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PubMed2002

Impaired coordination between grip force and load force in amyotrophic lateral sclerosis: a case-control study.

Moving a grasped object involves predictive grip force adjustments for fluctuations in inertial load force. The anticipatory grip force adjustment to movement-induced load fluctuations suggests that motion planning is based on an internal model of both the limb dynamics and the physical object properties. In the present study we analysed grip force control in a patient with amyotrophic lateral sclerosis and in three healthy sex- and age-matched control subjects. Amyotrophic lateral sclerosis is a progressive degenerative disorder of motor neurons in the spinal cord, brainstem and motor cortex. All participants performed discrete vertical arm movements with an instrumented hand-held object. In between the discrete up and down movements the object was held stationary. The patient produced a significantly greater ratio between maximum grip and load forces and a greater grip force to hold the object stationary than the control subjects. When performing downward directed arm movements, the control subjects anticipated an early decrease of load force by constant or decreasing grip forces. The patient showed an early increase of grip force during both upward and downward movements. We conclude that amyotrophic lateral sclerosis impairs the ability to adjust the grip force magnitude relative to the actual loading requirements in an economical way. In addition, there may be a particular problem in adjusting the temporal grip force profile relative to the movement-induced load force profile. Thus, in amyotrophic lateral sclerosis an undifferentiated grip force increase is produced when grasped objects are accelerated, irrespective of actual loading conditions and this force increase may override the precise motor output from an internal forward model.

Acceleration↗
PubMed2006

Monozygotic twins discordant for primary lateral sclerosis.

The genetics of the motor neuron diseases are becoming increasingly important. The relationship of primary lateral sclerosis and amyotrophic lateral sclerosis remains debated. Here a pair of monozygotic twins discordant for primary lateral sclerosis is presented. This monozygotic twin pair suggests that environmental factors were most relevant to this subject's development of primary lateral sclerosis. Their life history suggests very similar social and professional exposures without any apparent distinctions.

Adult↗
PubMed2004

Conservative management of pulmonary lymphangioleiomyomatosis and tuberous sclerosis complicated by renal angiomyolipomas in pregnancy.

Both pulmonary lymphangioleiomyomatosis and tuberous sclerosis are rare diseases. The optimal management in pregnancy is unclear. A primigravida with pulmonary lymphangioleiomyomatosis and tuberous sclerosis complicated by worsening renal function secondary to angiomyolipomas was managed conservatively. Favorable maternal and neonatal outcomes were achieved. Pulmonary lymphangioleiomyomatosis is a consideration in tuberous sclerosis patients with respiratory symptoms. Tuberous sclerosis patients with pulmonary lymphangioleiomyomatosis require cautious and calculated expectant management in an effort to avoid adverse outcomes.

Adult↗
PubMed2006

Learning of a novel visuo-postural co-ordination task in adults with multiple sclerosis.

OBJECTIVE: A behavioural study was conducted to investigate how cerebellar dysfunction associated with multiple sclerosis affects the ability to learn a novel visuo-postural co-ordination task. DESIGN: A prospective design, 2 group by 1 treatment (4 practice blocks). SUBJECTS: Ten patients with multiple sclerosis diagnosed with cerebellar ataxia and 10 age-matched healthy controls. METHODS: Participants stood over a dual force platform (ERBE Balance System) and performed visually guided lateral weight-shifting movements. The task required subjects to gradually transfer weight between sides while maintaining each foot's force vector within visually specified force constraints ranging from 0% to 100% of bodyweight with maximum allowed variation set to +/-20%. The time required to complete the task and the number of spatial errors (noted each time the foot's vector exceeded the +/-20% force constraint) were recorded. Training consisted of 3 blocks of 5 trials separated by 1-minute intervals and followed by 5 retention trials. RESULTS AND CONCLUSION: Statistics revealed a significant decrease in movement time and spatial errors across trial blocks in both groups; however, the group with multiple sclerosis showed a limited and slower rate of performance improvement characterized by increased within- and between-subject variability. These findings may have important implications in the design of rehabilitation protocols for improving motor skill performance in adults with multiple sclerosis.

Adult↗
PubMed2006

Physical functioning in multiple sclerosis: a population-based study in central Finland.

OBJECTIVE: To describe multiple sclerosis and its impact on individuals' perceived problems in functioning, particularly in the domains of self-care, mobility and domestic life. DESIGN: A population-based study in a prevalence cohort of multiple sclerosis subjects in Central Finland region carried out in the year 2000. SUBJECTS: A total of 240 subjects with multiple sclerosis. METHODS: A postal questionnaire for assessing physical functioning was developed. RESULTS: Ninety percent of the study population completed the study. Subjects' average age was 48.2 years (range 20-76 years) and time since symptom onset was 15.8 years (range 0-56 years). Of the subjects, 82% were fully independent in self-care activities and 53% in domestic life, 50% were able to walk without any perceived problems and 38% had a permanent need for a walking aid. Fatigue was the most frequent complaint having an impact on subjects' daily life. Ninety-five subjects out of 240 (40%) were engaged in working life. CONCLUSION: These data give a clear indication of favourable functioning in mobility, self-care and domestic life. However, the fact remains that multiple sclerosis is a disabling and costly disease. These results provide information for use by local and national authorities in planning and co-ordinating rehabilitation interventions and social services.

Activities of Daily Living↗
PubMed2002

Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene.

Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate modifier gene in FALS with mutations in the SOD-1 gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model.

Adult↗
PubMed1976

The significance of focal glomerular sclerosis in children who have nephrotic syndrome.

This study was undertaken to learn the significance of focal glomerular sclerosis in children who have nephrotic syndrome. Tissue obtained by percutaneous renal biopsy 10-15 years previously was re-examined. Initially, two of the 29 biopsy specimens contained focal segmental hyalinosis or sclerosis and five of the 29 had focal glomerular obsolescence. The paraffin blocks were serially sectioned and examined. Following this procedure, seven of the 29 biopsies had focal segmented hyalinosis and 16 of the 29 had focal glomerular obsolescence. The percentages of focal segmental hyalinosis and focal glomerular obsolescence were recorded. Only those patients whose focal segmental hyalinosis exceeded 2% progressed to renal failure. Age-matched autopsy material from patients dying without renal dysfunction was used as a control. Focal glomerular sclerosis was seen in 75.8% of the control specimens, although few glomeruli within each specimen were involved. Focal glomerular sclerosis may be found normally; it may be found in nephrotic children who do not develop renal failure. The quantification of sclerotic lesions may be of prognostic significance in childhood nephrosis.

Age Factors↗
PubMed1982

Immunonephelometric quantitation of central nervous system IgG daily synthesis in multiple sclerosis. Clinical evaluation using predictive value theory.

With a laser nephelometric immunoassay and an empirical formula for the quantitation of central nervous system (CNS) daily IgG synthesis, we studied prospectively a population of 101 individuals divided into four groups: 31 normals, 25 patients with definite multiple sclerosis (DMS), 18 patients with probable or possible multiple sclerosis (PMS), and 27 patients with neurologic disease other than multiple sclerosis (NMS). By the Kruskal-Wallis, test the results of the DMS and PMS patients were significantly different from the normals and NMS patients (P less than 0.0003). Considering normals, DMS, and NMS patients only, the sensitivity of the test was 96%, the specificity was 98%, the positive predictive value was 96%, the negative predictive value was 98%, and the efficiency was 98%. Based on our study data, we applied the predictive value theory to different hypothetical populations (our Neurology Ward, Northeastern U. S., and patients with optic neuritis and chronic progressive myelopathy). In all these situations, the test gave a diagnostic efficiency for multiple sclerosis greater than 95%.

Adult↗
PubMed1984

Increase of S-100 immunoreactivity in the urinary bladder from patients with multiple sclerosis, an indication of peripheral neuronal lesion.

The Schwann cells in urinary bladder biopsies from multiple sclerosis patients and controls were examined by immunocytochemistry with an antiserum to S-100. S-100 immunoreactivity was found to be markedly increased in these tissues as compared with the controls, indicating a Schwann cell hyperplasia in the urinary bladder in multiple sclerosis. This finding suggests that local neuronal damage exists in the urinary bladder of patients with multiple sclerosis. Therefore, the concept of multiple sclerosis as a disease wholly of the central nervous system should be reexamined.

Animals↗
PubMed1994

Automatic and controlled information processing in multiple sclerosis.

The purpose of this study was to evaluate the kind of slowing of information processing associated with multiple sclerosis and how this possible slowness is related to cognitive deterioration. We selected 45 patients with definitive multiple sclerosis diagnosis and 35 control subjects. Twenty-two patients had mild cognitive deterioration and 23 patients had preserved cognitive capacities, otherwise the groups were matched. Using computerized tests, we investigated three separate stages of information processing: automatic and controlled processing, and motor programming. The results indicate that patients with mild cognitive deterioration are slower than patients with preserved capacities or controls in every stage of processing measured in this study. Additionally, the preserved patients showed signs of mild slowing in automatic visual processing. These results show that, in multiple sclerosis patients, widespread information processing slowness is associated with multiple sclerosis-related cognitive deterioration. This study emphasizes the importance of studying subgroups rather than cognitively heterogeneous patient samples and, furthermore, the need to divide information processing into different stages is indicated.

Adult↗
PubMed1994

Multiple sclerosis lesions of the auditory pons are not silent.

To understand the relationship between brainstem lesions and auditory neurology in patients with multiple sclerosis, we compared behavioural, electrophysiological and imaging data in 38 patients with probable or definite multiple sclerosis and normal or near normal hearing. Behavioural measures included (i) general hearing tests (audiogram, speech discrimination) and (ii) hearing tests likely to be critically dependent upon brainstem processing (masking level difference, interaural time and level discrimination). Brainstem auditory evoked potentials provided the electrophysiological data. Multiplanar high-resolution MRI of the brainstem provided the anatomical data. Interaural time discrimination for high-frequency sounds was by far the most sensitive of all tests with abnormalities in 71% of all subjects. Whenever any other test was abnormal this test was always abnormal. Interaural time discrimination for low-frequency sounds and evoked potentials were closely related and next most sensitive with abnormalities in approximately 40% of all subjects. Interaural level discrimination and masking level difference were least sensitive with abnormalities in < 10% of subjects. Speech discrimination scores correlated significantly with the masking level differences, as well as with interaural time discrimination for high-frequency sounds. Pontine lesions were found in five of the 16 patients, in whom an objective method for detecting magnetic resonance lesions could be applied. All four with lesions involving the pontine auditory pathway had marked abnormalities in interaural time discrimination and evoked potentials. None of the other 12 had evoked potentials abnormalities. We conclude that neurological tests requiring precise neural timing can reveal behavioural deficits for multiple sclerosis lesions of the auditory pons that are otherwise 'silent'. Of all neurological systems the auditory system at the level of the pons is probably the most sensitive to multiple sclerosis lesions, because of its exceptional dependence upon neural timing in the microsecond range and the lack of redundancy in the encoding of high-frequency sounds. Precise neural timing may be critical for some aspects of speech processing.

Adult↗
PubMed1996

Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI.

Although MRI detects the white matter lesions of multiple sclerosis within the brain with high sensitivity, a minority of patients have normal brain MRI. We describe 20 patients, selected from over 170 who had undergone brain imaging with minimal (n = 12) or no (n = 8) abnormalities (median number of lesions = I, range, 0-3) but in whom spinal MRI was abnormal. Twelve had clinically definite or laboratory supported definite multiple sclerosis according to the Poser criteria; one had clinically probable disease and seven, not fulfilling the Poser criteria, were classified as possible multiple sclerosis. All had presented with symptoms and signs referable to the spinal cord or optic nerves. Eleven had a primary progressive course, eight relapsing-remitting and only one secondary progressive. Moderate or severe disability was the rule in the primary progressive cases; all the relapsing-remitting patients had minimal disability. All had at least one lesion visible in the spinal cord (median 2; range 1-6). In patients in whom the diagnosis of multiple sclerosis is not supported by abnormalities on brain MRI, imaging of the spinal cord can be of considerable value.

Adult↗
PubMed1996

Cerebral benzodiazepine receptors in hippocampal sclerosis. An objective in vivo analysis.

We objectively delineated the extent of abnormalities in central benzodiazepine receptor (cBZR) binding using [11C]flumazenil (FMZ)-PET and high resolution volumetric MRI in 12 patients with mesial temporal lobe epilepsy (mTLE) associated with unilateral hippocampal sclerosis, who underwent presurgical evaluation and subsequent temporal lobe surgery. We compared parametric 3D-images of regional cerebral [11C]FMZ volume of distribution (Vd) obtained from individuals and groups of patients with [11C]FMZ-Vd from a group of 17 healthy controls using statistical parametric mapping (SPM). The [12C]FMZ-Vd was significantly reduced (P < 0.001) in the affected hippocampus in the group of 12 patients with unilateral hippocampal sclerosis. Analysis of individual patients reflected the group finding and there was no significant abnormality of cBZR binding outside the hippocampus in any patient. We conclude that SPM is an useful objective method for detecting changes in regional cerebral [11C]FMZ binding and that in patients with mTLE and unilateral hippocampal sclerosis reduction of cBZR binding is restricted to the area of hippocampal sclerosis with no abnormalities being detected in the temporal neocortex or elsewhere in the neocortex.

Adult↗
PubMed1996

Progressive cerebral atrophy in multiple sclerosis. A serial MRI study.

Recent studies of the spinal cord and cerebellum have highlighted the importance of atrophy in the development of neurological impairment in multiple sclerosis. We have therefore developed a technique to quantify the volume of another area commonly involved pathologically in multiple sclerosis: the cerebral white matter. The technique we describe extracts the brain from the skull on four contiguous 5 mm periventricular slices using an algorithm integrated in an image analysis package, and quantifies their volume. Intra-observer scan-rescan reproducibility was 0.56%. We have applied this technique serially to 29 patients with multiple sclerosis selected for an 18-month treatment trial with a monoclonal antibody against CD4+ lymphocytes (deemed clinically ineffective). A decrease in volume beyond the 95% confidence limits for measurement variation was seen in 16 patients by the end of the 18-month period. The rate of development of atrophy was significantly higher in those who had a sustained deterioration in their Kurtzke expanded disability status scale (EDSS) score compared with those who did not (respective means: -6.4 ml year-1 and -1.8 ml year-1, P < 0.05) but in both groups these changes differed significantly from baseline (P < 0.05). Baseline T2 lesion load, change in T2 lesion load over 18 months and the volume of new gadolinium enhancing lesions on monthly scans for the first 10 months showed no correlation with the development of atrophy. This study demonstrates that progressive cerebral atrophy can be detected in individual patients with multiple sclerosis, correlates with worsening disability and gives additional information to that obtained with conventional MRI. The effect of putative therapies aimed at preventing disability could be objectively assessed by this measure.

Adult↗
PubMed1997

An electrophysiological study of the mechanism of fatigue in multiple sclerosis.

Fatigue is a common and disabling symptom in multiple sclerosis but is poorly understood. We investigated 'physiological' fatigue in 21 patients with multiple sclerosis who complained of disabling fatigue by measuring the decline in strength during a 45 s maximal contraction of the adductor pollicis muscle. The results were compared with those from a control group of 19 healthy subjects. The strength of control subjects declined by approximately 20% during the contraction; twitch interpolation showed central drive remained almost maximal throughout, and therefore that the fatigue was peripheral in origin. Patients had normal baseline strength, but developed greater fatigue (approximately 45%), which was central in origin. In both cases, the decline in strength followed a roughly linear time course suggesting that the patients, like the normals, were trying to maintain a maximum voluntary effort. Evidence for frequency-dependent conduction block (FDCB) in the patients' central motor pathways was sought by measuring the EMG responses to single and paired transcranial magnetic stimuli. Fatigue had no effect on the latency or size of EMG responses to transcranial magnetic stimulation, suggesting that FDCB was unlikely to have occurred. This was supported by measurements of the maximum speed of voluntary muscle contraction; although the patients showed relatively slow speeds before exercise, the decline in speed after fatigue was no greater than in normal subjects. We conclude that excessive 'physiological' fatigue contributes to the symptom of fatigue in multiple sclerosis and is central in origin. However, since the degree of exercise-induced fatigue did not correlate with the baseline complaint of fatigue, other factors must also be operating to produce the full range of clinical symptoms. We found no conclusive evidence that central fatigue is related to increased dysfunction in the primary central motor pathways and no evidence that FDCB is the pathophysiological mechanism. We postulate that central fatigue in multiple sclerosis is due to impaired drive to the primary motor cortex and several lines of evidence strongly suggest that this is not due to a lack of motivation.

Adult↗
PubMed1997

Multiple sclerosis: comparison of the human T-cell response to S100 beta and myelin basic protein reveals parallels to rat experimental autoimmune panencephalitis.

The adoptive transfer of autoreactive S100 beta-specific T cells induces experimental autoimmune panencephalomyelitis and uveoretinitis in the Lewis rat, mimicking the distribution of lesions seen in a subset of patients with multiple sclerosis. We studied the frequency and functional properties of the human T-cell response to S100 beta in eight patients (two relapsing-remitting multiple sclerosis, one chronic-progressive multiple sclerosis, two with multiple sclerosis and uveitis, two neuromyelitis optica, one panuveitis) and in seven healthy individuals, using bovine S100 beta for T-cell stimulation. Both in patients and controls, the frequency of S100 beta-specific T-cell responses was half of that obtained for myelin basic protein (MBP), and only 10% of that obtained using purified protein derivative (PPD). The stimulation indices obtained in response to S100 beta were also less than half those obtained with either MBP or PPD. However, four long-term S100 beta-specific T-cell lines were established and studied in more detail. The four T-cell lines all exhibited a CD4+, CD8-, T-cell receptor alpha beta + surface phenotype and secreted tumour necrosis factor-alpha, interferon-gamma, interleukin-10 and interleukin-4 upon antigenic stimulation, but they were heterogenous with respect to T-cell receptor usage; two T-cell lines expressed V beta 2, one V beta 6.7 and one V beta 13. Antigen-specificity was confirmed using bovine S100 beta beta and alpha beta-isoforms, as well as a recombinant rat S100 beta preparation. The response to S100 beta was shown to the HLA-(human leukocyte antigen-) DR-restricted for two of the S100 beta-specific T-cell lines. Human S100 beta-specific T-cell lines were cytotoxic, although to a lesser extent than MBP-specific T-cell lines derived from the same donors. The phenotypic and functional properties of human S100 beta-specific T-cell lines raise the possibility that these T cells are pathogenic, as they are in the rat. The low frequency and proliferative index of S100 beta-specific, as opposed to MBP-specific T-cell responses suggests that the T-cell response to this widely expressed calcium-binding protein is under more efficient regulatory control.

Adult↗
PubMed1998

Imaging axonal damage of normal-appearing white matter in multiple sclerosis.

The current study was designed to determine the relative distribution of decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions and normal-appearing white matter of patients with established multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA:Cr) in those compartments and changes in disability. Data were collected from a 30-month longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/remitting) (11 patients) or a course of progressively increasing disability, following a period of relapsing/remitting disease (secondary progressive) (17 patients). Proton magnetic resonance spectroscopic imaging (MRSI) and conventional MRI examinations were performed at 6-8-month intervals with concurrent clinical assessments of disability. General linear models were used to test associations between MRSI, MRI, lesion volume and clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than in the normal-appearing white matter (-15.3% in relapsing/remitting multiple sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower NAA:Cr ratio per unit lesion volume previously observed for secondary progressive relative to relapsing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any differences within lesions. The importance of changes in the normal-appearing white matter was emphasized further with the observation that the NAA:Cr ratio in the normal-appearing white matter accounted for most of the observed 15.6% (P < 0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients over the period of study. The decrease in the NAA:Cr ratio in normal-appearing white matter correlated strongly (P < 0.001) with changes in disability in the relapsing/remitting subgroup. These results add to data suggesting that axonal damage or loss may be responsible for functional impairments in multiple sclerosis. The accumulation of secondary axonal damage in the normal-appearing white matter may be of particular significance for understanding chronic disability in this disease.

Aspartic Acid↗
PubMed1998

The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen.

Genetic susceptibility to multiple sclerosis is implicated on the basis of classical family studies and phenotype analyses. The only reproducible legacy from the candidate gene approach has been the discovery of population associations with alleles of the major histocompatibility complex. Systematic genome scanning has since been applied using a panel of anonymous markers to identify areas of linkage in co-affected siblings. Here, we describe the principles of genome screening and update the UK survey of multiple sclerosis. This identified 20 regions of potential interest, but in none was there unequivocal linkage. In theory, attempting to replicate these findings in a second set of sibling pair families is the most appropriate way to distinguish true from false positives, but unfortunately the number of families required to do this reliably is prohibitively large. We used three approaches to increase the definition achieved by the screen: (i) the number of sibling pairs typed in an identified region of potential linkage was extended; (ii) the information extraction was increased in an identified region; and (iii) a search was made for missed regions of potential linkage. Each of these approaches has considerable limitations. A chromosome-by-chromosome account is given to direct future searches. Although an additional marker placed distal to the 'hit' on chromosome 14q increased linkage in this area, and typing extra sibling pairs increased linkage on chromosomes 6p and 17q, evidence for linkage was more commonly reduced and no additional regions of interest were found. A further refinement of the genome screen was undertaken by conditioning for the presence of HLA-DR15. This produced a surprising degree of segregation among the regions of interest, which divided into two distinct groups depending on DR15 sharing: the DR15-sharing cohort comprised loci on chromosomal areas 1p, 17q and X; and the DR15-non-sharing cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlights the genetic complexity of multiple sclerosis. What can now be inferred is that a gene of major effect is excluded from 95% of the genome and one with a moderate role from 65%, whereas genes which make a very small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on independent or epistatic effects of several genes each with small individual effects, rather than a very few genes of major biological importance.

Genetic Linkage↗