Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study.

BACKGROUND: Beta(2) adrenoreceptor expression on peripheral blood mononuclear cells is increased in progressive multiple sclerosis. This increase has been correlated with disease activity in relapsing-remitting multiple sclerosis. OBJECTIVE: To determine the beta(2) adrenoreceptor expression in primary and secondary progressive multiple sclerosis in relation to findings on magnetic resonance imaging (MRI) and clinical disease activity. METHODS: 10 patients with multiple sclerosis were studied (five with primary progressive and five with secondary progressive forms of the disease) over a period of six months. Monthly clinical and MRI assessments of the brain and spinal cord were carried out. Beta(2) adrenoreceptor expression was assessed monthly using a ligand binding assay with [(125)I]iodocyanopindolol. Expression of beta(2) adrenoceptors on peripheral blood mononuclear cells was also assessed in five normal controls over a similar period. RESULTS: The mean (SEM) value of beta(2) adrenoreceptor density for the five normal controls was 1346 (183) sites/cell, with affinity Kd of 120 (40) pM. MRI disease activity in primary progressive multiple sclerosis was reported on two occasions and on those occasions the expression of beta(2) adrenoreceptors was increased in excess of 1900 sites/cell; in the remaining 28 observations beta(2) adrenoreceptor expression was within the normal range (800 to 1900 sites/cell). In patients with secondary progressive disease, MRI disease activity was observed on 16 occasions. In these patients expression of beta(2) adrenoreceptors was increased in excess of 2000 sites/cell in all measurements except in one subject who did not show MRI activity throughout the six months period of study. The affinity of the receptors was within the normal range in all cases. CONCLUSIONS: Increased expression of beta(2) adrenoreceptors was correlated with MRI disease activity in two patients with primary progressive multiple sclerosis. In secondary progressive multiple sclerosis, increased expression of beta(2) adrenoreceptors tended not to correlate with MRI disease activity. This may reflect a persistent Th1 immune reaction in the secondary progressive form of the disease.

Central defects of autonomic function in secondary progressive multiple sclerosis: observations based on cardiovascular and growth hormone responses to clonidine.

The haemodynamic, autonomic and hormonal effects of the centrally acting sympatholytic drug clonidine have been studied in 10 patients with secondary progressive multiple sclerosis (MS) and 10 age- and sex-matched normal subjects (controls). Detailed physiological studies, previously described in these 10 MS patients, indicated that none had postural hypotension or an abnormal Valsalva manoeuvre; six, however, had impaired responses to a range of pressor tests, suggestive of a central autonomic abnormality. In the controls after clonidine, there was a fall in blood pressure and superior mesenteric artery vascular resistance. Finger temperature and growth hormone levels rose. In the MS patients after clonidine, the haemodynamic responses varied. In five out of ten MS patients, as in the controls, there was a fall in blood pressure and superior mesenteric vascular resistance, while finger temperature rose. There was no haemodynamic response to clonidine in the other five MS patients. In eight out of ten MS patients there was no rise in plasma growth hormone levels after clonidine. The abnormal haemodynamic responses to clonidine, taken in conjunction with the previous physiological studies, suggest involvement of central sympathetic interconnections in five of the MS patients, probably as part of the demyelinating process. The impaired growth hormone response to clonidine occurred in a greater number of patients and may indicate lesions in the hypothalamus. These observations in MS patients, without overt clinical evidence of autonomic failure, indicate that the haemodynamic and growth hormone responses to clonidine may be an early indicator of autonomic dysfunction involving central autonomic centres and pathways.

Physiological assessment of aspects of autonomic function in patients with secondary progressive multiple sclerosis.

A detailed non-invasive study of systemic and regional haemodynamic responses to a range of autonomic tests which assess sympathetic and parasympathetic pathways (mental arithmetic, cutaneous cold, isometric exercise, deep breathing, Valsalva manoeuvre and head-up tilt) were performed in ten patients with secondary progressive multiple sclerosis and ten age- and sex-matched healthy normal subjects (controls). Blood pressure rose in controls during the pressor tests and was maintained during tilt. In six out of ten patients with multiple sclerosis blood pressure was unchanged during one or more of the three pressor tests, but was maintained in all during tilt. In the controls, superior mesenteric artery blood flow fell during pressor tests and head-up tilt. In multiple sclerosis patients, superior mesenteric artery blood flow did not change during pressor tests but fell during tilt. Cardiac index rose during isometric exercise and fell during head-up tilt in controls. Forearm blood flow rose during mental arithmetic in the controls only, but fell during tilt in both groups. Individual analysis indicated that of the ten multiple sclerosis patients, four had responses during the pressor tests similar to controls. Responses to deep breathing and to the Valsalva manoeuvre in controls and multiple sclerosis patients were similar. We conclude that some patients with an aggressive and disabling form of multiple sclerosis have selective autonomic dysfunction, in particular involving pressor responses, despite the lack of postural hypotension. The autonomic abnormality is likely to involve central autonomic interconnections rather than afferent or sympathetic efferent pathways. Further clarification of the nature, site and progression of these lesions is needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone response to clonidine in central and peripheral primary autonomic failure.

Patients with primary autonomic failure may have either pure autonomic failure (PAF) or multiple system atrophy (MSA) in which there is additional neurological involvement. Distinction between PAF and MSA at an early stage is important because a wide range of complications is associated with MSA, which has a poor response to drug therapy and a less favourable prognosis. We have investigated the growth hormone (GH) releasing effects of clonidine in patients with PAF and MSA to see whether this hormonal response could serve as a neuroendocrine marker to distinguish between the groups. Age-matched normal subjects were studied as controls. Both groups of patients had severe postural hypotension due to primary sympathetic failure of presumed central origin in MSA and peripheral origin in PAF. After clonidine, plasma GH concentrations increased in controls and PAF, with no change in MSA. Changes in plasma glucose and insulin concentrations were similar in all groups. Clonidine, therefore, stimulates growth hormone release in PAF but not MSA and may serve as a neuroendocrine marker in differentiating patients with MSA and a central autonomic defect from those with PAF with a peripheral defect.

Differential responses in superior mesenteric artery blood flow may explain the variant pressor responses to clonidine in two groups with sympathetic denervation.

1. Measurement of superior mesenteric artery blood flow along with systemic and regional haemodynamic changes in blood pressure, heart rate, cardiac index, forearm blood flow, digital skin blood flow and index finger temperature were made before and after administration of clonidine (2 micrograms/kg body weight intravenously) in 10 patients with multiple-system atrophy, 10 patients with pure autonomic failure and 15 age-matched healthy control subjects. 2. After clonidine, blood pressure fell in patients with multiple-system atrophy and control subjects but not in patients with pure autonomic failure. 3. Resting superior mesenteric artery blood flow was similar in patients with multiple-system atrophy and control subjects, but was higher in patients with pure autonomic failure. The fall in blood pressure after clonidine was accompanied by active dilatation of the superior mesenteric artery in patients with multiple-system atrophy and control subjects. This did not occur in patients with pure autonomic failure. 4. After clonidine, there was a fall in cardiac index in patients with multiple-system atrophy. 5. After clonidine, changes in other haemodynamic parameters were not significant in any group, except for a fall in forearm blood flow and a rise in index finger temperature in control subjects. 6. We conclude that after clonidine there are differential superior mesenteric artery blood flow responses in the two groups with autonomic failure (multiple-system atrophy and pure autonomic failure). These may relate to differences in the site of the sympathetic lesion, which is considered to be mainly central in multiple-system atrophy but peripheral in pure autonomic failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermal thresholds and motor sensory conduction measurements in Guillain Barré syndrome: 12-month follow-up study.

We performed serial neurophysiological tests in 22 patients with confirmed Guillain Barré syndrome (GBS) for 12 months following onset of the disease. Twenty-five age- and sex-matched healthy controls were also tested. Tests included nerve conduction and automated quantitative thermal threshold measurements. The commonest early abnormality was delayed distal motor latency, F wave abnormality and abnormal thermal threshold measurements in 1 or more nerves. Further abnormalities of all measurements were observed during maximum disability. After 12 months, all measured parameters returned to normal levels in the majority of patients except the thermal thresholds which remained abnormal in a large proportion of asymptomatic patients. The findings are suggestive of an early pathological involvement of the smaller nerve fibres with slow recovery in GBS.

Study of EEGs following 24-hour sleep deprivation in patients with posttraumatic epilepsy.

Routine and awake EEGs following 24-hour sleep deprivation were studied in 119 patients with closed head injury, 64 epileptics without any history of head injury and 53 healthy controls. The results were compared to CT brain scan findings. There were no epileptic discharges in routine EEGs, while EEGs after 24-hour sleep deprivation showed considerable activation, ranging from 28 to 37.5% in those with a history of head injury or epilepsy. No correlation was found between the period elapsed between the time of injury and the activation of the EEG. Most of the patients with EEG activation after sleep deprivation had abnormal CT scans. EEGs following 24-hour sleep deprivation therefore appear to be a useful adjunct to other methods used in detecting brain damage in patients with head injury or epilepsy.