Biomedical subjects
Publications and source records attributed to A J Thompson.
The increased awareness of the impact and complexity of management of symptoms in multiple sclerosis has resulted in advances in the understanding of their mechanisms, and in improvements in their measurement and management. It has also highlighted the paucity of evidence-based practice in this area and the need to develop agreed and comprehensive management strategies.
OBJECTIVES: Serial brain MRI is widely used in pilot studies of new agents to monitor treatment efficacy in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS). For pilot trials, sample size calculations for the RR subgroup are based on the data from small numbers of patients and separate calculations for the SP subgroup have not been performed. The present study considers these issues. METHODS: The sample size calculations were based on data from six months of monthly T2 weighted and gadolinium enhanced MRI in 31 RR and 28 SP untreated patients undergoing natural history studies or in the placebo arm of a therapeutic trial. The calculations were for a placebo controlled, parallel groups design lasting six months. The sample sizes were based on bootstrap analysis with an 80% likelihood of showing a given treatment effect. RESULTS: With a single pretreatment scan, demonstration of a 70% reduction in newly active lesions required 2x30 RR and 2x50 SP patients. With an extra run-in scan one month before treatment, the sample sizes were 2x20 for RR and 2x30 for SP patients. CONCLUSIONS: The sample sizes required for RR patients were comparable with previous smaller studies. Larger sample sizes were needed for the SP group, but the extra run in scan resulted in a reduction in both groups. The larger sample sizes in the SPMS group were probably due to the combination of a higher proportion of patients with low MRI activity (< or =2 active MRI lesions in 50% of SP and 32% RR patients), as well as a few patients who displayed extremely high activity, thus increasing interpatient variability. These data should be considered in planning pilot MRI outcome trials.
OBJECTIVES: To assess whether multiple sclerosis lesion volume measurements derived using the fast fluid attenuated inversion recovery (fFLAIR) sequence show better reproducibility or correlation with disability than those derived using the conventional spin echo (CSE) sequence. METHODS: Part I: twenty five patients with multiple sclerosis were scanned with CSE, fast spin echo (FSE), and fFLAIR. Lesion volume was determined twice for each sequence using a local threshold segmentation technique. Part II: fifty six patients with multiple sclerosis were scanned with CSE and fFLAIR. Total and regional brain lesion volumes were compared with the Kurtzke extended disability scale (EDSS) and functional systems scores (FSS). RESULTS: Part I: analysis times were significantly longer for CSE than for FSE or fFLAIR. There was no significant difference in the reproducibility of the three sequences. Part II: total lesion volumes were similar but posterior fossa lesion volumes were significantly greater for CSE and subcortical lesion volumes significantly greater for fFLAIR. There was a significant correlation between total volume and EDSS with both sequences (CSE r=0.49; fFLAIR r=0.44). Correlations for the two sequences showed minor differences when anatomical region and FSS were considered separately. CONCLUSIONS: CSE, FSE, and fFLAIR are equally reproducible; FSE yields lower volumes than CSE; fFLAIR gives similar volumes to CSE but underscores the posterior fossa. Overall clinical correlations are similar for CSE and fFLAIR.
OBJECTIVES: Conventional T2 weighted MRI studies have highlighted the fact that the presence of clinically silent brain lesions increases the risk of developing clinically definite multiple sclerosis after an isolated syndrome of the optic nerve, brain stem, or spinal cord. The objectives of the present study are: (1) to show whether or not these patients also have asymptomatic abnormalities of the spinal cord, and (2) to recruit a new cohort of such patients using high resolution MRI of both brain and spinal cord. METHODS: The brain was imaged in the axial plane with 3 mm thick contiguous slices using a proton density and T2 weighted fast spin echo (FSE) sequence; a T1 weighted sequence after the injection of gadolinium-DTPA; and a fast fluid attenuated inversion recovery (fFLAIR) sequence. The spinal cord was imaged in the sagittal plane with 3 mm thick slices using a T2 weighted FSE and a T1 weighted gadolinium enhanced sequence. RESULTS: Thirty three patients, mean age 31 (16-46) were recruited. There were 14 men and 19 women. Brain MRI was abnormal in 22 (67%); no patient was seen with abnormalities on only one or other sequence. Six patients (18%) displayed one or more gadolinium enhancing lesions on brain MRI. In the spinal cord, nine (27%) patients displayed one or more clinically silent lesions on FSE. Two patients showed one and two gadolinium enhancing lesions in the spinal cord respectively. CONCLUSION: This high incidence of spinal cord lesions emphasises that asymptomatic demyelinating lesions may also involve clinically eloquent pathways. Follow up studies are required to determine their prognostic importance.
OBJECTIVES: To examine cognitive and neurological changes and their relation to brain pathology in patients with multiple sclerosis during acute relapse. METHODS: Thirteen patients with multiple sclerosis were examined with a battery of neuropsychological tests during acute relapse and six weeks later. Their performance was compared with the performance of 10 controls matched for age and premorbid IQ. Gadolinium (Gd) enhanced MRI was also performed in patients on both occasions. RESULTS: The patients with multiple sclerosis performed significantly worse than controls on most tests of attention and memory during acute relapse and in remission. At follow up there was a significant or trend of improvement in performance on some tests of attention for patients in whom the Gd enhanced lesion load had decreased. In this subgroup of patients, their improvement also correlated significantly with the reduction in acute lesion load. CONCLUSIONS: The findings suggest that certain neuropsychological deficits detected during an acute relapse may be reversible, particularly in patients who initially have mild cognitive impairment.
OBJECTIVES: Recovery from focal motor pathway lesions may be associated with a functional reorganisation of cortical motor areas. Previous studies of the relation between structural brain damage and the functional consequences have employed MRI and CT, which provide limited structural information. The recent development of diffusion tensor imaging (DTI) now provides quantitative measures of fibre tract integrity and orientation. The objective was to use DTI and functional MRI (fMRI) to determine the mechanisms underlying the excellent recovery found after a penetrating injury to the right capsular region. METHODS: DTI and fMRI were performed on the patient described; DTI was performed on five normal controls. RESULTS: The injury resulted in a left hemiplegia which resolved fully over several weeks. When studied 18 months later there was no pyramidal weakness, a mild hemidystonia, and sensory disturbance. fMRI activation maps showed contralateral primary and supplementary motor cortex activation during tapping of each hand; smaller ipsilateral primary motor areas were activated by the recovered hand only. DTI disclosed preserved structural integrity and orientation in the posterior capsular limb by contrast with the disrupted structure in the anterior limb on the injured side. CONCLUSIONS: The findings suggest that the main recovery mechanism was a preservation of the integrity and orientation of pyramidal tract fibres. The fMRI studies do not suggest substantial reorganisation of the motor cortex, although ipsilateral pathways may have contributed to the recovery. The initial deficit was probably due to reversible local factors including oedema and mass effect; permanent damage to fibre tracts in the anterior capsular limb may account for the persistent sensory deficit. This study shows for the first time the potential value of combining fMRI and DTI together to investigate mechanisms of recovery and persistent deficit in an individual patient.
To substantiate differences in magnetic resonance (MR) patterns in clinical subgroups of multiple sclerosis (MS), we analyzed T2-weighted MR images of a large regional population of MS patients (n = 188). The patients had already been classified according to recent consensus definitions regarding the clinical course of MS into relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP). Significant (p < 0.01; Spearman test) differences were present between RR and SP patients regarding total lesion load, size and location of lesions. RR and PP patients showed similar MR patterns. PP and SP patients differed in total lesion load, small and medium-sized lesions. The degree of atrophy was highest for SP patients. The clinical progression rate [Expanded Disability Status Scale (EDSS)/disease duration] was similar for various subgroups; the MR progression rate (total lesion score/disease duration) was significantly larger for SP than for PP patients. The lesions load disability quotient (total lesion load/EDSS) differed between RR and PP patients and also between SP and PP patients. In SP patients, the total lesion load correlated significantly (Spearman rank correlation coefficient of 0.52) with EDSS. We conclude that PP patients differ in MR abnormalities from SP patients, that PP and RR patients have similar MR abnormalities and that RR and SP patients are at a different end of the same spectrum of the disease. As the dynamics and clinical impact of MS lesions are different in the various clinical subgroups, they should be considered separately in clinical trials.
The rehabilitation of progressive neurological disorders, such as Multiple Sclerosis (MS) requires comprehensive, expert management which is demanding of both time and resources. Mechanisms to monitor and audit both process and outcome are therefore essential. Integrated care pathways (ICPs) which detail the expected interventions during a given episode of clinical care, provide such a mechanism. In this study three cohorts of patients (totalling 125 episodes) with clinically definite progressive MS underwent a rehabilitation programme audited through ICPs. The cohorts were similar in relation to disability and age. Variations (departures from the expected pathway) were documented for both the rehabilitation process and goal achievement. Duration of stay reduced from 28 days for the first cohort to 18 days for the third and there was greater multidisciplinary input and carer involvement over time. Goal achievement increased from 79% for the first cohort to 87% for the third and there was an increased emphasis on cognitive function and fatigue management in relation to goals set. ICPs provide an excellent mechanism for closing the audit loop and have the potential to play an important role in improving service provision in MS.
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CRH and POMC-derived peptides are produced at a number of intrauterine sites in both the nonpregnant and pregnant states. It is hypothesized that CRH and POMC-derived peptides may be produced locally by the uterus to modulate myometrial contractility. This study has examined the distribution of these peptides in human uterine tissue during the ovulatory cycle and pregnancy. The immunoperoxidase staining method was used to localize CRH and POMC-derived peptides: ACTH, beta-endorphin, and alphaMSH. Immunoreactive (IR-) CRH and IR-POMC-derived peptides, beta-endorphin and alphaMSH, were observed in the myometrial smooth muscle, vascular smooth muscle, endometrial glandular epithelium, and luminal epithelium of the nonpregnant uterus (n = 17). Staining for IR-CRH did not change during the cycle from the proliferative (n = 8) to the secretory phases (n = 9). Conversely, staining for IR-beta-endorphin and IR-alphaMSH was only observed during the secretory phase of the cycle (n = 9). In uterine tissue obtained from pregnant women (n = 20) IR-CRH was present in the myometrial smooth muscle, vascular smooth muscle, decidua, and glandular epithelium. IR-POMC-derived peptides were not detectable at any uterine site during pregnancy (n = 20). IR-CRH was measurable in myometrial extracts collected from pregnant women undergoing cesarean section (20.9+/-3.8 ng/g wet wt; n = 7) and from nonpregnant premenopausal women undergoing hysterectomy (7.7+/-2.1 ng/g wet wt; n = 6). IR-CRH concentrations significantly increased with pregnancy. Levels of messenger ribonucleic acid encoding for CRH were examined in nonpregnant (n = 4) and pregnant (n = 10) myometrial smooth muscle and were also significantly increased with pregnancy. This study has demonstrated that levels of CRH and POMC peptide in human uterine tissue change with pregnancy and that CRH is produced locally by myometrial smooth muscle cells. These studies are consistent with the possibility that the CRH peptide has an autocrine/paracrine activity during pregnancy and labor that may be related to the modulation of myometrial contractility.
OBJECTIVE: To assess whether it is possible to measure changes in cord cross-sectional area during a 1-year period in patients with MS reliably. BACKGROUND: Involvement of the spinal cord in MS is extremely common and an important element in the development of disability. Although little relation has been shown between the cord lesion load and disability, a strong correlation between spinal cord atrophy and the expanded disability status scale (EDSS) has been demonstrated in cross-sectional studies. METHOD: A highly reproducible semiautomated technique that measures the cross-sectional area of the cord at the C2 level was applied to 13 healthy control subjects and 28 patients serially. RESULTS: This study confirms that patients have significantly smaller cords than control subjects at baseline (control subjects: mean 80.95 mm2, patients: mean 71.25 mm2, p = 0.01) and demonstrates that patients have a significant loss in cord cross-sectional area during 12 months, which was not seen in control subjects (p < 0.001). This reduction in cord size was most marked in the primary progressive patients who had a mean cord cross-sectional area loss of 3.52 mm2 (5.2%) and least in the secondary progressive (-0.26 mm2, 0.7%) and benign patients (-0.41 mm2, 0.8%). The baseline cord cross-sectional area correlated strongly with the EDSS (r = -0.52, p = 0.005) and with disease duration (r = -0.75, p < 0.001); however, there was no significant difference in cord area (p = 0.69) or change in cord area (p = 0.51) between those patients with a definite increase in EDSS and those without. CONCLUSION: This study demonstrates, for the first time, that it is possible to measure changes in cord cross-sectional area over time. The serial measurement of spinal cord atrophy may thus make an important contribution to the evaluation of therapeutic efficacy, especially in primary progressive disease.
Multiple sclerosis (MS) is the commonest neurological cause of disability in young adults. The clinical course is extremely variable, but typically a relapsing-remitting phase of variable duration is followed by a gradual progression in disability. However, the diagnosis of MS may have an impact that reaches beyond the physical disabilities into many other aspects of life, including career and family. The time of diagnosis is one of the most important in the course of the illness and the way in which investigations are conducted, the timing and manner of imparting the diagnosis, and subsequent support and education may have far-reaching consequences. The diagnostic phase thus presents a difficult management challenge for the neurologist and other health workers attempting to address these issues. This review considers the steps involved in reaching the diagnosis, together with ways in which the overall quality of life of the patient may be maximized during this period.
Management of the patient with multiple sclerosis (MS) encompasses a number of distinct, if overlapping, areas. They include anticipation and prevention of problems, symptom control, drug therapies aimed at reducing disease activity and finally, rehabilitation and service delivery. The recent advent of new immunosuppressant treatments for MS is extremely exciting. Beta-interferons (1a and 1b) are now licensed worldwide and glatiramer acetate (Copaxane) is in use in the United States. Many more drugs, including intravenous immunoglobulin, mitoxantrone, methotrexate and cladribine, are undergoing trials and some are showing promising results. Future therapies with monoclonal antibodies and adhesion molecules are also undergoing extensive research. Realistically, however, these new treatments aimed at reducing disease activity will have little impact on existing problems or the degree of disability. Consequently, much of the management of a patient with MS relates to control of the vast array of symptoms. These range from the obvious problems of weakness and spasticity, ataxia and sphincter disturbance, to less common but still important problems such as visual, cognitive, swallowing and respiratory difficulties. Some of the most common, and to the patient most disabling, symptoms are fatigue, thermal sensitivity and pain, areas often neglected by the physician in the face of more obvious physical needs. Much can be done for the patient in all areas. A combination of education, physiotherapy and drug therapy is usually required but occasionally there is a place for more invasive treatments such as intrathecal baclofen administration for severe spasticity or thalamic surgery for cerebellar tremor. A multidisciplinary team approach is essential in the overall management of the patient with MS, particularly when assessing their needs as a basis for both inpatient rehabilitation programs and in the provision of a comprehensive community-based service.
One of the primary aims of rehabilitation for patients with multiple sclerosis (MS) is to reduce their levels of disability and handicap, yet little systematic research into the outcomes of this intervention has been undertaken. This stratified, randomized, wait-list controlled study evaluated the effectiveness of a short period of multidisciplinary inpatient rehabilitation in people with MS. Sixty-six patients in the progressive phase of the disease were assessed at 0 and 6 weeks with validated measures of impairment (Expanded Disability Status Scale and Functional Systems), disability (Functional Independence Measure), and handicap (London Handicap Scale). Both groups were comparable in terms of age, sex, disease duration and severity, disability, and handicap. At the end of 6 weeks, although the level of impairment in both groups remained the same, those who participated in a short period of inpatient rehabilitation (average of 25 days) significantly improved their level of disability and handicap compared with those in the wait-list control group. Despite unchanging impairment, inpatient rehabilitation resulted in reduced disability and handicap in patients with progressive MS.
MRI readily detects the lesions of multiple sclerosis (MS) in the brain and spinal cord. Conventional MRI sequences do not, however, permit distinction between the various pathological characteristics (oedema, demyelination, axonal loss and gliosis) of lesions in MS. Magnetisation transfer (MT) imaging may be more specific in distinguishing the pathologies responsible for disability in MS, namely demyelination and axonal loss, and therefore may have a potential role in monitoring treatment. We have applied MT imaging to the cervical spinal cord to see if it is feasible to measure MT ratios (MTR) in this region where pathological changes may result in considerable disability. We studied 12 patients with MS and 12 age- and sex-matched normal controls using a sagittal T2-weighted fast spin-echo sequence with and without an MT pulse. The median value for cervical cord mean MTR measurement in normal controls was 19.30% units (interquartile range 19.05-19.55), whereas values were significantly lower in MS patients (median = 17.95% units, interquartile range 17.25-19.00, P = 0.0004). There was a low intrarater variability for repeated mean MTR measurements. We conclude that it is possible to measure MTR in the cervical spinal cord, that a significant reduction occurs in patients with MS, and that there may be a role for this measure in future MS treatment trials.
Serial magnetic resonance imaging (MRI) detects substantial subclinical disease activity in multiple sclerosis (MS) and is presently included in most treatment trials as an objective outcome measure. Our current knowledge of the role of MRI in MS treatment trials is derived from very limited patient studies, and the aim of this paper is to identify strategies to optimize the use of MRI in monitoring disease activity in treatment trials. The number of active lesions revealed by MRI can be used as the primary outcome measure in exploratory treatment trials. With monthly scanning, the majority of active lesions will be seen by virtue of a limited number of new areas of gadolinium enhancement. The contrast between enhancing lesions and background could be increased by: (1) using higher doses of gadolinium, (2) suppressing the background signal with magnetization transfer, (3) delayed scanning, or (4) a combination of these. Following a systematic comparison of those approaches, the effect on the sensitivity in detecting active lesions should be analysed with reference to the power of treatment trials. We present preliminary results showing marked agreement between observers in reporting enhancing lesions; however, with new acquisition strategies, the observer variation should be re-established in a multicentre fashion. In definitive trials, the increase in total lesion load serves as a secondary outcome measure. Since the majority of lesions making up the total lesion load are inactive during the study, spatial resolution should be maximized in order to preclude any artificial changes in lesion load to be superimposed (noise) upon the relatively small actual change (information). Reduction in measurement error can be attempted by improved acquisition techniques with increased lesion to background contrast. More importantly, improvement in quantitation techniques is warranted. With a 6% coefficient of variation in measuring a baseline lesion load, we calculate the standard error of the mean yearly increase in T2 lesion load (typically 10% in untreated patients) in a treatment arm of 124 patients to be 7.5%. A comparison of several quantitation techniques should be performed in a multicentre longitudinal fashion in order to include variation caused by both scanner and segmentation technique, in addition to biological activity.
Recent reports have suggested that fluid attenuated inversion recovery (FLAIR) is a technique superior to conventional (CSE) or fast spin echo (FSE) T2-weighted sequences in detecting intrinsic lesions both in the brain and spinal cord. We report our experience of an inversion recovery prepared FSE, which we refer to as fast FLAIR, in a comparative study of ten patients with clinically definite multiple sclerosis (MS) who underwent cervical cord and brain imaging with both FSE and fast FLAIR. The results showed that in the cerebral hemispheres fast FLAIR detected more lesions than FSE (P < 0.001). However, FSE detected more lesions than fast FLAIR in the posterior fossa (P = 0.02) and in the cord fast FLAIR was much inferior detecting only 2 of 33 lesions seen on FSE. Estimating the T2 relaxation times of lesions in each of three areas (periventricular, posterior fossa, cervical cord) showed that the T2 value of posterior fossa and cervical cord lesions was significantly lower than that of periventricular lesions, suggesting that the lesion composition is different and consequently their imaging appearances are different. In conclusion, although fast FLAIR improves the detection of MS lesions in the cerebral hemispheres, its substantially lower sensitivity in the posterior fossa and spinal cord is a potentially important limitation to its use as a tool for the diagnosis of MS and for monitoring therapies. Further studies are needed to elucidate the mechanisms underlying the loss of sensitivity.
The characteristics of transverse magnetisation decay of 120 longstanding lesions and 40 regions of normal-appearing white matter have been analysed in 40 patients with multiple sclerosis (MS) and 10 normal controls. Fifty lesions showed a biexponential decay in which two water compartments-one probably intracellular, the other extracellular-could be defined. There was a higher frequency of biexponential lesions in patients with a primary progressive course but no significant difference between benign and secondary progressive groups. Seventy lesions showed a monoexponential decay, of which 31 showed a T2 of greater than 200 ms, implying that these lesions were predominantly composed of extracellular rather than intracellular water. The results imply that an expanded extracellular space within chronic MS brain lesions is a common finding at all levels of disability and disease course. In so far as an expanded extracellular space implies axonal loss, the results suggest that the latter occurs commonly in longstanding MS lesions. The lack of correlation with disability suggests a limited role for the technique in therapeutic monitoring.