Pharmacoeconomics and motor neuron disease.
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Costs and Cost Analysis↗
Biomedical subjects
M Swash
Publications and source records attributed to M Swash.
Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations.
We describe 3 new families affected by Alzheimer's disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large "cotton wool" plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin-1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Abeta42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid-beta concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimer's disease and have implications for the pathogenesis of the disease in general.
Alzheimer Disease↗
Shortening the time to diagnosis in ALS: the role of electrodiagnostic studies.
The early diagnosis of ALS has become an issue in management of the disease with the introduction of a therapy. As more effective treatment becomes available early diagnosis will become increasingly important. Electromyography (EMG) has potential value in this area, but will need to be applied not only with conventional methods but also quantitatively in order to refine the accuracy of diagnosis itself, and to evaluate progression. If a treatment is effective then progression will not occur and one of the major cornerstones of current diagnosis will disappear. For early diagnosis much will depend on appropriate recognition of the possibility of amyotrophic lateral sclerosis by primary care physicians, and other specialists. A semi-quantitative evaluation, utilizing clinical and EMG assessments, would help in this appraisal.
Algorithms↗
The skin in ALS.
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Amyotrophic Lateral Sclerosis↗
Nature and nurture in ALS.
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Amyotrophic Lateral Sclerosis↗
What is primary lateral sclerosis?
Primary lateral sclerosis (PLS) is a rare degenerative disorder of the upper motor neuron. Its nosological status and relationship to other motor neuron syndromes, especially amyotrophic lateral sclerosis (ALS), is uncertain. Diagnostic criteria have been proposed. We discuss the history of this rare clinical disorder, its relationship to the motor neuron disease syndrome, and reports of overlapping clinico-pathological conditions. Two patients with the clinical syndrome of PLS are described to illustrate current understanding of the clinical, laboratory, and neurophysiological features.
Diagnosis, Differential↗
Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research.
BACKGROUND: In 1994 consensus guidelines were developed for conducting clinical trials in ALS. With growing experience in clinical trials, it has become clear that a number of further guidelines were needed. METHODS: Under the auspices of the World Federation of Neurology Committee on Research, a multinational group of neurologists, statisticians, patient advocates, representatives from the pharmaceutical industry as well as regulatory agencies developed consensus about a number of revisions to the existing guidelines during a 2 day conference in April 1998. RESULTS: Expanded areas of focus include greater protection of patient rights, more detailed guidelines for outcome measures statistical analyses, disclosure of study results and improved interaction between investigators and the corporate sector. COMMENT: Substantial progress has been made in standardizing and improving the quality of clinical trials in ALS through these consensus guidelines.
Amyotrophic Lateral Sclerosis↗
I.v. immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barré syndrome.
BACKGROUND: Treatment with human i.v. immunoglobulin (IVIg) modifies the course of Guillain-Barré syndrome (GBS), but its specific mode of action is unknown. Cellular interactions mediated through the release of cytokines play a role in the pathogenesis of GBS and may be regulated by IVIg therapy. OBJECTIVE: To delineate possible immunoregulatory mechanisms of IVIg in patients with GBS. METHODS: Circulating levels of the proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, were assayed in 21 patients with GBS before and serially after IVIg therapy. Comparisons were made with serum concentration of the anti-inflammatory cytokines, soluble TNF-alpha receptor and IL-10. Serial measurements were also performed in 12 untreated patients with relatively mild disease and 7 patients treated by plasma exchange. RESULTS: Circulating levels of TNF-alpha and IL-1beta decreased after treatment with IVIg but remained relatively high in untreated patients and in those treated by plasma exchange. Clinical improvement in patients treated with IVIg was associated with a reduction in unbound TNF-alpha during the acute phase of the illness. Circulating levels of anti-inflammatory cytokines were not affected by IVIg treatment. CONCLUSION: Data presented here suggest a novel mechanism of action of IVIg that involves selective modulation of circulating proinflammatory cytokines.
Adult↗
Paraneoplastic painful ulnar neuropathy.
A 58-year-old woman developed painful, bilateral ulnar neuropathy in conjunction with small cell lung carcinoma and high serum titer of anti-Hu antibody. An incidental stage I plasma cell dyscrasia, with immunoglobulin G kappa monoclonal protein, was also present. Electropysiological assessment excluded a generalized neuropathy, and nerve biopsy showed marked loss of myelinated and small unmyelinated fibers, without inflammatory changes or amyloid deposition. High titers of circulating anti-Hu antibody can be associated with symptoms resembling a paraneoplastic mononeuropathy.
Antibodies↗
Development and validation of a short measure of health status for individuals with amyotrophic lateral sclerosis/motor neurone disease: the ALSAQ-40.
In recent years there has been an increased appreciation of the importance of measuring health status from the patient's point of view, but until now no attempt has been made to develop an amyotrophic lateral sclerosis (ALS)-specific health status measure. The development of such an instrument is especially relevant now with the introduction of drugs that prolong life in ALS but limited data is available on the impact such treatments have on quality of life. This paper reports on the development of an ALS-specific measure, the forty item ALS assessment questionnaire (ALSAQ-40). The development of the ALSAQ-40 followed three main stages. Stage 1 consisted of in-depth, semi-structured exploratory interviews conducted on a sample of 18 patients to identify areas of salience and concern to patients with ALS. These interviews generated 78 candidate questions. In stage 2, the 78-item questionnaire was used in a postal survey to identify appropriate rephrasing/shortening and to determine the acceptability of the measure. In addition, this exercise helped identify sub-scales of the instrument addressing different dimensions of ALS. Finally in stage 3 the data collected in stage 2 was analysed to areas measured by the instrument and to remove redundant questions. The resulting measure contains forty questions measuring five areas of health status: Eating and Drinking, Communication, ADL/independence, Physical mobility, Emotional Functioning. The measure has high face, internal and construct validity and is likely to prove a useful measure in the evaluation of treatment regimes for ALS/MND.
Activities of Daily Living↗
IgM paraproteinemia in a patient with primary lateral sclerosis.
Primary lateral sclerosis is an uncommon, distinct clinical entity. We report a patient with primary lateral sclerosis in whom investigations revealed an IgM monoclonal gammopathy, raised CSF protein and persistently high ESR. A number of reports suggest that lymphoproliferative disorders, paraproteinemia and clinico-pathological syndromes mimicking motor neuron diseases may be associated. We discuss the clinical features noted in our patient in relation to these reports, and the possible pathogenetic mechanisms.
Aged↗
Hugh Cairns, Dorothy Russell and the first pleomorphic xanthoastrocytoma?
The 40-year survival of a patient with an unusual astrocytoma, excised in 1930, has been re-evaluated by study of the original microfilmed records, histological slides and paraffin-wax embedded tissue blocks. The operation and neuropathological examination were carried out by Mr Hugh Cairns and Dr Dorothy Russell, in the very early days of neurosurgery. Review of the original tissue specimen with immunocytochemistry has revealed that the tumour was a pleomorphic xanthoastrocytoma, the earliest recorded example.
Astrocytoma↗
Evidence for the validity and reliability of the ALS assessment questionnaire: the ALSAQ-40.
OBJECTIVES: The purpose of the study was to assess the validity and reliability of a new disease specific measure of health-related quality of life for ALS/MND: the 40-item ALS Assessment Questionnaire (ALSAQ-40). DESIGN: We carried out a longitudinal postal survey. The two administrations of the questionnaire were separated by 3 months. SAMPLE: Subjects were patients diagnosed with ALS/MND and registered with the UK MND Association. RESULTS: Dimensions of the ALSAQ-40 were shown to have high levels of internal reliability. The ALSAQ-40 was found to be sensitive to changes in self reported overall health state. CONCLUSION: We concluded that the ALSAQ-40 has high levels of reliability and validity and can be used as an outcome measure in studies evaluating new treatment regimes and therapies.
Amyotrophic Lateral Sclerosis↗
Dopaminergic therapy in acute encephalitis lethargica.
We describe a patient with an acute illness, with clinical features characteristic of encephalitis lethargica, who responded repeatedly to trials of an apomorphine infusion and subsequently to oral levodopa therapy. This observation implies a direct acute neurotropic effect of the encephalitis on nigral dopaminergic cells. Dopaminergic medication may therefore be helpful in the acute stage of encephalitis lethargica as well as in the delayed post-encephalitic parkinsonian phase of the syndrome.
Acute Disease↗
Extrapyramidal involvement in amyotrophic lateral sclerosis: backward falls and retropulsion.
Three patients with sporadic amyotrophic lateral sclerosis (ALS) presented with a history of backward falls. Impaired postural reflexes and retropulsion accompanied clinical features of ALS. Hypokinesia, decreased arm swing, and a positive glabellar tap were noted in two of these three patients. Cognitive impairment, tremor, axial rigidity, sphincter dysfunction, nuchal dystonia, dysautonomia, and oculomotor dysfunction were absent. Brain MRI disclosed bilateral T2 weighted hyperintensities in the internal capsule and globus pallidus in one patient. Necropsy studies performed late in the course of ALS have shown degeneration in extrapyramidal sites-for example, the globus pallidus, thalamus, and substantia nigra. Clinically, backward falls and retropulsion may occur early in ALS. This may reflect extrapyramidal involvement.
Aged↗
An algorithm for ALS diagnosis and management.
The diagnosis of ALS is often delayed, probably largely because the disease is relatively uncommon. A practical approach to diagnosis, with a simple algorithm for investigation, might improve diagnostic sensitivity in the early stages of the disease. It is clear that the first step in the diagnostic algorithm must be referral to a neurologist, which implies recognition by the primary care physician that the illness is neurologic in origin. It is the role of the neurologist to make the diagnosis, to confirm it beyond all reasonable doubt, to exclude other treatable conditions, and to inform the patient and the family of the diagnosis in a timely, honest, and compassionate way. Definition of different disease stages allows a model of the process of care to be formulated and indicates the time points at which intervention may be possible. There are two pathways to diagnosis of ALS, which overlap to a considerable extent. Diagnosis by positive criteria is limited by the absence of a specific diagnostic test, whereas diagnosis by exclusion of other disorders may introduce delay that can be tempered only by efficiency in the investigative pathway. The imperative necessity for diagnostic review is perhaps the most important aspect of the diagnosis of ALS, in view of the increasing recognition of the need for early diagnosis, and when an effective therapy becomes available, this process of review will become more important, albeit more difficult.
Algorithms↗
Dropped-head and bent-spine syndromes; axial myopathies?
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Biopsy↗
Fasciculation potentials: a study of amyotrophic lateral sclerosis and other neurogenic disorders.
We studied fasciculation potentials in amyotrophic lateral sclerosis (ALS), and in other neurogenic disorders, in strength and single-fiber electromyography-matched muscles. Benign fasciculations were studied in 3 normal subjects. Fasciculations were more stable and easier to recruit voluntarily in the early phase of ALS; later, fasciculations were more unstable, more complex, and less likely to be voluntarily recruited. Stable fasciculations, representing part of large, reinnervated motor units, and probably arising from distal axonal sprouts, usually had a higher firing rate than more complex and unstable fasciculations. In weak muscles in ALS, fasciculations were generally more unstable than in other neurogenic disorders. In normal-strength muscles fasciculations are less complex in ALS than in other disorders. Benign fasciculations have a high firing rate and normal morphologic parameters. In ALS fasciculations arise proximally early in the disease and distally in the later stages. Fasciculation may be important in excitotoxic cell death in ALS.
Adult↗