Marburg Type Research Articles

Fulminant case of multiple sclerosis (marburg variant) with atypical MRI presentation

Marburg type is a rare variant of Multiple Sclerosis (MS) characterized by a severe and progressive course/evolution leading to exitus in few months. Its radiological presentation commonly raises suspicion of a malignancy, often requiring a brain biopsy for histological confirmation. Hereby we report an atypical radiological presentation and progression of a pathologically confirmed case of Marburg MS Keywords: Multiple Sclerosis; Marburg variant; Magnetic resonance imaging.

An Autopsy Case of the Marburg Variant of Multiple Sclerosis (Acute Multiple Sclerosis)

We herein report an autopsy case of the Marburg variant of multiple sclerosis (MS). A 29-year-old woman developed acute and progressive neurological symptoms. A diagnosis of MS was suspected based on the patient's clinical background and brain MRI findings and the lack of evidence of malignancy on a brain biopsy. Despite the administration of typical treatment for MS, a fatal outcome occurred three months after disease onset. The autopsy revealed multiple inflammatory demyelinating lesions in the central nervous system. In addition, two noteworthy histopathological features were observed compared with prototypical MS. We evaluate the pathogenic differences between the Marburg type and prototypical MS by discussing the neuropathology and cerebrospinal fluid (CSF) findings of our case.

Marburg’s disease: a diagnostic dilemma

This report describes the clinical, radiological and autopsy findings of a young male suffering from acute, monophasic demyelinating disease presenting with acute onset of altered sensorium and a short past history of progressive multiple neurological deficits. The radiological findings revealed acute infarcts in the territory of anterior cerebral artery. The antemortem diagnosis centred on an infective (tubercular) aetiology leading to demyelination based on presence of tubercle bacilli in bronchoalveolar lavage (BAL) fluid. The autopsy revealed multiple subacute and acute plaques showing demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation, thereby confirming the diagnosis of Marburg's type of multiple sclerosis. Marburg's type is a fulminant demyelinating disorder characterised by a severe, rapidly evolving clinical course. Death occurs due to brain stem involvement or severe widespread cerebral lesions.

Multiple Sclerosis: Autoimmune Disease or Autoimmune Reaction?

Multiple sclerosis (MS) is traditionally considered an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) with much knowledge available to support this view. However, this characterization implies that the primary event is an aberrant immune response directed at CNS antigens, promoting inflammation and later driving progressive axo-glial degeneration. Trials with potent anti-inflammatory agents and detailed neuropathological studies raise questions about this sequence of events. This hypothetical paper argues that MS may be primarily a "cytodegenerative" disease, possibly first involving the oligodendrocyte/myelin unit. Liberation of autoantigens secondarily recruits an immune response, the force of which heavily depends on the host's immune predisposition. Thus, the spectrum of MS from highly aggressive Marburg type, to primary progressive disease with little inflammatory burden, is governed by a "convolution" between the underlying cytodegeneration and the host's immune predilection. Clinical heterogeneity may be a reflection of a variable immune response, whereas in reality, the "real MS" may be a homogeneous degenerative process analogous to well known primary neurodegenerative diseases.

An autopsy case of acute multiple sclerosis (Marburg's type) during pregnancy

We report a case of a 9-month pregnant woman who presented acute psychiatric and neurological symptoms with extensive involvement of the white matter on MRI and no oligoclonal bands on CSF examination. Despite high doses of intravenous steroids, plasmapheresis and immunosuppressive drugs, a fatal outcome (coma) was noted 8 months later. Neuropathological examination confirmed the diagnosis of Marburg's type of multiple sclerosis showing sharp-edged lesions of demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation. We discuss the definition and limits of the Marburg entity with reference to acute disseminated encephalomyelitis, impact of pregnancy, unusual MRI features, neuropathology and treatment.

Marburg type and Bal�?s concentric sclerosis: rare and acute variants of multiple sclerosis

Marburg type and Balò's concentric sclerosis are considered particular variants of multiple sclerosis, clinically characterized by a severe, rapidly evolving clinical course, and by unusual neuropathological changes, often large tumor-like demyelinating plaques in Marburg type and concentric layers of partial demyelination alternating with demyelinating bands in Balò's concentric sclerosis. These forms now can be diagnosed in vivo, with complete clinical and laboratory examination and MRI follow up. Although in some patients a favourable clinical course has been described, the poor prognosis of the majority of these cases justifies a treatment with intense immunosuppression.

Electron Microscopy of Myelin Basic Protein (MBP) Organized as Planar Arrays on a Lipid Monolayer Surface: Deimination of MBP Hinders Its Organizational Properties

Abstract Myelin basic protein (MBP) is one of the principal constituents of the mammalian myelin sheath. It is a basic peripheral membrane protein in the major dense line and is believed to play a structural role in maintaining myelin stability through its close association with lipids and other proteins. Immune responses to MBP have been implicated in the pathogenesis of multiple sclerosis (MS), the most common autoimmune disease of the central nervous system in North America and Northern Europe. The correlation between the severity of MS and the deimination of arginyl to citrullinyl residues in MBP was well illustrated in the acute case of MS (Marburg type) that contained MBP with 18 out of 19 arginines citrullinated. We have studied a recombinant hexahistidine-tagged murine MBP (rmMBP, 18.5 kDa isoform) by electron microscopy of the protein organized as planar arrays on lipid monolayers that consisted of the nickel chelating lipid, l,2-dioleoyl-.yn-glycero-3-[(N(5-amino-l-carboxypentyl)iminodiacetic acid)succinyl] (Nickel salt) (Ni2+-NTADOGS), and the filler lipid, liver phosphatidylinositol (PI).

Highly deiminated isoform of myelin basic protein from multiple sclerosis brain causes fragmentation of lipid vesicles

Myelin basic protein (MBP) occurs as a number of charge isomers due to phosphorylation, deamidation, and deimination of arginine to citrulline. All of these modifications decrease the net positive charge of the protein and its ability to cause aggregation of negatively charged lipid vesicles. This is used as a model system for the ability of MBP to cause adhesion of the cytosolic surfaces of myelin. Therefore, the effect of two deiminated forms of MBP on lipid vesicles was compared with that of the unmodified, most positively charged isomer, C1, to determine how loss of positively charged arginines would affect the function of MBP. The deiminated forms were the isomer isolated from normal human brains, in which only 6 Arg are deiminated to citrulline (MBP-Cit(6)), and an isomer isolated from the brain of a patient who died with acute, fulminating multiple sclerosis (Marburg type), in which 18 of the 19 Arg were deiminated (MBP-Cit(18)). Whereas C1 caused aggregation of lipid vesicles, resulting in an increase in absorbance due to light scattering, MBP-Cit(18) caused a decrease in absorbance of the lipid vesicles. Size exclusion chromatography and negative staining electron microscopy showed that this was due to fragmentation of the large multilayered vesicles into much smaller vesicles. MBP-Cit(6) caused less aggregation of lipid vesicles than did C1. However, no fragmentation of the vesicles into smaller ones in the presence of C1 and MBP-Cit(6) was detected by size exclusion chromatography or electron microscopy. The membrane fragmentation caused by MBP-Cit(18) is dramatically different from the effects of other forms of MBP from normal brain and may indicate a pathogenic effect of this charge isomer, which may have contributed to the severity of the Marburg type of multiple sclerosis. Alternatively, the deimination may have been a secondary effect resulting from the disease process. Regardless of the role of MBP-Cit(18) in multiple sclerosis, the effect of this modification indicates that, when most of the arginines of MBP are modified to an uncharged amino acid, the protein acquires properties similar to an apolipoprotein; thus, it may take up an amphipathic structure when bound to lipid. A partly amphipathic character may also be related to the role of MBP-Cit(6) in normal immature myelin, where it is the predominant charge isomer.

Highly deiminated isoform of myelin basic protein from multiple sclerosis brain causes fragmentation of lipid vesicles

Myelin basic protein (MBP) occurs as a number of charge isomers due to phosphorylation, deamidation, and deimination of arginine to citrulline. All of these modifications decrease the net positive charge of the protein and its ability to cause aggregation of negatively charged lipid vesicles. This is used as a model system for the ability of MBP to cause adhesion of the cytosolic surfaces of myelin. Therefore, the effect of two deiminated forms of MBP on lipid vesicles was compared with that of the unmodified, most positively charged isomer, C1, to determine how loss of positively charged arginines would affect the function of MBP. The deiminated forms were the isomer isolated from normal human brains, in which only 6 Arg are deiminated to citrulline (MBP-Cit6), and an isomer isolated from the brain of a patient who died with acute, fulminating multiple sclerosis (Marburg type), in which 18 of the 19 Arg were deiminated (MBP-Cit18). Whereas C1 caused aggregation of lipid vesicles, resulting in an increase in absorbance due to light scattering, MBP-Cit18 caused a decrease in absorbance of the lipid vesicles. Size exclusion chromatography and negative staining electron microscopy showed that this was due to fragmentation of the large multilayered vesicles into much smaller vesicles. MBP-Cit6 caused less aggregation of lipid vesicles than did C1. However, no fragmentation of the vesicles into smaller ones in the presence of C1 and MBP-Cit6 was detected by size exclusion chromatography or electron microscopy. The membrane fragmentation caused by MBP-Cit18 is dramatically different from the effects of other forms of MBP from normal brain and may indicate a pathogenic effect of this charge isomer, which may have contributed to the severity of the Marburg type of multiple sclerosis. Alternatively, the deimination may have been a secondary effect resulting from the disease process. Regardless of the role of MBP-Cit18 in multiple sclerosis, the effect of this modification indicates that, when most of the arginines of MBP are modified to an uncharged amino acid, the protein acquires properties similar to an apolipoprotein; thus, it may take up an amphipathic structure when bound to lipid. A partly amphipathic character may also be related to the role of MBP-Cit6 in normal immature myelin, where it is the predominant charge isomer. J. Neurosci. Res. 57:529–535, 1999. © 1999 Wiley-Liss, Inc.

Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination

Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination

Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology.

Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination. In the present study we actively induced MOG-experimental autoimmune encephalomyelitis (EAE) in different inbred rat strains using different immunization protocols. The pathology found in our models closely reflects the spectrum of multiple sclerosis (MS) pathology: Classical MS as well as variants such as optic neuritis, Devic's disease and Marburg's type of acute MS are mimicked in rats immunized with MOG antigen. Furthermore we demonstrate, that by using the proper strain/sensitization regime, subforms of MS such as for instance neuromyelitis optica can be reproducibly induced. Our study further supports the notion, that incidence and expression of the disease in this model, alike the situation in multiple sclerosis, is determined by genetic and environmental factors.

Identification of macrophage populations expressing tumor necrosis factor-alpha mRNA in acute multiple sclerosis.

Macrophages are involved in central nervous system (CNS) demyelination in multiple sclerosis (MS) and other demyelinating diseases. Macrophages seen in MS lesions form a heterogeneous population with respect to their stage of activation and differentiation. We have analyzed macrophages from active demyelinating lesions of a patient who died from fulminant MS of Marburg's type to define the functional heterogeneity of different macrophage populations in acute demyelination. We examined tumor necrosis factor-alpha (TNF-alpha) mRNA expression in macrophages defined by different activation markers. The majority of TNF-alpha mRNA-positive cells were macrophages positive for the pan-macrophage marker KiM1P. A subgroup of TNF-alpha mRNA-positive macrophages was stained by the early activation marker MRP14. In contrast, macrophages positive for the acute activation marker 27E10 were entirely negative for TNF-alpha mRNA. In conclusion, macrophages in acute demyelinating CNS lesions are heterogeneous as shown by staining for different activation markers. This heterogeneity is also of functional relevance as certain subpopulations are involved in TNF-alpha mRNA expression, while others are not. This may be important for directing therapeutic strategies against well-defined pathogenic macrophage populations.

Fulminant inflammatory demyelination: long‐term course and magnetic resonance imaging findings

The course and prognosis of adult patients who recover from acute and extensive inflammatory demyelination, variously termed fulminant or Marburg's type of multiple sclerosis (MS), is poorly known. We report long-term magnetic resonance imaging (MRI) and neuropsychological findings in two patients who developed acute psychosis and a state resembling akinetic mutism, with CT scan evidence of extensive cerebral white matter damage. Both patients ultimately recovered, but were left with a severe, non-progressive dementia with prominent frontal lobe signs unassociated with motor impairment. Extensive residual MRI lesions with evidence of tissue destruction in the white matter and callosal atrophy were visible many years after the initial event One of the patients developed a single relapsing-remitting episode with multifocal neurological deficits several years after the onset, whereas the condition remained monophasic in the other patient during an 8 year follow-up. Our observations suggest that while patients with so-called "fulminant" demyelinating disorders may nowadays survive with supportive measures, the disorder may remain stabilized for many years following disease onset.

Emerging and reemerging of filoviruses.

Filoviruses are causative agents of a hemorrhagic fever in man with mortalities ranging from 22 to 88%. They are enveloped, nonsegmented negative-stranded RNA viruses and are separated into two types, Marburg and Ebola, which can be serologically, biochemically and genetically distinguished. In general, there is little genetic variability among viruses belonging to the Marburg type. The Ebola type, however, is subdivided into at least three distinct subtypes. Marburg virus was first isolated during an outbreak in Europe in 1967. Ebola virus emerged in 1976 as the causative agent of two simultaneous outbreaks in southern Sudan and northern Zaire. The reemergence of Ebola, subtype Zaire, in Kikwit 1995 caused a worldwide sensation, since it struck after a sensibilization on the danger of Ebola virus disease. Person-to-person transmission by intimate contact is the main route of infection, but transmission by droplets and small aerosols among infected individuals is discussed. The natural reservoir for filoviruses remains a mystery. Filoviruses are prime examples for emerging pathogens. Factors that may be involved in emergence are international commerce and travel, limited experience in diagnosis and case management, import of nonhuman primates, and the potential of filoviruses for rapid evolution.

PRODUCTION AND PROPERTIES OF 2,3-BUTANEDIOL: XVII. FERMENTATION OF GLUCOSE BY STRAINS OF BACILLUS SUBTILIS

Under aerobic conditions both the Marburg and Ford types of Bacillus subtilis dissimilate glucose, giving carbon dioxide, acetoin, and 2,3-butanediol as the main products, and small amounts of glycerol and acetic, formic, lactic, and n-butyric acids. The Ford type cultures dissimilate the sugar more rapidly and also give a small amount of ethanol.Under anaerobic conditions Marburg type cultures will not ferment glucose while the Ford type cultures dissimilate it as rapidly as they do under aerobic conditions. Some strains give 2,3-butanediol, glycerol, and carbon dioxide as the major products while others give chiefly lactic acid. As much as 86% and as little as 8% of the glucose was converted to 2,3-butanediol plus glycerol. The 2,3-butanediol was a mixture of 65% meso- and 35% levo-isomers, while the lactic acid was approximately 90% dextro-isomer in most cases.It is suggested that the Ford type deserves separate species rank.