence (IF) until 3 months postinfection (PI). Serum anti-MHV-A59 antibodies were detected from 7 days to 5 months PI. The induction of demyelination by MHV-A59 provides a suitable system to study virus-induced demyelination further.

Animals↗
PubMed1986

Cerebrospinal fluid C9 in demyelinating disease.

We measured CSF and plasma concentrations of C9, IgG, and albumin in 91 patients with demyelination and 73 controls with other neurologic diseases. The C9 index was reduced and IgG index increased in patients with multiple sclerosis and those with isolated demyelinating lesions, irrespective of disease activity; abnormalities were less marked in patients with isolated lesions than in those with MS. Humoral mechanisms may not be responsible for initiating demyelination, but activation of the complement system could amplify tissue damage and account for some symptomatic recovery.

Complement C9↗
PubMed1989

Is ischemia implicated in chronic multifocal demyelinating neuropathy?

We describe a patient with chronic multifocal demyelinating neuropathy associated with persistent conduction block. Multifascicular lesions in sural nerve included a complete loss of myelinated fibers, demyelination, remyelination, onion bulb formation, and axonal attenuation. On the basis of these morphometric results we hypothesize that nerve ischemia may be involved in the pathogenesis of chronic multifocal demyelinating neuropathy.

Brain Ischemia↗
PubMed1989

Electrophysiologic study of experimental demyelination induced by serum of patients with IgM M proteins and neuropathy.

We induced progressive conduction block in feline sciatic nerve by endoneurial injection of serum from 2 patients with demyelinating neuropathy and an anti-myelin-associated glycoprotein (MAG) IgM M protein. The block was longlasting (up to 4 days) and affected about half the motor nerve fibers. Control serum from patients with an IgM M protein that did not react with MAG produced a transient block (less than 48 hours) that affected an average of 25% of motor fibers. Nerves with sustained block showed widespread demyelination of many nerve fibers, exceeding controls. The findings support the view that chronic demyelinating neuropathy in these patients is caused by the anti-MAG M protein.

Animals↗
PubMed1993

Effect of brain irradiation on demyelinating lesions.

Demyelinating lesions, such as those in multiple sclerosis, may resemble primary or metastatic brain tumors on CT or MRI, and even be mistaken for neoplasms on biopsy. We encountered five such patients in whom an incorrect diagnosis of CNS neoplasm was made on the basis of radiologic appearance (five) and biopsy (four). All five received radiation therapy, and three chemotherapy. Review of the pathologic findings indicated that the original lesions were not neoplastic but demyelinative. The four patients who received radiation in full tumoricidal doses had unexpectedly poor clinical outcome, suggesting that radiation is especially injurious to patients with demyelinating disease.

Adult↗
PubMed1997

Delayed posthypoxic demyelination. Association with arylsulfatase A deficiency and lactic acidosis on proton MR spectroscopy.

Delayed demyelination is a rare and poorly understood complication of hypoxic brain injury. A previous case report has suggested an association with mild-to-moderate deficiency of arylsulfatase A. We describe a 36-year-old man who recovered completely from an episode of hypoxia related to drug overdose, and 2 weeks later progressed from a confusional state to deep coma. MRI showed diffuse white matter signal changes, and brain biopsy demonstrated a noninflammatory demyelinating process. Proton magnetic resonance spectroscopy revealed elevated choline and lactate and reduced N-acetyl aspartate signal in the affected white matter, consistent with demyelination and a shift to anaerobic metabolism. Arylsulfatase A activity from peripheral leukocytes was approximately 50% of normal, consistent with a "pseudodeficiency" phenotype. These findings confirm the hypothesis that relative arylsulfatase A deficiency predisposes susceptible individuals to delayed posthypoxic leukoencephalopathy and implicates lactic acidosis in the pathogenesis of this disorder.

Acidosis, Lactic↗
PubMed1998

Fulminant progression of demyelinating disease after valproate-induced encephalopathy.

We report the clinical, radiologic, and pathologic features of a patient who had fulminant demyelinating disease and who experienced acute progression of his disease after an episode of valproate-induced hyperammonemic encephalopathy. The role hyperammonemia played in the progression of the demyelination is uncertain. This case raises concern of a possible risk with the use of valproic acid in the subset of patients with fulminant demyelinating disease.

Adult↗
PubMed1999

Matrix metalloproteinases in inflammatory demyelination: targets for treatment.

Matrix metalloproteinases (MMPs) degrade all protein components of the extracellular matrix. Functionally, they contribute to several different physiologic conditions, such as angiogenesis or bone remodeling, as well as pathologic conditions in humans, such as rheumatoid arthritis and tumor growth. MMPs seem to be important in the pathogenesis of inflammatory demyelinating diseases of the central and peripheral nervous system, especially in MS and in Guillain-Barré syndrome (GBS). Key mechanisms in the genesis of inflammatory demyelination, such as leukocyte recruitment, blood-brain barrier or blood-nerve barrier breakdown, myelin destruction, and release of disease-promoting cytokines, are considered to be MMP-dependent processes. In experimental autoimmune encephalomyelitis, an animal model of MS, and experimental autoimmune neuritis, an animal model of GBS, different synthetic inhibitors targeting MMP activity are able to suppress and even reverse ongoing disease. This evidence points to MMPs as new targets for treatment in inflammatory demyelination.

Animals↗
PubMed1999

Matrix metalloproteinase upregulation in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy.

OBJECTIVE: To determine the expression pattern and cellular source of matrix metalloproteinases (MMPs) in chronic inflammatory demyelinating polyneuropathy (CIDP) and nonsystemic vasculitic neuropathy (NSVN). BACKGROUND: MMPs are endopeptidases involved in tissue destruction and infiltration by immune cells in multiple sclerosis and Guillain-Barré syndrome. Enzyme inhibitors of MMPs attenuate clinical symptoms in corresponding animal models of these diseases. MMP inhibition may therefore be a novel approach for the treatment of CIDP and NSVN. However, the spectrum of MMPs expressed in chronic inflammatory neuropathies has not been established. METHODS: The expression of MMP-2, MMP-3, MMP-7, and MMP-9 in T cells, macrophages, and stromal cells in CIDP, NSVN, and noninflammatory neuropathies (NIN) was quantitated by immunohistochemistry. Results were correlated with clinical and electrophysiologic findings. RESULTS: The production of MMP-2 and MMP-9 is increased in nerve tissue in CIDP and NSVN compared with NIN. T cells are the predominant source of MMP-2 and MMP-9 in CIDP and NSVN, whereas macrophages contribute only to a minor extent. Stromal cells of the perineurium/epineurium are an additional source of MMP-2 in NSVN, but not in CIDP. Expression of MMP-3 and MMP-7 was not detectable in CIDP or NSVN. Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity and electrophysiologic measurements. CONCLUSIONS: The upregulation of MMP-2 and MMP-9 is a specific feature of CIDP and NSVN, and selective inhibitors of these enzymes could be used to prevent inflammatory tissue damage. The similar increase of MMP-2 and MMP-9 in both demyelinating (CIDP) and nondemyelinating (NSVN) neuropathies raises doubts about whether MMPs play a primary role in demyelination.

Adult↗
PubMed1999

Diagnostic value of myotactic reflexes in axonal and demyelinating polyneuropathy.

In 11 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 11 patients with chronic idiopathic axonal polyneuropathy (CIAP), absent myotatic reflexes were significantly associated more often with CIDP than with CIAP, an absent biceps-reflex having the highest sensitivity and specificity for the diagnosis of CIDP. In CIDP, the latencies of electromyographically recorded myotatic reflexes often indicated demyelination, notwithstanding normal clinically assessed myotatic reflexes. Myotatic reflexes may therefore be useful for the distinction between axonal and demyelinating polyneuropathy.

Aged↗
PubMed2007

The origins of concentric demyelination: self-organization in the human brain.

Baló's concentric sclerosis is a rare atypical form of multiple sclerosis characterized by striking concentric demyelination patterns. We propose a robust mathematical model for Baló's sclerosis, sharing common molecular and cellular mechanisms with multiple sclerosis. A reconsideration of the analogies between Baló's sclerosis and the Liesegang periodic precipitation phenomenon led us to propose a chemotactic cellular model for this disease. Rings of demyelination appear as a result of self-organization processes, and closely mimic Baló lesions. According to our results, homogeneous and concentric demyelinations may be two different macroscopic outcomes of a single fundamental immune disorder. Furthermore, in chemotactic models, cellular aggressivity appears to play a central role in pattern formation.

Brain↗
PubMed2006

Neuronal nitric oxide synthase plays a key role in CNS demyelination.

Nitric oxide (NO) is a small, short-lived molecule released from a variety of cells that is implicated in a multitude of biological processes. In pathological conditions, overproduction of NO may lead to the generation of highly reactive species, such as peroxynitrite and stable nitrosothiols, that may cause irreversible cell damage. Accordingly, several studies have suggested that NO may be involved in the pathogenesis of various neuroinflammatory/degenerative diseases. Increased concentrations of NO in the CNS in such cases are usually attributed to an increase in the inducible isoform of NO synthase (iNOS) usually produced by inflammatory cells. However, recent reports have suggested that the constitutive isoforms of NOS, neuronal (nNOS) and endothelial (eNOS), can also play a role. Here we examined the role that the constitutive isoforms of NOS might play in the cuprizone-induced model of demyelination/remyelination. Our results demonstrate that demyelination was greatly prevented in mice lacking nNOS. Protection was associated with a dramatic increase in mature oligodendrocyte survival and a decrease in apoptosis. Moreover, nNOS-/- mice did not respond to cuprizone with the extensive recruitment of microglia/macrophages and astrocytes, which is a typical feature in wild-type mice. Although demyelinating less, nNOS-/- mice exhibited a delay in remyelination. In eNOS-/- mice, demyelination progressed to the same extent as in wild type, but they showed a slight delay in spontaneous remyelination. In conclusion, this study highlights the importance of considering the source of NO when assessing its role in neuroinflammation/degeneration and emphasizes the differing pathological effects driven by the different NOS isoforms.

Animals↗