The demonstration of recurrent demyelination and remyelination of axons in the central nervous system

Summary A model for studying recurrent demyelination and remyelination in the central nervous system was developed by means of repeated administration of Cuprizone to mice. In contrast to the demyelination seen during the first course of Cuprizone, the recurrent demyelination was markedly protracted, displayed features of a dying-back gliopathy, and resulted in a greatly reduce inflammatory and glial reaction. The repeat remyelination also occurred at a slower tempo, varied markedly in completeness, and was associated with a diminished regeneration of oligodendrocytes. These results demonstrated that axons of the central nervous system in this model can be recurrently remyclinated if oligodendrocytes are available, that regeneration of oligodendrocytes is dependent upon the tissue reaction to demyelination, and that remyelinated axons are not more susceptible to demyelination than normal ones.     

An immunohistochemical study of myelin proteins during remyelination in the central nervous system

Summary The process of remyelination in the superior cerebellar peduncles of mice following demyelination with Cuprizone was studied immunohistochemically using antisera to myelin basic protein (MBP) and myelin-associated glycoprotein (MAG). Demyelination occurred after formation of myelinic vacuoles and resulted in almost complete loss of demonstrable MBP and MAG from the peduncle. Prior to the onset of remyelination, oligodendrocytes with cytoplasmic staining for both proteins appeared in the peduncle. These cells were then associated with remyelinating axons. The axons were remyelinated in clusters until the MBP and the MAG in the whole peduncle were reconstituted, although the axon sheaths were thinner than those in normal animals. The results show that the immunohistochemical distribution of MBP and MAG in remyelinating axons resembles that in normal axons, and that the expression of myelin proteins in oligodendrocytes during remyelination reverts to that seen during normal development.Supported by MRC grant no. MT 5818Presented in part at the 59th Meeting of the American Association of Neurologists, St. Louis, MO, USA, June 1983     

Morphology of demyelination in the human central nervous system

The principles of the neuropathological classification of disorders of central nervous system myelin are recalled. They are illustrated by a few selected examples. Dysmyelination is characterized by the production of an abnormal and unstable myelin sheath; it is often associated with hypomyelination (paucity of myelin formation) and is due to metabolic disorders. It is the main process in leukodystrophies. Storage of different lipids (e.g. sulfatides, long-chain fatty acids) or associated pathology of various cell types (in Alexander's disease, for example) are used for classifying these disorders. Biochemical and genetic characterizations are presently ongoing. Demyelination is the destruction of apparently normal myelin. It is often followed by remyelination. Our present knowledge on the neuropathology of multiple sclerosis, the most common demyelinating disease, is summarized. Cell-mediated demyelination affects the myelin sheaths for an obscure reason. The causes of the multifocal and sharply demarcated plaques, and of the fading of the remyelination process at the edge of some plaques, are not clear. A few examples of demyelinating diseases of known etiology and of various mechanisms are given. The similarities between acute disseminated leukoencephalitis and experimental autoimmune encephalitis are stressed. In progressive multifocal leukoencephalopathy, chronic infection of oligodendrocytes by JC virus induces poorly defined areas of demyelination. In AIDS, the pathogenesis of the myelin change is unclear. Macrophages may be responsible. Toxic and vascular disorders provide also good models for the understanding of mechanisms of demyelination.     

Oligodendrocyte/myelin injury and repair as a function of the central nervous system environment

Multiple sclerosis is a chronic neurologic disorder considered to result from relatively selective immune mediated injury of central nervous system (CNS) myelin and/or its cell of origin, the oligodendrocyte (OGC). Constituents of both the innate and adaptive immune systems are potential contributors to this process. Endogenous (microglia) and infiltrating (macrophages, dendritic cells) constituents of the innate immune system serve as sensors of events occurring within the CNS; their response to such events underlies the extent of their interaction (chemoattraction, antigen presentation) with the components of the adaptive immune system (alphabeta T cells, B cells) and ultimately the extent of the resultant inflammatory response. Constituents of both the innate and adaptive immune system can serve as effectors of tissue injury. The susceptibility of specific types of neural cells to injury further reflects the extent to which immune mediators modulate expression of crucial molecules (adhesion molecules, receptors) involved in effector-target interactions. Ongoing interactions between the constituents of the immune system themselves and between these constituents and neural cells are important determinants of disease recurrence and/or progression. Conversely, these interactions also impact on the mechanisms involved in target protection and repair.     

Monoclonal anti-T cell antibodies are applicable to the study of inflammatory infiltrates in the central nervous system

Monoclonal anti-human T cell antibodies were tested by a modified PAP technique on frozen sections of human central nervous system (CNS) tissue from inflammatory and non-inflammatory conditions. It was found that whole T cells and T cell subset - T4⁺ (helper-induced)_ and T8⁺ (suppressor/cytotoxic) T cells - could could be differentiated specifically from other mononuclear cells and their these markers did not cross-react with human CNS tissue elements, particulary oligodendrocytes, under the same conditions. The lack of cross-reactivity between monoclonal antibodies to T cells and oligondendrocytes was further confirmed by double-labelling with an anti-galactocerebroside serum. It is concluded that in inflammatory condition like multiple sclerosis, monoclonal antibodies promise considerable elucidation of immunopathogenetic events.     

Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination

Interferon-beta (IFN-β) is a pleiotropic cytokine that is known to modulate the immune response in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Spontaneous remyelination and repair mechanisms in MS are mostly insufficient and contribute to clinical disability. Here, we investigated whether IFN-β has a potential in modifying the extent of de- and remyelination in a toxic model of CNS demyelination induced by the copper chelator cuprizone. IFN-β deficient (k/o) mice showed an accelerated spontaneous remyelination. However, the amount of remyelination after 6 weeks did not differ between the two groups. Demyelination in IFN-β k/o mice was paralleled by a diminished astrocytic and microglia response as compared with wildtype controls, whereas the accelerated remyelination was paralleled by an increased number of oligodendrocyte precursor cells (OPC) within the demyelinated lesion at the beginning of the remyelination phase. We hypothesize that the absence of IFN-β leads to more efficient recruitment and proliferation of OPC already during demyelination, thus allowing early remyelination. These results demonstrate that IFN-β is able to alter remyelination in the absence of an immune-mediated demyelination. The first two authors contributed equally to this work.     

Observations on demyelinating lesions induced by Theiler's virus in CBA mice

Summary We examined demyelinating lesions in the spinal cord of CBA mice infected with the BeAn strain of Theiler's virus to see if it was possible to document the sequence of changes which result in demyelination. It was found that the lesions which develop in the late stages of the disease were progressive. Therefore, by examining the different zones of a single lesion, it was possible to follow a sequence of changes which lead to demyelination. There was a clear progression from normal myelin, to vacuolated myelin, to myelin phagocytosis, to demyelinated axons, to remyelinated axons. Virus was detected in degenerating oligodendrocytes in the area showing myelin vacuolation by both electron microscopy and immunocytochemistry, a finding which indicated that virus infection precedes demyelination. The area of normal myelin which surrounded the zone of vacuolated myelin was infiltrated by lymphocytes, indicating that lymphocytic infiltration preceded viral replication and oligodendrocyte degeneration. Our observations indicate that cells of the immune system may play a role in the initiation of virus replication which appears to be a prerequisite for demyelination.Supported by grants from the Multiple Sclerosis Society     

Mechanism of demyelination in JHM virus encephalomyelitis

Summary Weanling mice were given intraperitoneal inoculations of the neurotropic, JHM strain of mouse hepatitis virus, the virulence of which had been altered by repeated mouse passages. Five to seven days later many animals developed hind leg paralysis. The pathology consisted of an acute encephalomyelitis with patchy demyelinating lesions in the brain stem and spinal cord. Virus particles, consistent with the appearance of corona viruses, were found in the cytoplasm of cells that were identified as oligondendrocytes by demonstrating connections of their plasma membranes with myelin lamellae. Following the degeneration of oligodendrocytes the myelin sheaths disintegrated or were stripped off intact axons by cytoplasmic tongues of polymorpho- and mononuclear leucocytes that intruded between myelin lamellae. The findings indicate that JHM virus has an affinity for oligodendrocytes in weanling mice and that demyelination occurs subsequently to the degeneration of the infected oligodendrocytes.Supported by United States Public Health Research Grant NS 09053 from the National Institutes of Neurological Diseases and Stroke.     

Peripheral nervous system demyelination from systemic transfer of experimental allergic neuritis serum

The ability of systemically transferred experimental allergic neuritis (EAN) serum to produce EAN lesions in recipient animals was studied. Seventeen Lewis rats received five daily 1-ml intraperitoneal (i.p.) injections of sera from rabbits with EAN induced with bovine myelin/complete Freund's adjuvant (CFA). Another 17 rats received similar injections of sera from rabbits inoculated with CFA alone. On day 0 (the first day of i.p. injections), all rats were injected in the proximal tibial branch of the right sciatic nerve with a single 10-microliters injection of 0.03 M 5-hydroxytryptamine (5-HT) in sterile 0.15 M saline. Proximal tibial branches of left sciatic nerves received similar single injections of saline alone. Animals were then studied using electrophysiological and histological techniques. In all animals, intraneural saline injection had no significant effect upon nerve conduction. In the presence of circulating CFA serum, 5-HT injection caused a mild gradual decrease in amplitude ratio becoming maximal by day 17 (P < 0.005) and partially resolving by day 28. In contrast, in the presence of circulating EAN serum, 5-HT injection caused a more rapid and severe decrease in amplitude ratio becoming maximal by days 6-10 (P < 0.001 day 6; P < 0.0001 day 10) and completely resolving by day 28. Histological analysis of nerves injected with 5-HT in CFA serum-treated animals showed areas of mild demyelination, axonal degeneration and some fibre loss consistent with needle trauma. In contrast, 5-HT-injected nerves in animals administered EAN serum showed areas of marked cellular infiltration and severe demyelination in association with numerous debris-filled infiltrating cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuroimaging of infections of the central nervous system

Neuroimaging plays a crucial role in the diagnosis and therapeutic management of neurologic infections. This article summarizes imaging findings in brain abscesses, ventriculitis, viral diseases, and opportunistic infections. In cases of uncomplicated meningitis, cranial computed tomography is sufficient to exclude brain edema, hydrocephalus, and skull base pathology. Magnetic resonance imaging (MRI) is superior in depicting complications (e.g., empyema, vasculitis). Diffusion-weighted imaging (DWI) shows parenchymal complications of meningitis earlier and is of help in differentiation of pyogenic abscess from other ring-enhancing lesions. Proton magnetic resonance spectroscopy can produce specific peak-patterns in cases of abscess, such as the presence of lactate and cytosolic amino acids. In toxoplasmosis, DWI may help to differentiate from lymphoma, showing no restriction of water diffusion. In patients with viral encephalitis, DWI allows earlier lesion detection. MRI has revolutionized the rapid diagnosis of spinal abscess.     

Ret expression in the central nervous system

The ret proto-oncogene product (Ret) has been shown to be one of the glial cell line-derived neurotrophic factor (GDNF) receptors in dopaminergic, norepinephric and motor neurons. We immunohistochemically examined the expression of Ret in the human central nervous system (CNS). The distribution of Ret was generally identical to that of myclin as stained using the Klüver-Barrera method. We further investigated the expression of Ret in human fetal brains (19, 29 and 39 weeks gestation) and various brain tumors. The Ret positivity was observed to be associated with the myelin sheath of the cerebral white matter in 29-and 39-week-old fetal brains. Ret is known to be expressed in neural crest-derived cells. We could immunohistochemically confirm the Ret expression in the pheochromocytomas and neuroblastomas of retroperitoneal space. As for the brain tumors, no Ret expression was observed in glioblastomas, oligodendrogliomas, and schwannomas examined, although the glial cells surrounding the tumor and the pre-existing myelin sheath revealed positivity for Ret. In the CNS, Ret expression appears to be closely associated with the myelin sheath; therefore, Ret immunostaining may be useful in ascertaining the demyelinating lesions in the CNS.     

实验性自身免疫性脑脊髓炎的小胶质细胞和星形胶质细胞反应

目的确定小胶质细胞和星形胶质细胞在实验性自身免疫性脑脊髓炎（ＥＡＥ）发病及病变发展中的作用。方法用牛脊髓髓鞘碱性蛋白（ＭＢＰ）免疫豚鼠发生ＥＡＥ,用免疫组化法观察ＥＡＥ不同病期小胶质细胞和星形胶质细胞对炎性脱髓鞘病灶的反应。结果发生ＥＡＥ的前３天,小胶质细胞即开始激活,在临床症状出现时其数量及激活程度达高峰,并持续至高峰期。恢复期数量逐渐减少,激活程度逐渐减弱。星形胶质细胞在症状高峰期开始激活并围绕在浸润细胞和病变血管周围,似有隔离小胶质细胞与病灶接触的作用,至恢复期激活明显。结论小胶质细胞激活在ＥＡＥ的发病及进展中起重要作用,而星形胶质细胞主要与疾病的恢复有关。     

Cerebrospinal fluid myelin basic protein as predictive marker of demyelination in AIDS dementia complex

Myelin basic protein (MBP) was measured in cerebrospinal fluid (CSF) of patients with acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) in order to investigate the degree of white matter destruction. Results show that increased CSF levels of MBP were detected in all patients with severe ADC (10/10) and, less often, in subjects with mild (2/7) or moderate dementia (7/16). No evidence of MBP-elevated concentration was observed in 14 human immunodeficiency virus (HIV)-seropositive subjects without neurological disorders and in nine HIV-seronegative controls. Our findings suggest that the measurement of CSF MBP concentration may represent a predictive marker of myelin injury and neurologic damage during the course of ADC.     

Spontaneous central nervous system remyelination in strain A mice after infection with the Daniel’s (DA) strain of Theiler’s virus

Intracerebral infection of susceptible SJL/J (H-2^s) mice with the Daniel’s strain of Theiler’s murine encephalomyelitis virus produces chronic, progressive, inflammatory central nervous system demyelination, with minimal spontaneous remyelination. To assess the role of host genetic factors in spontaneous myelin repair following chronic infection with the Daniel’s strain of Theiler’s virus, we examined demyelination and spontaneous remyelination in strain A mice after infection with Theiler’s virus. We found that A.BY/SnJ (H-2^b) mice were resistant to Theiler’s virus-induced demyelination, whereas A/J (H-2^a), A/WySnJ (H-2^a), and A.SW/SnJ (H-2^s) mice all developed chronic demyelination with substantial spontaneous remyelination 90 days after infection. In the spinal cords of both A/J and A/WySnJ mice, one quarter of the total lesion area showed spontaneous remyelination, whereas in A.SW/SnJ mice, the extent of remyelination increased to two thirds of the total lesion area. The spontaneous remyelination seen in strain A mice was consistent with myelin repair by oligodendrocytes and Schwann cells, and occurred despite the presence of persistent virus antigen. These results indicate that host-pathogen interactions play an important role in myelin regeneration after virus-induced demyelination, and suggest that host genetic factors influence spontaneous remyelination. Received: 3 October 1995 / Revised, accepted: 28 November 1995     

Long-term remyelination fails to reconstitute normal thickness of central myelin sheaths

The relationship between the thickness of the myelin sheath and the square area of the axon was measured in both short-term and long-term remyelinated axons following demyelination in the central nervous system, and compared with that of controls. The normal linear relationship between thickness of myelin sheath and axon size was not present in either group of remyelinated axons even though there was a trend, not statistically significant, in the long-term remyelinated animals to approach that of normal animals.     

Myelination, demyelination and re-myelination in the central nervous system

The myelin sheaths that surround axons in the CNS are made and maintained by oligodendrocytes. These glial cells can form variable numbers of myelin segments (internodules): from 1 to 200 so that when one oligodendrocyte is destroyed with preservation of the axon, many internodules can be lost, constituting a demyelinating process. As a consequence of the destruction of myelin and sheath cells a rapid and abundant cell response takes place. The response is made up by resident (microglia) and haematogenous phagocytes which phagocytose myelin and cellular debris leaving the axons demyelinated. Demyelinated axons may either stay demyelinated and clumped together or they may be separated by astrocytic processes, yet they can be remyelinated. The occurrence of remyelination depends upon the intensity and time of exposition to the demyelinating agent. Remyelination in the CNS with complete restoration of conduction may be made by oligodendrocytes or Schwann cells which invade the CNS when astrocytes are destroyed.     

Aggressive central nervous system demyelination in an adolescent

A 15-year-old boy diagnosed with a severe, active, and aggressive form of multiple sclerosis (MS) failed conventional, evidence-based therapy. The optimal treatment of the child or adolescent failing federally approved therapy for MS is unclear, similar to the situation in adults. This case history demonstrates that aggressive immunosuppression might be of at least short-term value in controlling disease acutely in an adolescent, as in adults with MS, when evidence-based therapies do not provide an adequate response.     

Multiple sclerosis and malignant neoplasms in the central nervous system

Summary There is some evidence that the incidence of malignant neoplasms in the central nervous system of patients with multiple sclerosis (MS) is more infrequent than among the general population. The examination of 3 MS cases with different type of neoplasms in the central nervous system revealed mainly inactive demyelinated plaques. These plaques and the neoplastic lesions were dispersed diffusely and coincidentally all over the brain and spinal cord. The benign course of MS in all three cases is discussed in relation to the malignant diseases.Supported by the Deutsche Forschungsgemeinschaft, Schwerpunktprogramm Ätiologie und Pathogenese der Multiplen Sklerose und verwandter Erkrankungen     

Peripheral nerve lesion in spongy degeneration of the central nervous system

Summary This report describes a peripheral nerve lesion found in a case of spongy degeneration of the central nervous system. The lesion consisted of abnormal cellular infiltrates in the peri- and endoneurium, axonal changes, and demyelination. Possible relation of the lesion to that of the central nervous system is discussed.Supported by grant NB-02255 from the National Institutes of Health, United States Public Health Service.