Multiple Sclerosis: Scolding N

Elovaara I, Apostolski S, van Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J, van Schaik IN, Scolding N, Soelberg Sørensen P, Udd B, Anonymous00010. · Department of Neurology and Rehabilitation, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland. · Eur J Neurol. · Pubmed #18796075 No free full text.

Abstract: Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Scolding N. · No affiliation provided · Mult Scler. · Pubmed #17262993 No free full text.

This publication has no abstract.

Wilkins A, Scolding N. · Department of Neurology, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Bristol, UK. · Mult Scler. · Pubmed #18632772 No free full text.

Abstract: Typically patients with multiple sclerosis (MS) experience acute episodes of neurological dysfunction, which recover followed, at a later stage, by slow and insidious accumulation of disability (disease progression). Disease progression reflects axon damage and loss within the central nervous system. However, the precise mechanism of axon injury in MS is not clear. Inflammation occurring during acute relapses undoubtedly causes some degree of acute axon damage, but epidemiological data and treatment studies have suggested that inflammation alone is not the sole cause of axonopathy. Indeed, there appears to be dissociation between inflammation and disease progression once a certain level of clinical disability has been reached because immune suppression in patients who have established disease progression does not halt the slow decrease of function. The slow and insidious loss of neurological function that occurs during the progressive phase of the disease implies a degenerative process. Whether axon drop-out occurs at these later stages because of previous inflammatory damage to axons; because of low grade inflammation causing damage to already vulnerable demyelinated axons; because of loss of trophic environment for axons to survive; or as part of a completely independent neurodegenerative process is not clear. Understanding disease mechanisms involved in the axonopathy of MS allows for the development of rational therapies for disease progression.

Scolding N, Marks D, Rice C. · University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol BS16 1LE, UK. · J Neurol Sci. · Pubmed #17904159 No free full text.

Abstract: A number of practical problems need to be addressed before any form of cell therapy can be widely applied in patients with multiple sclerosis. The choice of cell type is one considered elsewhere in this issue; others include the question of axon loss, that of continuing inflammatory disease activity, the mode of delivery of cells (bearing in mind the presence of innumerable lesions scattered throughout the CNS), the problem of measuring directly or indirectly the impact (if any) of an intervention, the timing of any treatment and perhaps above all the safety of the patient. All converge on the one increasingly relevant underlying question: when should stem cell treatments begin to be tested in patients? Here we review the progress in various of these practical problems in order to explain how we have arrived at the conclusion that the clinical science has progressed to a stage where the 'translation threshold' can be safely and appropriately crossed, and therefore why we have already commenced in Bristol a small pilot/feasibility study of autologous bone marrow cell treatment in patients with multiple sclerosis.

Rice C, Scolding N. · Department of Neurology, University of Bristol, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, BS16 1LE, UK. · J Neurol. · Pubmed #17345032 No free full text.

Abstract: A number of factors more or less unique to multiple sclerosis have suggested that this disease may be particularly amenable to cell-based reparative therapies. The relatively focussed damage to oligodendrocytes and myelin at least in early disease implies that only a single population of cells need be replaced-and that the daunting problem of re-establishing connectivity does not apply. The presence of significant though partial spontaneous myelin repair in multiple sclerosis proves there to be no insurmountable barrier to remyelination intrinsic to the CNS: the therapeutic challenge becomes that of supplementing this spontaneous process, rather than creating repair de novo. Finally, the large body of available knowledge concerning the biology of oligodendrocytes, and the success of experimental myelin repair, have allowed cautious optimism that future prospects for such therapies are not unrealistic. Nonetheless, particular and significant problems are not hard to list: the occurrence of innumerable lesions scattered throughout the CNS, axon loss, astrocytosis, and a continuing inflammatory process, to name but a few. Here we review the progress and the areas where difficulties have yet to be resolved in efforts to develop remyelinating therapies for multiple sclerosis.

Rice C, Halfpenny C, Scolding N. · University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol, BS16 1LE, United Kingdom. · NeuroRx. · Pubmed #15717045 links to  free full text

Abstract: Multiple sclerosis presents particular and serious problems to those attempting to develop cell-based therapies: the occurrence of innumerable lesions scattered throughout the CNS, axon loss, astrocytosis, and a continuing inflammatory process, to name but a few. Nevertheless, the limited and relatively focused nature of damage to oligodendrocytes and myelin, at least in early disease, the large body of available knowledge concerning the biology of oligodendrocytes, and the success of experimental myelin repair, have allowed cautious optimism that therapies may be possible. Here, we review the clinical and biological problems presented by multiple sclerosis in the context of cell therapies, and the neuroscientific background to the development of strategies for myelin repair. We attempt to highlight those areas where difficulties have yet to be resolved and draw on a variety of more recent experimental findings to speculate on how remyelinating therapies are likely to develop in the foreseeable future.

Bennetto L, Scolding N. · Institute of Clinical Neurosciences, Department of Neurology, University of Bristol, Frenchay Hospital, Bristol, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #14978147 links to  free full text

This publication has no abstract.

Scolding N. · University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, BS16 1LE, Bristol, UK. · Lancet Neurol. · Pubmed #12941570 No free full text.

This publication has no abstract.

Halfpenny C, Benn T, Scolding N. · Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK. · Lancet Neurol. · Pubmed #12849543 No free full text.

Abstract: A decade ago, therapeutic strategies to remyelinate the CNS in diseases such as multiple sclerosis had much experimental appeal, but translation of laboratory success into clinical treatments appeared to be a long way off. Within the past 12 months, however, the first patients with multiple sclerosis have received intracerebral implants of autologous myelinating cells. Here we review the clinical and biological problems presented by multiple sclerosis disease processes, and the background to the development of myelin-repair strategies. We attempt to highlight those areas where difficulties have yet to be resolved, and draw on various experimental findings to speculate on how remyelinating therapies are likely to develop in the foreseeable future.

Wiles CM, Brown P, Chapel H, Guerrini R, Hughes RA, Martin TD, McCrone P, Newsom-Davis J, Palace J, Rees JH, Rose MR, Scolding N, Webster AD. · Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, London WCIN 3BG, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #11909900 links to  free full text

Abstract: Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Scolding N. · Institute of Clinical Neurosciences, Department of Neurology, University of Bristol, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #11701778 links to  free full text

This publication has no abstract.

Benn T, Halfpenny C, Scolding N. · Department of Neurology, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Bristol, United Kingdom. · Glia. · Pubmed #11596128 No free full text.

Abstract: Oligodendrocytes and Schwann cells are the glia principally responsible for the synthesis and maintenance of myelin. Damage may occur to these cells in a number of conditions, but perhaps the most studied are the idiopathic inflammatory demyelinating diseases, multiple sclerosis in the CNS, and Guillain-Barré syndrome and its variants in the peripheral nervous system (PNS). This article explores the effects on these cells of cytotoxic immunological and inflammatory mediators: similarities are revealed, of which perhaps the most important is the sensitivity of both Schwann cells and oligodendrocytes to many such agents. This area of research is, however, characterised and complicated by numerous and often very substantial inter-observer discrepancies. Marked variability in cell culture techniques, and in assays of cell damage and death, provide artifactual explanations for some of this variability; true inter-species differences also contribute. Not the least important conclusion centres on the limited capacity of in vitro studies to reveal disease mechanisms: cell culture findings merely illustrate possibilities which must then be tested ex vivo using human tissue samples affected by the relevant disease.

Scolding N. · Department of Neurology, Addenbrooke's Hospital, Cambridge, UK. · Philos Trans R Soc Lond B Biol Sci. · Pubmed #10603622 links to  free full text

Abstract: Spontaneous myelin repair in multiple sclerosis (MS) provides a striking example of the brain's inherent capacity for sustained and stable regenerative tissue repair--but also clearly emphasizes the limitations of this capacity; remyelination ultimately fails widely in many patients, and disability and handicap accumulate. The observation of endogenous partial myelin repair has raised the possibility that therapeutic interventions designed to supplement or promote remyelination might have a useful and significant impact both in the short term, in restoring conduction, and in the long term, in safeguarding axons. Therapeutic remyelination interventions must involve manipulations to either the molecular or the cellular environment within lesions; both depend crucially on a detailed understanding of the biology of the repair process and of those glia implicated in spontaneous repair, or capable of contributing to exogenous repair. Here we explore the biology of myelin repair in MS, examining the glia responsible for successful remyelination, oligodendrocytes and Schwann cells, their 'target' cells, neurons and the roles of astrocytes. Options for therapeutic remyelinating strategies are reviewed, including glial cell transplantation and treatment with growth factors or other soluble molecules. Clinical aspects of remyelination therapies are considered--which patients, which lesions, which stage of the disease, and how to monitor an intervention--and the remaining obstacles and hazards to these approaches are discussed.

Mallam E, Scolding N. · University of Bristol Institute of Clinical Neurosciences, Burden Neurological Institute, Frenchay Hospital, Bristol, UK. · Int MS J. · Pubmed #19413922 links to  free full text

Abstract: Diagnosing multiple sclerosis (MS) is not always straightforward. The very nature of this disease means that it can manifest in multiple varied clinical presentations. Diagnosis is further confounded by the lack of a single diagnostic test and a gargantuan list of differential diagnoses. Traditionally the diagnosis of MS is a clinical one: with the history and/or examination revealing the separation in time and space of neurological episodes. In some cases, however, a diagnosis of "possible MS" might have to be made, for example, when the patient presents after a single event. Paraclinical investigations and diagnostic criteria may be of help in these situations. It is recommended that any diagnostic uncertainty is discussed openly with patients.

Snethen H, Love S, Scolding N. · Department of Neurology, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS161LE, UK. · Regen Med. · Pubmed #18947307 No free full text.

Abstract: AIMS: Spontaneous tissue repair occurs in multiple sclerosis (MS), but the origin of remyelinating cells remains obscure. Here we explore the hypothesis that endogenous neural precursors are involved in MS disease processes. MATERIALS & METHODS: We studied postmortem brain and spinal cord samples from MS patients using immunocytochemical techniques. RESULTS: We show that cells co-positive for nestin and musashi-1 are not merely present in lesions, but found in markedly increased numbers (up to fivefold). Small numbers of nestin-positive cells show direct evidence of proliferation, co-staining for Ki67; some also coexpress glial fibrillary acidic protein or oligodendrocyte progenitor markers (NG-2 or PDGF-alpha receptor), or the early neuronal marker doublecortin, consistent with transition from neural precursors. CONCLUSIONS: These findings suggest that endogenous neural precursors react to disease processes in MS.

Gray E, Thomas TL, Betmouni S, Scolding N, Love S. · MS Laboratories, Burden Centre, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS16 1JB, United Kingdom. · Neurosci Lett. · Pubmed #18723077 No free full text.

Abstract: Recent studies have revealed extensive axonal damage in patients with progressive multiple sclerosis (MS). Axonal damage can be caused by a plethora of factors including the release of proteolytic enzymes and cytotoxic oxidants by activated immune cells and glia within the lesion. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we have measured MPO levels in post-mortem homogenates of demyelinated and non-demyelinated regions of white matter from nine patients with MS and seven controls, and assessed MPO immunoreactivity within MS brain. In homogenates of MS white matter, demyelination was associated with significantly elevated MPO activity when compared to controls. Immunohistochemistry showed MPO to be expressed mainly by macrophages within and adjacent to plaques. Demyelination in MS is associated with increased activity of MPO, suggesting that this production of reactive oxygen species may contribute to axonal injury within plaques.

Gray E, Thomas TL, Betmouni S, Scolding N, Love S. · MS Laboratories, Burden Centre, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK. · J Neuropathol Exp Neurol. · Pubmed #18716555 No free full text.

Abstract: Matrix metalloproteinases (MMPs) degrade extracellular matrix; MMP activity, particularly of MMP-9, is elevated in the white matter in multiple sclerosis (MS) patients. The cerebral cortical extracellular matrix includes perineuronal nets (PNs) that surround parvalbumin-positive neurons (PV-positive neurons) and are important for their function. We measured active and total MMP-9 levels in postmortem homogenates of demyelinated and nondemyelinated cerebral cortical regions from 9MS and 7 control cases and assessed Wisteria floribunda agglutin (WFA)-positive PNs in paraffin sections from 15 MS and 6 controls and PV-positive neurons in sections from 26 MS and 6 controls. Active MMP-9 levels were higher in demyelinated than in nondemyelinated or control cortex (p < 0.05). The area fraction positive for WFA was lower in demyelinated than nondemyelinated MS or control cortex; the latter difference was significant (p < 0.05). Most PV-positive neurons in demyelinated but not intact cortex lackeda PN, and some showed perikaryal phosphorylated neurofilament protein accumulation. Loss of WFA-labeled PNs was not associated with reduced PV-positive neurons numbers. Thus, elevated MMP-9 in cortical plaques is associated with loss of PNs; PV-positive neurons are preserved but show abnormal neurofilament accumulations. Matrix metalloproteinase-mediated degradation of PNs in cortical plaques may, therefore, contribute to neuronal dysfunction and degeneration in MS patients.

Hirst C, Ingram G, Pearson O, Pickersgill T, Scolding N, Robertson N. · Helen Durham Neuro-inflammatory Centre, Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, UK. · J Neurol. · Pubmed #18204919 No free full text.

Abstract: The impact of relapses on long-term disability in multiple sclerosis remains unclear; however some evidence suggests that relapses play an important role in determining subsequent prognosis. We report on outcome, prognostic factors for recovery and the contribution of relapses to the accumulation of fixed disability in a large series of patients with documented relapses. Two hundred and seventy-nine relapses in 182 patients were assessed before, during and after relapse by expanded disability status scale and data analysed to assess degree of recovery. Factors affecting outcome were considered including sex, age and site of relapse. Mean EDSS prior to relapse was 3.73, during relapse 5.18 and post relapse 4.23. Mean interval to post relapse assessment was 127 days post relapse. Mean residual change in EDSS score (pre to post relapse) was 0.50 points. Overall 49.4 % of patients had a residual increase in disability post relapse of at least 0.5 EDSS points and 32.7 % had an increase of at least 1 point. No significant difference was observed in mean residual EDSS for sex, site of relapse or age at relapse or in the proportion of patients with a residual increase in disability of > or = 1 EDSS point post relapse. 14.4 % of patients had no increase in EDSS score during relapse compared to pre relapse.These results suggest that acute relapses are commonly associated with an objective worsening of disability in the majority of patients with MS and that recovery is incomplete in approximately half and not influenced by gender, age or site of lesion. Therapies which reduce relapse frequency and/or severity might therefore be expected to slow or prevent worsening of disability if initiated prior to the onset of more permanent damage.

Gray E, Thomas TL, Betmouni S, Scolding N, Love S. · Glial Cell Biology Laboratories, University of Bristol Institute of Clinical Neuroscience, Frenchay Hospital, Bristol, UK. · Brain Pathol. · Pubmed #18042261 No free full text.

Abstract: Recent studies have revealed extensive cortical demyelination in patients with progressive multiple sclerosis (MS). Demyelination in gray matter lesions is associated with activation of microglia. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we examined the extent of microglial activation in the cerebral cortex and the relationship of microglial activation and MPO activity to cortical demyelination. Twenty-one cases of neuropathologically confirmed multiple sclerosis, with 34 cortical lesions, were used to assess microglial activation. HLA-DR immunolabeling of activated microglia was significantly higher in demyelinated MS cortex than control cortex and, within the MS cohort, was significantly greater within cortical lesions than in matched non-demyelinated areas of cortex. In homogenates of MS cortex, cortical demyelination was associated with significantly elevated MPO activity. Immunohistochemistry revealed MPO in CD68-positive microglia within cortical plaques, particularly toward the edge of the plaques, but not in microglia in adjacent non-demyelinated cortex. Cortical demyelination in MS is associated with increased activity of MPO, which is expressed by a CD68-positive subset of activated microglia, suggesting that microglial production of reactive oxygen species is likely to be involved in cortical demyelination.

Scolding N. · Clinical Neurosciences, University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol BS31 1 hS, UK. <> · Lancet Neurol. · Pubmed #15721820 No free full text.

This publication has no abstract.

Christopher V, Scolding N, Przemioslo RT. · No affiliation provided · J Neurol. · Pubmed #15742101 No free full text.

This publication has no abstract.