Spinal cord lesions of multiple sclerosis

The neuropathological findings of the spinal cord lesions of six human multiple sclerosis cases are described. The spinal cord was extensively necrotic and occasionally cystic in five remitting and relapsing cases. The lesions became more severe as the disease course prolonged and relapses increased. The spinal cords of two cases in particular, with a duration of illness of more than 5 years, were severely atrophic. In these cases, peripheral type remyelination was prominent, although central type remyelination was minimal. In contrast, in mouse spinal cords, in which experimental demyelination and remyelination were induced by ethidium bromide, the degree of central type remyelination and peripheral type remyelination was almost the same. Longitudinal sections of the transitional zone between the areas of central type remyelination and peripheral type remyelination contrained Ranvier nodes, in which central type myelin and peripheral type myelin were situated side by side around a central type axon. These transitional zones were similar to those of the normal transitional zone between the central nervous system and peripheral nervous system of the nerve roots. One chronic progressive case, despite the very long duration of illness, showed classical sharply demarcated demyelinated lesions with marked fibrillary gliosis. The spinal cord of this case was not atrophic and axons were well preserved.     

Spinal cord axonal loss in multiple sclerosis: a post-mortem study

There is increasing interest in the contribution that axonal damage may make to clinical disability in multiple sclerosis (MS). The present study reports a post-mortem examination of the area occupied by the lateral white matter columns of the spinal cord and nerve fibre density in the corticospinal tracts at C3 and T2 in 23 males and 20 females with MS, who lacked plaques at these levels, and in 31 controls who, although most had had some neurological disease, showed no sign of cervical or spinal cord thoracic disease. The lateral column cross-sectional area, measured by low power image analysis of the outlined lateral columns, was reduced in MS by 17% at C3 and 21% at T2 in males and by 13% at C3 and 18% at T2 in females. These reductions were significant at both levels in males (P<0.004 at C3 and P<0.009 at T2 ) but only at T2 in females (P<0. 03). The nerve fibre density, measured by automatic image analysis of x200 microscopic fields in the region occupied by the crossed pyramidal tracts, was reduced by 41% at C3 and 42% at T2 in males and by 19% at both C3 and T2 in females. These reductions were likewise significant at both levels in males (P<0.003 and P<0.000 at C3 and T2, respectively) and T2 only in females (P<0.045). In MS, nerve fibre density was significantly lower at C3 (P<0.004) and T2 (P<0.000) in males than females. No differences were seen in these parameters between males and females in controls. The reductions in total nerve fibre densities were entirely accounted for by reductions in small nerve fibres (cross sectional area less than 5 microm2 ). No significant reductions were seen in large fibre (cross sectional area 5 microm2 or more) densities. It is concluded that substantial axonal loss and spinal cord lateral column white matter atrophy occur at C3 and T2 in MS, and that these changes can be detected in some patients from early in the course of the disease.     

Grey matter pathology in multiple sclerosis

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed 'general cortical subpial demyelination'. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.     

Monoclonal remyelination-promoting natural autoantibody SCH 94.03: pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis

Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis (Miller et al., 1994; J. Neurosci. 14: 6230–6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3–4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5–2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMκ antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.     

Motor evoked potentials in a mouse model of chronic multiple sclerosis

We tested cortical motor evoked potentials (cMEPs) as a quantitative marker for in vivo monitoring of corticospinal tract damage in a murine multiple sclerosis model (experimental autoimmune encephalomyelitis, EAE). The cMEPs, previously standardized in naive C57BL/6 developing and adult mice, were studied longitudinally in adult EAE mice. Central conduction times (CCTs) increased significantly shortly before the earliest clinical signs developed (10 days postimmunization, dpi), with peak delay in acute EAE (20-40 dpi). In clinically stable disease (80 dpi), CCTs did not increase further, but cMEP amplitude declined progressively, with complete loss in >80% of mice at 120 dpi. Increase in CCT correlated with presence of inflammatory infiltrates and demyelination in acute EAE, whereas small or absent cMEPs were associated with continuing axonal damage in clinically-stabilized disease and beyond (>80 dpi). These results demonstrate that cMEPs are a useful method for monitoring corticospinal tract function in chronic-progressive EAE, and provide insight into the pathological substrate of the condition.     

Different mechanisms underlying changes in excitability of peripheral nerve sensory and motor axons in multiple sclerosis

Introduction: Subtle involvement of peripheral nerves may occur in multiple sclerosis. Motor excitability studies have suggested upregulation of slow K⁺ currents, probably secondary to altered motoneuron properties resulting from the central lesion. This study concentrates on sensory axons. Methods: Excitability of median nerve axons at the wrist was studied in 26 patients. Results: Sensory recordings were possible in 22 patients, and reduced superexcitability was the sole abnormality. There was no evidence for changes in membrane potential or demyelination. The decrease was significant in patients taking immunomodulatory therapy. These findings could be reproduced in a computer model by changing the gating of fast K⁺ channels. Motor axon findings were consistent with previously reported increased slow K⁺ current. Conclusions: The sensory findings differ from motor findings. They can be explained by a humoral factor, possibly cytokines, which can penetrate the paranode and have been documented to alter the gating of K⁺ channels. Muscle Nerve, 2013     

Cerebrospinal fluid total tau protein levels in patients with multiple sclerosis

BACKGROUND: Tau protein is present in the microtubules of axons. Markers of various types have been used to demonstrate multiple sclerosis (MS) activity and axonal damage. This study aimed to demonstrate the association between cerebrospinal fluid (CSF) tau protein concentrations and clinical prognosis in MS patients. METHODS: We included 45 patients that were diagnosed according to the McDonald's criteria. The control group was made up of 38 patients that had no signs or symptoms related to the primary central nervous system lesion correlated with the patient group. CSF total tau protein was measured using the ELISA method based on the sandwich method with Innogenetics Innotest hTau antigen kit in pg/ml type. RESULTS: In the patient group, the mean CSF total tau protein level was 238.66 +/- 237.44, whereas it was 93.65 +/- 82.14 in the control group. The mean total tau protein was higher in the three clinical forms when compared with the control group and it was statistically significant (P<0.05). CONCLUSIONS: High tau protein level may be an early marker of axonal damage and this marker may be used for monitoring axon preventing therapies in the follow-up.     

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de‐ and remyelination, we employed cuprizone‐ and focal lysolecithin‐induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP‐ and SMI32‐ positive damaged axons and the density of SMI31‐positive and silver impregnated preserved axons. Early de‐ and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult.     

High field MRI correlates of myelin content and axonal density in multiple sclerosis

Abstract. Different MRI techniques are used to investigate multiple sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to demyelination and axonal loss.The aim of this study was to evaluate the pathological substrate of high field MRI in post-mortem (PM) spinal cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine.Quantitative MRI maps (PD; T2; T1; magnetization transfer ratio, MTR; diffusion weighted imaging) were obtained. After scanning, the myelin content and the axonal density of the specimens were evaluated neuropathologically using quantitative techniques. Myelin content and axonal density correlated strongly with MTR, T1, PD, and diffusion anisotropy, but only moderately with T2 and weakly with the apparent diffusion coefficient.Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful. Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between axonal loss and demyelination and between demyelinated and remyelinated lesions.     

Remyelination in multiple sclerosis: Cellular mechanisms and novel therapeutic approaches

The myelin sheath that coats axons allows rapid propagation of electrical impulses across the nervous system. Oligodendrocytes (ODs) are myelin‐producing cells of the central nervous system (CNS) responsible for wrapping the axons of neurons. Multiple sclerosis (MS) is a demyelinating disease of the CNS identifiable by white and gray matter lesions. These lesions consist of axons that have lost their myelin through an autoimmune response to myelin and ODs. Current treatments for MS target the autoimmune aspect of the disease. However, these immunomodulators do not directly enhance the process of remyelination. The ability to remyelinate lesions can be enhanced by neural progenitor cells that can differentiate into ODs and replace lost myelin, although successful remyelination is complex and dependent on multiple factors. The restoration of lost myelin might protect the axon from degeneration and restore optimal conduction of impulses in MS patients, requiring further research on proremyelinating therapies. The combination of immunomodulators and remyelinating enhancers might be the best course of treatment for many MS patients. This Review discusses demyelination in MS, the mechanisms of remyelination, and current therapies designed to promote remyelination in MS patients. © 2014 Wiley Periodicals, Inc.     

Spinal and cranial hypertrophic neuropathy in multiple sclerosis

Two patients with multiple sclerosis developed symptomatic chronic inflammatory demyelinating polyneuropathy with massive spinal or cranial nerve hypertrophy revealed by neuroimaging. Sural nerve biopsy in one showed only moderate demyelination, axonal loss, and onion-bulb formation, illustrating dichotomy between severe proximal and milder distal nerve involvement. Patients with coexistent central and peripheral demyelination usually are symptomatic from dysfunction at one site or the other, but not from both. Our patients showed minimal response to steroids, intravenous immunoglobulin, or azathioprine. These cases suggest that the mechanism of disease in symptomatic central and peripheral demyelination may differ from that of disease in only one region, and that optimal therapy in this situation must be explored further.     

The pathological evolution of multiple sclerosis

The new technique of nuclear magnetic resonance imaging (NMR) has been found to have particular value in the study of the evolution of the plaque of multiple sclerosis. Particularly when combined with gadolinium enhancement, the method not only shows very dramatically the waxing and waning of the plaque with time, it also demonstrates with remarkable clarity the important role of changes in vascular permeability in the pathological process. In this Annotation the ability of this technique to throw new light on the process of plaque formation and evaluation is critically assessed. In addition, the role of changing fluid content of the extracellular spaces of the CNS in influencing interpretation of the more conventional clinical and electrophysiological findings is discussed. While the method of NMR analysis does not yet show us how the plaque is initiated, it is suggested that future studies with these new techniques in the living subject may well lead us to rational therapeutic approaches based on pathogenetic mechanisms.     

The conus demyelination syndrome in multiple sclerosis

Bowel, bladder and sexual dysfunction are common in multiple sclerosis and are generally attributed to the widespread nature of the involvement of the neuroaxis by the demyelinating plaques. Recently we encountered a specific subset of patients within this group who had characteristic clinical complaints of hesitancy, straining and incomplete voiding, perineal hypesthesia on examination, areflexia by cystometry and colonometry and electrophysiological parameters suggesting involvement of the conus medullaris. This heretofore postulated but undocumented mechanism of neurovisceral dysfunction in multiple sclerosis is detailed and discussed in 2 patients in this report.     

Remyelination can be extensive in multiple sclerosis despite a long disease course

Experimental studies using models of multiple sclerosis (MS) indicate that rapid and extensive remyelination of inflammatory demyelinated lesions is not only possible, but is the normal situation. The presence of completely remyelinated MS lesions has been noted in numerous studies and routine limited sampling of post mortem MS material suggests that remyelination may be extensive in the early stages but eventually fails. However, visual macroscopic guided sampling tends to be biased towards chronic demyelinated lesions. Here we have extensively sampled cerebral tissue from two MS cases to investigate the true extent of remyelination. Sections were cut from 185 cerebral tissue blocks and stained with haematoxylin and eosin (H&E), luxol fast blue and cresyl fast violet (LFB/CFV) and anti-myelin oligodendrocyte glycoprotein, human leucocyte antigen-DR (HLA-DR) and 200 kDa neurofilament protein antibodies. Demyelinated areas were identified in 141 blocks, comprising both white matter (WMLs) and/or grey matter lesions. In total, 168 WMLs were identified, 22% of which were shadow plaques, 73% were partially remyelinated and only 5% were completely demyelinated. The average extent of lesion remyelination for all WMLs investigated was 47%. Increased density of HLA-DR(+) macrophages and microglia at the lesion border correlated significantly with more extensive remyelination. Results from this study of two patients with long standing disease suggest that remyelination in MS may be more extensive than previously thought.     

The basis for treatment in multiple sclerosis

Contemporary licensed treatments for multiple sclerosis fail to provide a solution for the disease because their effects are limited to a modest reduction in the frequency of new episodes. They do not reduce disability or materially influence the progressive phase of the disease. A contemporary strategy for management requires a more detailed analysis of the separate contributions to the clinical features and overall course made by inflammation, axonal injury, compensatory mechanisms, and remyelination. From this formulation emerges the need either for early and fully effective suppression of the inflammatory response, limiting the damage to all components of the axon-glial unit; or the development of strategies for axonal and myelin repair that solve the issues of controlled differentiation, delivery and timing of these cell and growth factor-based interventions.     

Myelopathy patients studied with magnetic resonance for multiple sclerosis plaques

Seven patients with isolated spinal cord symptoms, and with evoked potential (EP) recordings and/or cerebrospinal fluid (CSF) findings supporting a demyelinating cause for their myelopathy, were examined with cervical and cranial magnetic resonance imaging (MRI). Lesions in the cervical spinal cord were detected in 6 of the patients, including 2 who also had disseminated lesions in the brain compatible with multiple sclerosis (MS). In one patient MRI of the cervical spinal cord was normal, while plaques were seen in the periventricular region of the brain and in the brain stem. Thus, in the 3 patients with cerebral plaques, MRI supported the diagnosis of MS by showing dissemination in space. In the remaining 4 patients MRI provided support for the diagnosis of MS by demonstrating the cervical spinal cord plaques while excluding other potential causes of myelopathy, such as spinal cord compression and intramedullary tumor.     

Tau protein concentrations in cerebrospinal fluid of patients with multiple sclerosis

FUNDAMENTALS AND OBJECTIVE: Multiple sclerosis (MS) is the prototype of demyelinating disease, but recently, it has been shown that the existence of axonal lesions contribute to irreversible central nervous system damage in this disease. Tau proteins are considered to be important for maintaining the stability of axonal microtubules involved in the mediation of fast axonal transport of synaptic constituents. There have been reports of increased cerebrospinal fluid (CSF) tau concentrations in patients with MS, and it has been suggested that this could be a marker of axonal damage. The objective of the present study was to elucidate whether CSF tau levels could be a marker of MS activity. PATIENT AND METHODS: We measured tau concentrations in the CSF of 20 patients with MS (nine in the first, seven in the second, one in the fourth exacerbation, and three patients with chronic progressive course) and 32 age- and sex-matched controls, using a specific enzyme-linked immunosorbent assay method. RESULTS: The CSF tau concentrations of patients with MS did not differ from those of controls, and they were not correlated with age at onset and duration of the disease. CONCLUSION: CSF tau concentrations are not a marker of MS activity.