Книги з теми "Progressive systemic sclerosi"

Multiple sclerosis is a chronic inflammatory and degenerative disorder of the central nervous system. Measuring disease activity and progression are an integral part of the management of the disorder. A number of different approaches, including clinical measures, imaging metrics, and blood/cerebrospinal fluid biomarkers have been investigated for their utility in monitoring disease activity and progression. Each of these different approaches has certain advantages, as well as limitations, and this chapter provides an overview of these different assessment strategies.

Magnetic resonance imaging (MRI) of the brain and spinal cord plays an integral role in establishing the diagnosis of multiple sclerosis (MS). The use of MRI leads to earlier recognition of MS, allowing for earlier treatment initiation and more efficient monitoring of disease treatment and progress. This chapter outlines conventional MRI imaging sequences that are used to evaluate MS white matter lesions in the central nervous system. It also addresses the incorporation of new imaging techniques that have increased understanding of clinically definite MS, its variants, and how various diseases can mimic traditional MS. Finally, it examines novel imaging protocols that have been implemented in MS research, which have elucidated radiographic and pathophysiologic nuances and involvement of deeper central nervous system structures and tracts that play a role in MS progression.

This chapter focuses on the symptom management of multiple sclerosis, Parkinson’s disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), motor neuron disease, neurological complications of AIDS, Creutzfeldt-Jakob disease (CJD), and useful contacts.

The motor neurone diseases are a group of disorders in which there is selective loss of function of upper and/or lower motor neurones in the motor cortex, brainstem, and spinal cord resulting in impairment in the nervous system control of voluntary movement. The term ‘motor neurone disease’, often abbreviated to ‘MND’, is used differently in different countries. In the United Kingdom it is used as an umbrella term to cover the related group of neurodegenerative disorders including amyotrophic lateral sclerosis, the commonest variant, as well as progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy. However, in many other countries amyotrophic lateral sclerosis, referred to as ALS, has been adopted as the umbrella term for this group of clinical variants of motor system degeneration. There is a tendency now internationally to use the ALS/MND abbreviation to cover this group of conditions. Careful diagnosis within the motor neurone diseases is essential for advising about prognosis, potential genetic implications, and for identifying those with acquired lower motor neurone syndromes who may benefit for the administration of immunomodulatory therapy.

The pathology of multiple sclerosis is complex, extends beyond the white matter plaque, and is influenced by stage of demyelinating activity, clinical course, disease duration, and treatment. Technological advances in immunology, molecular biology, and “omic” biology have provided novel insights into the mechanisms for development of white matter plaques, axonal damage, cortical demyelination, and disease progression. Detailed, systematic, and statistically rigorous pathological studies on clinically well-characterized MS cohorts have helped define the heterogeneous pathological substrates of MS and unravel the complex molecular pathogenic mechanisms, with the ultimate goal of identifying targets for therapeutic interventions. It is increasingly clear that the use of human tissues is imperative to improve current diagnostic, prognostic, and therapeutic modalities. Preclinical animal models have been invaluable for discovery of key immune processes, basic disease mechanisms, and candidate immune targeting strategies, but the conclusions have yet be reconciled with the essential features of the human disease.

The oligodendrocyte–myelin unit subserves saltatory conduction of the nerve impulse in the healthy central nervous system. At one time, many disease processes were thought exclusively to target the structure and function of myelin. Therefore, they were designated ‘demyelinating diseases’. But recent analyses, based mainly on pathological and imaging studies, (re)emphasize that axons are also directly involved in these disorders during both the acute and chronic phases. Another ambiguity is the extent to which these are inflammatory conditions. Here, distinctions should be made between inflammation, as a generic process, and autoimmunity in which rather a specific set of aetiological and mechanistic conditions pertain. And there are differences between disorders that are driven primarily by immune processes and those in which inflammation occurs in response to pre-existing tissue damage.With these provisos, the pathological processes of demyelination and associated axonal dysfunction often account for episodic neurological symptoms and signs referable to white matter tracts of the brain, optic nerves, or spinal cord when these occur in young people. This is the clinical context in which the possibility of ‘demyelinating disease’ is usually considered by physicians and, increasingly, the informed patient. Neurologists will, with appropriate cautions, also be prepared to diagnose demyelinating disease in older patients presenting with progressive symptoms implicating these same pathways even when there is no suggestive past history. Both in its typical and atypical forms multiple sclerosis remains by far the commonest demyelinating disease. But acute disseminated encephalomyelitis, the leucodystrophies, and central pontine myelinolysis also need to be considered in particular circumstances; and multiple sclerosis itself has a differential diagnosis in which the relapsing-remitting course is mimicked by conditions not associated with direct injury to the axon–glial unit. Since our understanding of the cause, pathogenesis and features of demyelinating disease remains incomplete, classification combines aspects of the aetiology, clinical features, pathology, and laboratory components. Whether the designation ‘multiple sclerosis’ encapsulates one or more conditions is now much debated. We anticipate that a major part of future studies in demyelinating disease will be further to resolve this question of disease heterogeneity leading to a new taxonomy based on mechanisms rather than clinical empiricism. But, for now, the variable ages of onset, unpredictable clinical course, protean clinical manifestations, and non-specific laboratory investigations continue to make demyelinating disease one of the more challenging diagnostic areas in clinical neurology.

A 16-year-old girl with a diagnosis of diffuse cutaneous systemic sclerosis is referred to a specialist pulmonary hypertension centre with a history of progressive breathlessness, reduced exercise tolerance, and raised pulmonary pressures on transthoracic echocardiogram. She is found to have pulmonary arterial hypertension on right cardiac catheterization and is started on sildenafil, a phosphodiesterase-5 inhibitor, which stabilizes her condition. An endothelin receptor antagonist is added, which provides some initial symptomatic improvement. She continues to deteriorate over a period of 5 years, ultimately requiring intravenous prostanoids, the only treatment to provide a real symptomatic and haemodynamic improvement. This chapter explores the physiology and pathophysiology of pulmonary arterial hypertension, its classification, the means of investigation and diagnosis, who to refer to specialist centres, and the concepts behind current and future treatment strategies.

This chapter describes the main neuropathological features of the most common age associated neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies as well as other less frequent ones such as multiple system atrophy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, neurofibrillary tangle dominant dementia, frontotemporal lobar degeneration with TDP-43 pathology and Huntington's disease. Likewise cerebral amyloid angiopathy, hippocampal sclerosis, vascular dementia and prion diseases are described. A main aim of this chapter is to assist the reader in interpreting neuropathological reports, hence criteria for the neuropathological classifications of the major diseases are provided. One section covers general considerations on neurodegeneration and basic pathophysiological mechanisms of tau, amyloid-β, α-synuclein, TDP-43 and prions are briefly described in the sections on the respective diseases. Finally, one section is dedicated to cerebral multimorbidity and we give a view on currently emerging neuropathological methods.

Since the start of the international project in 1997, over 1500 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, with overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Multipotent mesenchymal stromal cells (MSC) have been recently tested in various autoimmune diseases, exploiting their immune modulating properties and apparent low acute toxicity. MSC display immune privilege in that the patient requires no immunosuppression prior to allogeneic MSC infusion. Despite encouraging small phase I/II studies, no positive data from randomized prospective studies are as yet available in the peer-reviewed literature.

Since the start of the international project in 1997, over 2000 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, with overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Multipotent mesenchymal stromal cells (MSC) have been recently tested in various autoimmune diseases, exploiting their immune modulating properties and apparent low acute toxicity. MSC display immune privilege in that the patient requires no immunosuppression prior to allogeneic MSC infusion. Despite encouraging many small phase I/II studies, only 2 prospective controlled trials which achieved their primary endpoints have been published.

The urinary system is the primary target of Schistosoma haematobium infection, which leads to granuloma formation in the lower urinary tract that heals with fibrosis and calcification. While the early lesions may be associated with distressing acute or subacute symptoms, it is the late lesions that constitute the main clinical impact of schistosomiasis. The latter include chronic cystitis, ureteric fibrosis, ureterovesical obstruction or reflux which may lead to chronic pyelonephritis. Secondary bacterial infection and bladder cancer are the main secondary sequelae of urinary schistosomiasis.The kidneys are also a secondary target of S. mansoni infection, attributed to the systemic immune response to the parasite. Specific immune complexes are responsible for early, often asymptomatic, possibly reversible, mesangioproliferative lesions which are categorized as ‘class I’. Subsequent classes (II–VI) display different histopathology, more serious clinical disease, and confounding pathogenic factors. Class II lesions are encountered in patients with concomitant salmonellosis; they are typically exudative and associated with acute-onset nephrotic syndrome. Classes III (mesangiocapillary glomerulonephritis) and IV (focal segmental sclerosis) are progressive forms of glomerular disease associated with significant hepatic pathology. They are usually associated with immunoglobulin A deposits which seem to have a significant pathogenic role. Class V (amyloidosis) occurs with long-standing active infection with either S. haematobium or S. mansoni. Class VI is seen in patients with concomitant HCV infection, where the pathology is a mix of schistosomal and cryoglobulinaemic lesions, as well as amyloidosis which seems to be accelerated by the confounded pathogenesis.Early schistosomal lesions, particularly those of the lower urinary tract, respond to antiparasitic treatment. Late urological lesions may need surgery or endoscopic interventions. As a rule, glomerular lesions do not respond to treatment with the exception of class II where dual antiparasitic and antibiotic therapy is usually curative. Patients with end-stage kidney disease may constitute specific, yet not insurmountable technical and logistic problems in dialysis or transplantation. Recurrence after transplantation is rare.