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  • Inflammation and neurovascular changes in amyotrophic lateral sclerosis

    24 October 2018

    Neuroinflammation in now established as an important factor in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). At various time points, astrocytes and microglia are markedly activated, either producing neuroprotective or pro-inflammatory molecules, which can decrease or increase the rate of primary motor neuron degeneration respectively. Recent research has shown that this neuroinflammatory component is affected by the peripheral immune system; T lymphocytes in particular are able to cross into the brain and spinal cord parenchyma, where they interact with resident microglia, either inducing them to adopt an M1 (cytotoxic) or M2 (protective) phenotype, depending on the stage of disease. Clearly understanding the changes that occur to allow the interaction between peripheral and central immune responses will be essential in any attempt to manipulate the disease process via neuroinflammatory mechanisms. However, our understanding of the endothelial changes, which facilitate the infiltration of peripheral immune cells into the brain and spinal cord, is still in its infancy. There are suggestions, though, of up-regulation of cellular adhesion molecules, which are able to arrest circulating leukocytes and facilitate diapedesis into the brain parenchyma. In addition, tight junction proteins appear to be down-regulated, leading to an increase in vascular permeability, an effect that is amplified by vascular damage late in the disease process. This review summarises our current knowledge regarding neuroinflammation, peripheral immune involvement, and endothelial changes in ALS. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. © 2012.

  • A proposed staging system for amyotrophic lateral sclerosis.

    24 October 2018

    Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2-3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged.

  • Prognostic modelling of therapeutic interventions in amyotrophic lateral sclerosis.

    24 October 2018

    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease with a widely varying prognosis. The majority of patients survive about 3 years, but a significant number survive for 10 years or more, leading to problems in clinical trial design. OBJECTIVE: To demonstrate that simple clinical variables can be used to construct a robust predictive model for survival, and to assess the effect of a known treatment within this model. METHODS: We carried out a retrospective multivariate modelling of a database of 841 patients with ALS seen over a 10-year period in a specialist motor neuron disorders clinic. The use of riluzole was tested as a prognostic factor within the model. RESULTS: A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r(2) = 0.78). Prognostic variables included site of onset, age of onset, time from symptom onset to diagnosis, and El Escorial category at presentation. Riluzole therapy was an independently significant prognostic factor (relative risk of death 0.48, P < 0.0001, model chi(2) 297, P < 0.0001). CONCLUSIONS: Clinical databases can be used to generate multivariate prognostic models in ALS. Such models could be used to predict survival, to improve criteria for matching of patients in future clinical trials, and to test the impact of interventions.

  • Neuroleptic malignant-like syndrome after abrupt withdrawal of baclofen.

    24 October 2018

    We present the case of a 36-year-old man who presented with a clinically neuroleptic malignant-like syndrome involving disorientation, signs of autonomic dysfunction, rigidity and raised total creatine kinase level, but in the absence of any neuroleptic medication. He had, however, abruptly stopped taking his long-term baclofen in the days prior to presentation. He improved markedly after the reintroduction of baclofen, and we postulate that his clinical syndrome resulted from the sudden withdrawal of this drug. We concur with the concept that neuroleptic malignant syndrome represents a spectrum of disorders, and add it to the list of possible sequelae after abrupt withdrawal of baclofen.