Biomedical subjects

D A Compston

Publications and source records attributed to D A Compston.

At least 37 records · Page 2Linked to original sources

PubMed1998

Secondary progressive multiple sclerosis: the relationship between short-term MRI activity and clinical features.

We report the findings in 60 patients with secondary progressive multiple sclerosis who had monthly brain MRI studies for 4 months (one baseline and three follow-up scans). The purpose was to define the short-term MRI natural history in a large cohort with secondary progressive disease and to ascertain its relationship with other clinical and MRI features. The patients were participating in either a natural history study or the placebo arm or non-treatment phase of a therapeutic trial. The cohort had clinical features typical of secondary progressive disease: thus, all had moderate or severe locomotor disabilities [Expanded Disability Status Scale (EDSS), score 3.5-8], with a median disease duration of 12 years. There was equal representation of males and females. During the 3 months of follow-up there was a total of 362 new enhancing lesions seen in 42 patients, and there were 24 relapses in 20 patients. There was no correlation between new enhancing lesions and age at study entry, age of disease onset, gender disease duration or EDSS, but there was a strong correlation with the number of enhancing lesions on the baseline scan (r = 0.65, P < 0.0001) and subsequent activity. There was a non-significant trend for higher numbers of new enhancing lesions in those having relapses during the 3 months of scanning (P = 0.14) or in the preceding 6 months (P = 0.06). The 34 patients who did not relapse in either period had significantly fewer new active lesions (P = 0.02) than those who relapsed at some stage during the 9 months. Nevertheless, considerable activity was seen in the non-relapsing cohorts: there was a mean of 3.5 (median 2) new enhancing lesions in those not relapsing during the 3 month study, and 5.5 (median 2) in those not relapsing in the previous 6 months. We conclude that short-term MRI activity is generally high in secondary progressive disease, confirming a useful role for the technique in exploratory trials. Further work should concentrate on elucidating the mechanisms of secondary progression by longer term follow-up studies of larger cohorts using multiple MRI and clinical measurements.

Adult↗

PubMed1998

Urgent neurology out-patient referrals from primary health care physicians.

We retrospectively analysed patients seen in a rapid referral clinic to identify those with abnormalities genuinely requiring urgent assessment, and to evaluate the impact of the clinic on routine services. After advertising the availability of the service, 25% of telephone referrals from primary-care physicians led to identification of patients considered suitable for urgent evaluation. We assessed 350 patients over an 18-month period. After neurological review, relevant abnormalities were identified in 73%, and 33% were considered to have warranted urgent assessment. In addition, 74% required radiological evaluation and 14% had a neurophysiological procedure; 19.4% were admitted on the same day, 13% underwent CSF analysis and 34% required some form of therapeutic intervention. In retrospect, patients with a clinical history of > 11 days rarely warranted urgent referral. Visual failure and diplopia provided the highest correlation with patients deemed to require urgent assessment, and syncope and headache the lowest. Despite the number of patients reviewed, no effect was demonstrated on waiting times for standard out-patient review.

Adolescent↗

PubMed1998

Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England.

OBJECTIVES: To perform a comprehensive survey of myasthenia gravis in the county of Cambridgeshire, England, establishing contemporary epidemiological data. METHODS: Cases were ascertained from multiple sources. Prevalent patients were visited and assessed by means of a standardised questionnaire and examination complemented by review of medical case notes. RESULTS: One hundred cases were identified in a population of 684000 (prevalence 15 per 100000 population, 95% confidence intervals (95% CIs) 12-18). Thirty eight new diagnoses were made over a five year period providing an incidence of 1.1/100000 population/year. The sex ratio was 2:1 F:M. After a mean follow up of 11.7 years, symptomatic disease was still restricted to ocular muscles in 25 patients. Thirty four of 100 patients underwent thymectomy a mean of 0.8 years after presentation, and a thymoma was present in 12. Highest remission rates were seen in patients presenting with generalised disease who underwent thymectomy but did not have a thymoma (27%). Cosegregation of an additional autoimmune disease occurred in 27 patients and in 24/49 (49%) women with onset<50 years of age. CONCLUSIONS: This, the second highest reported prevalence for myasthenia, is likely to be the result of optimum case ascertainment, increased disease duration, application of complex diagnostic tests, and the impact of an aging population leading to a relative increase in the prevalence of ocular myasthenia.

Adolescent↗

PubMed1998

Disease activity and the immune set in multiple sclerosis: blood markers for immunotherapy.

There is no established immunological marker of multiple sclerosis activity, which reflects the poor understanding of the immunopathogenesis of multiple sclerosis. Passive measurement of the levels of soluble inflammatory markers, whose half lives are usually measured in minutes and hours, can only indicate the extent of instantaneous inflammation, which is known to fluctuate in multiple sclerosis. We favour measurement of immune responses in vitro. As healthy individuals have T cell reactivities to myelin proteins that are postulated to be pathogenic in multiple sclerosis, we prefer non-antigen specific mitogen and recall antigen assays as immunological markers. We illustrate their use in the treatment of 27 patients with multiple sclerosis using a pulse of humanised anti-lymphocyte (CD52) antibody that caused prolonged T cell depletion. The mitogen-induced proliferation, and secretion of IFN-gamma, from peripheral blood mononuclear cells in vitro was significantly reduced after treatment, suggesting that immune responses had been modulated. Such observations will only gain credence as an outcome measure if they are shown to correlate with clinical or radiological measures of multiple sclerosis activity. Perhaps more importantly, aspects of the pathogenesis of multiple sclerosis may be revealed by close immunological surveillance of patients undergoing experimental treatments.

Antibodies, Monoclonal↗

PubMed1998

T1 hypointense lesion load in secondary progressive multiple sclerosis: a comparison of pre versus post contrast loads and of manual versus semi automated threshold techniques for lesion segmentation.

Magnetic resonance imaging (MRI) is increasingly being used as a monitoring tool for disease activity in therapeutic trials in multiple sclerosis. There is, however, only a limited relationship between MRI findings and clinical outcome measurements. It has been suggested that hypointense lesion load on T1 weighted imaging has a better correlation with disability than the more conventional T2 hyper intense lesion load. This study was undertaken to (i) evaluate different measurement techniques used to quantify T1 hypointense lesion load, and (ii) to compare lesion load as measured using different parameters and disability. Twenty-five patients with secondary progressive multiple sclerosis, mean age of 40 years (23-57), mean EDSS 5.7 (4-7) were analysed. T2 lesion load on FSE correlated well with both the hypointense lesion load on T1 pre-gadolinium (r = 0.8, P < 0.0001) and T1 post-gadolinium (r = 0.8, P < 0.0001) but less so with the enhancing lesion load (r = 0.4, P < 0.05). There was a very strong correlation with T1 hypo-intense lesion volume pre and post gadolinium (r = 0.96, P < 0.001). However, the EDSS was not correlated with the T2 lesion load (r = -0.27, P = 0.2), T1 pre-gadolinium load (r = -0.3, P = 0.1), T1 post gadolinium load (r = -0.4, P = 0.7) and enhancing lesion load (r = -0.28, P = 0.2), or with the degree of hypointensity of T1 weighted images determined using the threshold technique. There is a strong correlation between T1 hypointense lesion volume both pre and post gadolinium and also between T1 and T2 lesion volumes.

Adult↗

PubMed1998

Effects of intravenous methylprednisolone on outcome in MRI-based prognostic subgroups in acute optic neuritis.

Treatment of acute optic neuritis with steroids has been shown to hasten visual recovery without affecting the final degree of recovery. However, MRI-clinical studies indicate that patients with long optic nerve lesions, particularly those that involve the nerve within the optic canal, may have a worse prognosis for recovery of vision. Partly because such lesions could lead to swelling and subsequent ischemic optic nerve damage, steroids could have a selective beneficial effect on this subgroup of patients. The present randomized trial was designed to test this possibility. Sixty-six patients with acute optic neuritis received IV saline or IV methylprednisolone. The clinical, psychophysical, electrophysiologic, and MRI outcomes were assessed after 6 months. Patients with short lesions presented earlier than those with long lesions (involving three or more 5-mm-thick slices of any part of the optic nerve, as well as its intracanalicular portion), and lesion length was significantly less in patients presenting within a week of onset of symptoms. Lesions also tended to lengthen during follow-up in individual patients. Treatment did not limit lesion length in either the long or short lesion subgroup and had no significant effect on final visual outcome. We conclude that steroids do not improve visual outcome or lesion length in patients with acute optic neuritis.

Acute Disease↗

PubMed1997

Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis.

BACKGROUND: There has been no previous systematic study of conjugal multiple sclerosis. This study of conjugal pairs with complex traits investigated disease transmissibility and the genetic contribution to frequency and clinical course. METHODS: We studied 45 conjugal pairs concordant for multiple sclerosis from 58 pairs recorded in a national register of familial disease, 86 offspring of the 45 pairs were individually assessed for clinical evidence of neurological disease; those over age 16 underwent cranial magnetic resonance imaging. Clinical features were compared in 33 pairs in whom neither member had symptoms before they met. FINDINGS: Of the 86 offspring, five (6%) had clinically definite multiple sclerosis. A further five children had either characteristic imaging abnormalities or clinical symptoms consistent with demyelination, but did not meet the criteria for clinically definite disease. There was no evidence of clinical concordance, clustering at year of onset, or distortion of the expected pattern of age of onset in the second affected spouse from 33 pairs. The crude recurrence in children of conjugal pairs (1 in 17) is significantly higher than previously reported population-based risk for offspring of single affected parents (1 in 200). INTERPRETATION: Taken with the low prevalence of multiple sclerosis in the spouses of affected individuals, and the lack of concordance for age at onset in these families, the disparity in crude recurrence between children of conjugal pairs and those of single affected parents shows that the recurrence risk in children is determined by genetic factors inherited from both parents.

Adolescent↗

PubMed1997

beta-Interferon regulates the immunomodulatory activity of neonatal rodent microglia.

beta-interferon (beta-IFN) has both pro and anti-inflammatory properties, the balance of which leads to some suppression of disease activity in multiple sclerosis patients. Here, we examine the immunomodulation of neonatal rodent microglia, the principal CNS accessory cell, by beta-IFN and consider the interaction of beta-IFN and gamma-interferon (gamma-IFN). beta-IFN and gamma-IFN inhibit microglial proliferation. beta-IFN antagonises both gamma-IFN-induced upregulation of class II expression and the ability of gamma-IFN primed cells to mount a respiratory burst. In contrast, beta-IFN upregulates microglial Fc receptor expression and augments tumour necrosis factor alpha secretion from suboptimally stimulated microglia.

Adjuvants, Immunologic↗

PubMed1997

The effect of intravenous aminophylline on essential tremor.

AIMS: The effects of intravenous aminophylline (375 mg) or placebo (saline) were studied in 10 patients with benign essential tremor. METHODS: This was a single-blind crossover study. Patients received aminophylline by i.v. infusion over 15 min or saline at least 1 week apart. Tremor was measured by a peizoresistive accelerometer at 15 min intervals predose and up to 2 h. Plasma theophylline concentrations were measured by h.p.l.c. RESULTS: Tremor power was significantly greater following aminophylline (5.67-6.2 Hz) than placebo (5.6-5.9 Hz). CONCLUSIONS: We conclude that intravenous aminophylline potentiates benign essential tremor when given acutely by the intravenous route in the doses required to achieve therapeutic benefits in asthma.

Adolescent↗

PubMed1997

Analysis of the ion channel complement of the rat oligodendrocyte progenitor in a commonly studied in vitro preparation.

We have analysed the ion channel complement of the oligodendrocyte-type 2 astrocyte (O-2A) glial cell progenitor obtained from the commonly studied neonatal rat mixed brain preparation. Ionic currents, in O-2A progenitors identified on both morphological and immunological grounds, were recorded using the whole-cell variant of the patch-clamp technique. The cells had an average resting membrane potential close to -50 mV and fired single action potentials in response to suprathreshold current injections. Using voltage-clamp methods we were able to identify and characterize a voltage-activated TTX-sensitive Na+ current, two classes of voltage-activated outward K+ currents, an inactivating inwardly rectifying K+ current, a voltage-activated Cl- current and at least three classes of Ca2+ current.

Animals↗

PubMed1996

Growth factor stimulation triggers apoptotic cell death in mature oligodendrocytes.

Oligodendrocytes are responsible for myelination of axons within the central nervous system and are lost in the lesions of multiple sclerosis. The question of whether mature oligodendrocytes are capable of division, and hence of giving rise to new myelinating cells, remains controversial. We have studied the response in vitro of rat oligodendrocytes to growth factors. Unlike their progenitors which divided vigorously in response to growth factor stimulation, mature oligodendrocytes showed no mitotic response to a number of individual growth factors. However, when exposed to basic fibroblast growth factor (bFGF), mature oligodendrocytes expressed the immediate response gene c-fos and the cell cycle-associated protein proliferating cell nuclear antigen, but failed to divide and ultimately underwent cell death by apoptosis. These findings are consistent with the emerging view that mitosis and apoptosis are closely linked phenomena.

Animals↗

PubMed1996

Age-adjusted recurrence risks for relatives of patients with multiple sclerosis.

Familial aggregation is a cardinal epidemiological feature of multiple sclerosis, but few investigators have systematically examined recurrence risks for relatives of affected individuals in the United Kingdom. As part of a cross-sectional study of multiple sclerosis in Cambridgeshire, pedigree details were taken on 674 probands. Sex-specific, crude and age-adjusted recurrence risks were assessed amongst relatives of probands, applying a statistical model based on the observed age at onset of affected individuals and providing risks for clinical counselling. Details on year of birth, present age or age at death, and disease status were available on 11 391 relatives of successive probands. Nineteen percent of patients reported an additionally affected relative; 128 non-proband affected relatives were identified and the highest risk was observed for sisters. There was a systematic reduction in relative risk with genetic distance from the proband and no preferential recurrence for maternal or paternal relatives.

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

Multiple sclerosis in south Cambridgeshire: incidence and prevalence based on a district register.

STUDY OBJECTIVE: To establish an updated prevalence and incidence figure for multiple sclerosis on 1 July 1993, to determine the fate of the 374 patients prevalent in 1990, and to establish the origin of incident patients. DESIGN: Case ascertainment was from several sources including departmental records, local branches of the Multiple Sclerosis Society, general practitioners, nursing homes, and residential facilities for the disabled. Data collection was by personal interview using a standardised questionnaire and by retrospective analysis of departmental case notes. A prospective incidence register of newly diagnosed patents was maintained from 1990. SETTING: The Cambridge Health District of East Anglia covering 340,910 hectares in area and a population of 290,700. PATIENTS: Altogether 441 patients prevalent on 1 July 1993 were identified, of whom 328 were contacted so that clinical data could be collected. Seventy patients (16%) either declined to take part or access was denied by their general practitioner; 8 (2%) had died; and 35 (8%) were too ill or failed to respond to several requests for contact. MAIN RESULTS: A comprehensive re-evaluation of the south Cambridgeshire multiple sclerosis register revealed a prevalence of 441/290,700 population (152/10(5)) for all disease classifications on 1 July 1993. This represented an increase of 18% from 1990 and was a result of 138 additions and 71 deletions from the original list of 374 patients. The sex ratio of prevalent patients was 2.6 F:M, the mean age at disease onset was 31.7 years, and the mean age was 49 years. Mortality for 1990-93 was 3.3/10(5)/year and prospective maintenance of an incidence register recorded 96 new diagnoses for all classifications of multiple sclerosis over the five year period 1990-94 (6.6/10(5)/year). CONCLUSIONS: The increase in prevalence mainly resulted from improved case ascertainment identifying a further 58 patients who had been prevalent in 1990. Comparisons with other serial studies within the United Kingdom show similarities in proportional increase with successive studies indicating that serial survey may in part account for the observed latitudinal gradient within the United Kingdom. However, the observed prevalence (152/10(5)) in this second survey still falls short of the figure estimated from incidence and mortality data (186/10(5)).

Adolescent↗

PubMed1996

Clinical concordance in sibling pairs with multiple sclerosis.

As part of a linkage study, we obtained clinical, demographic, and genetic information on 210 families with siblings concordant for multiple sclerosis (MS). Twenty-eight pairs were excluded and information was incomplete in a further 16 pairs; intrafamilial comparisons of the clinical course are reported on the remaining 166 families (155 pairs and 11 trios) in whom complete data sets were available. The demographic characteristics were comparable to those of recently performed prevalence studies in the United Kingdom, supporting the application of results in these families for genetic linkage studies in MS. We observed no significant correlation for age at onset after correction for selection bias but found a minor correlation for year at onset, which we speculate is due to earlier recognition of symptoms in second affected siblings. There was no pair-wise concordance for presenting symptoms or disability at time of assessment. However, there was a strong correlation for disease course and to a lesser degree for gender. In addition, the familial recurrence rate was 33%, almost twice that previously recorded in a local prevalence study. These results suggest that the etiology of MS involves random exposure to an, as yet unidentified, environmental trigger and the clinical features of familial disease are modified by inherited factors. That the risk of developing MS is not spread uniformly among families has important implications for the counseling of individuals with familial disease.

Female↗

PubMed1996

Failure to achieve remyelination of demyelinated rat axons following transplantation of glial cells obtained from the adult human brain.

The ability of transplanted glial cells to myelinate axons in experimental animals offers the prospect that it may be possible to achieve remyelination in human demyelinating disease by the implantation of oligodendrocyte lineage cells. Autologous normal white matter could represent a potential source of cells whose use would avoid tissue rejection and overcome ethical and practical constraints associated with the use of fetal tissue. To determine the remyelinating potential of cells isolated from adult human CNS, a cell preparation prepared from adult human white matter which contained 56% oligodendrocytes, 3% preoligodendrocytes and 1% precursor cells was transplanted into non-repairing demyelinating lesions in immunosuppressed rats created by the injection of ethidium bromide into x-irradiated spinal cord white matter. The extent of remyelination was examined 3 and 5 weeks after transplantation. Although the transplanted oligodendrocytes survived in the area of demyelination, associated with demyelinated axons and produced myelin membranes, no myelin sheaths were produced and there was no evidence of cell migration or division. The failure of human oligodendrocytes to form myelin sheaths may reflect the poor remyelinating potential of post mitotic oligodendrocytes, and the failure of the small number of co-transplanted bipotential oligodendrocyte progenitor cells to differentiate and myelinate axons may be a consequence of lack of appropriate environmental factors within the rat lesion required for expansion and differentiation of these cells.

Adult↗

PubMed1995

A proliferative adult human oligodendrocyte progenitor.

The failure of oligodendrocytes to sustain repair of demyelinated axons contributes to the cumulative neurological disability which characterizes multiple sclerosis. In the rodent, transplanted neonatal glial progenitors efficiently remyelinate gliotoxic lesions. Proliferative bipotential progenitors are also present in the adult rat, but have not hitherto been identified in adult human tissue. Here we demonstrate cells in cultures of adult human temporal lobe which are morphologically and immunocytochemically identical to rate progenitors, are bipotential, and exhibit an astrocyte-driven proliferative response. The identification of an adult human oligodendrocyte progenitor is the first step towards developing interventional strategies for promoting repair of demyelinated lesions in patients with multiple sclerosis.

Astrocytes↗

PubMed1995

Growth factors fail to protect rat oligodendrocytes against humoral injury in vitro.

CNS growth factors protect neurons and glia against a wide variety of insults in vitro and in vivo by mechanisms which include buffering toxic rises in intracellular calcium. Cytosolic calcium elevation also plays a key role in complement injury, but the possibility that growth factors protect against antibody-mediated complement attack has not hitherto been addressed. In multiple sclerosis, antibodies and complement appear to contribute to the selective targeting and damage of oligodendrocytes and myelin. Here we have investigated the possibility that growth factors active in oligodendrocyte development and differentiation might protect these cells against injury mediated by antibody and complement in vitro. None was found to be protective.

Animals↗