Intravenous valproate aborts glyceryl trinitrate-induced migraine attacks: a clinical and quantitative EEG study.

We evaluated EEG changes and pain relief in migraineurs with glyceryl trinitrate (GTN)-induced attacks treated with intravenous sodium valproate (iSVP). EEG frequency analysis was performed in 45 migraineurs without aura and in 19 controls at baseline, at the time of maximum GTN-induced headache, and 30 min after 300 mg iSVP. Nineteen migraineurs presented early specific headache (migraine identical to spontaneous attacks; MSp) and 26 presented early non-specific headache (MnSp). During attacks in MSp there was an increase of theta [16.6% (14.8-19.3) to 19.4% (17.4-22.1), P = 0.02] and delta activity [3.6% (3.1-4.4) to 5.4% (3.9-6.5), P = 0.009], whereas there was no decrease in alpha [41.4% (36.2-45.1) to 39.7% (34.7-44.8)] or beta activity [37.6% (34.7-40.3) to 35.1% (33.5-38.8)]. iSVP reduced migraine from severe/moderate to mild/no pain in 17 (90%) MSp patients, and was associated with reversion of the slow rhythmic activity to baseline levels [theta 16.9% (14.6-18.9); delta 3.2% (3-4.1)]. There was no change in EEG frequency activity after administration of GTN or iSVP in controls and in MnSp. iSVP is well tolerated and effective in treating GTN-induced migraine in migraineurs without aura, and appears to restore the disturbances of cortical electrogenesis associated with these attacks.

Spectral filters can improve reading and visual search in patients with multiple sclerosis.

We investigated the possible benefit for 26 patients with multiple sclerosis of placing Intuitive Overlays (spectral filters) over the page during reading and visual search. Initially all patients were allowed to select an overlay of a colour that reduced perceptual distortion and were tested with and without that overlay. With the coloured overlay, 25/26 patients reported fewer symptoms of visual stress, 50% read at least 20% more quickly and 50% omitted at least 57% fewer targets during visual search. Subsequently, under double-masked conditions 13 randomly-selected patients were given grey overlays,while the remaining 13 gender- and agematched patients were each given an overlay of their individually selected colour. Patients were permitted to use their overlays as and when they wished during the next 2 weeks. The reading and visual search performance of those patients who had received a grey overlay did not change,whereas the performance of those who received an overlay of their selected colour subsequently improved, both when using the overlays and also when not. After testing, the 13 patients who had received a grey overlay returned it prior to subsequent testing. The 13 patients were then each given an overlay of their selected colour and their performance subsequently improved.A large proportion of patients with multiple sclerosis may benefit from the use of spectral overlays.

Gastric emptying after semi-solid food in multiple system atrophy and Parkinson disease.

BACKGROUND: Gastrointestinal symptoms such as nausea, abdominal pain, and bloating are frequent complaints in patients with Parkinson disease (PD) and in patients with multiple system atrophy (MSA), and may be associated with delayed gastric emptying (GE). Although several GE studies in patients with PD have been performed, scant data exist in patients with MSA. METHODS: We assessed GE half-times (T50) in 12 patients with MSA and compared them with those of 12 patients with PD and 12 age-matched healthy controls.GE was estimated scintigraphically using the left anterior oblique method after ingestion of a (99m)Tc colloid-labeled balanced semi-solid meal (yogurt). GE data were obtained every 15 minutes until there was complete emptying of the stomach. Blood pressure, heart rate, plasma glucose and glucosylated hemoglobin were regularly determined. RESULTS: Reproducibility of the GE technique was excellent (Bland-Altman analysis, limits of agreement: -2.3 to 2.8). T50 was longer in MSA (82+/-3.4 min) and in PD (90.6+/-3.9 min) patients compared with controls (46.2+/-0.7) (two-way ANOVA, p<0.0001). T50 did not differ between patients with MSA and those with PD. No correlation existed between T50 and age, duration of the disease, magnitude of postprandial hypotension, levels of plasma glucose and glucosylated hemoglobin (Kendall's tau, p>0.05). CONCLUSIONS: Our results suggest that patients with MSA have GE rates similar to those of patients with PD, but slower than healthy age matched individuals. It remains to be investigated whether gastrointestinal dysfunction in MSA is related to both brain and peripheral pathology, as is presumed for PD.

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.

Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interferon-beta therapy.

Treatment with interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The recently identified family of inhibitor of apoptosis (IAP) proteins is a potent regulator of cell death. The expression of IAP-1, IAP-2, and X-linked IAP (XIAP) is upregulated in mitogen stimulated T lymphocytes from MS patients, and this expression correlates with MS disease activity. In this study, we sought to evaluate the effect of interferon-beta on cellular expression of IAP proteins and other apoptosis regulatory molecules. In a prospective study, we evaluated the expression of IAP proteins, the anti-apoptosis Bcl-2 protein, and the death receptor Fas in in vitro stimulated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on cellular expression of these proteins and T lymphocyte apoptosis in a cross-sectional study of MS patients receiving drug therapy for a mean of 4.8 years. Treatment with interferon-beta reduced the expression of IAP-1, IAP-2 and XIAP in stimulated T lymphocytes. This reduced expression correlated with increased T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of Bcl-2 protein or the death receptor Fas. This downregulatory effect of interferon-beta on cellular expression of IAP proteins was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through an anti-apoptosis mechanism that involves the downregulation of cellular IAP proteins expression.

Interferon-beta therapy downregulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis.

Interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that may involve augmentation of programmed cell death (apoptosis) of T lymphocytes. The anti-apoptosis protein FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein) has been recently identified as a potent regulator of T lymphocyte susceptibility to apoptosis. In a prospective study, we evaluated the expression of FLIP and other apoptosis regulatory proteins in ex vivo activated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on T cell apoptosis in a cross-sectional study of MS patients receiving chronic drug therapy. Treatment with interferon-beta reduced the expression of FLIP isoforms in activated T lymphocytes. This reduced expression correlated with augmented T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of the anti-apoptotic protein Bcl-2. This downregulatory effect of interferon-beta on cellular FLIP expression was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through a pro-apoptosis mechanism that involves the downregulation of cellular FLIP expression.

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.

High beta-adrenoceptor density on peripheral blood mononuclear cells in progressive multiple sclerosis: a manifestation of autonomic dysfunction?

In multiple sclerosis (MS) up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMCs) has been attributed to either autonomic dysfunction, inflammation or a combination of the two. We have compared secondary progressive MS patients with normal subjects (NS) and two models of autonomic dysfunction; pure autonomic failure (PAF) and multiple system atrophy (MSA, Shy-Drager syndrome). There was up-regulation of beta-adrenoceptors on PBMCs in MS and PAF patients but not in MSA patients. Only in PAF patients beta-adrenoceptor up-regulation was correlated with low plasma levels of noradrenaline (NA) and adrenaline (Ad). In addition to studies in the basal state, measurements also were made after the centrally acting sympatholytic agent clonidine. These were combined with haemodynamic and neurohormonal measurements. After clonidine, there was a fall in blood pressure in NS and MSA patients but not in MS and PAF patients; a rise in growth hormone (GH) in NS and PAF patients but not in MS and MSA patients; and an up-regulation in PBMCs beta-adrenoceptors in NS but not in MS, MSA and PAF patients. Up-regulation of beta-adrenoceptors on PBMCs in MS could be attributed to autonomic dysfunction but the disparity between MS and PAF patients when considering their plasma levels of NA and Ad argue against. Although the neurohormonal responses to clonidine and the physiological assessment of autonomic function in progressive MS patients, demonstrate central autonomic dysfunction resembling that of the MSA patients, the normal basal beta-adrenoceptor densities in the latter, suggests that the up-regulation of these receptors is independent of the central autonomic dysfunction in MS.

Expression of beta-adrenoceptors on circulating mononuclear cells in hypertensives and normotensives before and after reduction of central sympathetic outflow by clonidine.

We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells (PBMCs) in normotensives (NT) and hypertensives (HT), before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine, there was a decrease in blood pressure and plasma noradrenaline (NA) and adrenaline (Ad) levels, with an increase in growth hormone (GH) levels, in both NT and HT. There was no difference in basal beta-adrenoceptor densities on PBMCs between NT and HT. After clonidine at 30 and 60 min, there was an increase in beta-adrenoceptor density associated with a low affinity in NT. In HT, no changes were observed. The increased beta-adrenoceptor densities on PBMCs in NT after clonidine, returned to baseline values after 2 h. Short term up-regulation of beta-adrenoceptors on PBMCs in NT after clonidine is accompanied by a fall in blood pressure (BP) and plasma levels of catecholamines. The changes may represent a compensatory mechanism reflecting a rapid externalization-activation of adrenoceptors residing on the internal surface of the membranes with a change of the coupling ability between the receptor and the catalytic component. In HT, although the haemodynamic and neurohormonal response to clonidine was similar to NT, short term upregulation of receptors did not occur. The lack of such response may mirror a form of regulatory dysfunction of beta-adrenoceptors in HT.

Increased expression of high affinity IL-2 receptors and beta-adrenoceptors on peripheral blood mononuclear cells is associated with clinical and MRI activity in multiple sclerosis.

Enhanced expression of beta-adrenoceptor densities on peripheral blood mononuclear cells (PBMCs) in progressive multiple sclerosis patients has been observed in a number of independent studies. A link between increased number of beta-adrenoceptors and inflammatory disease has been further indicated by studies in rheumatoid arthritis and relapsing-remitting multiple sclerosis patients. In a serial monthly assessment of relapsing-remitting multiple sclerosis patients, we have demonstrated that increased beta-adrenoceptors on PBMCs correlate with the expression of high affinity interleukin-2 receptors (IL-2Rs) and disease activity as determined by clinical and MRI findings. Magnetic resonance imaging activity was strongly correlated with IL-2R expression and it appears to be a sensitive marker of PBMC immunoactivation in multiple sclerosis. In vitro studies showed that beta-agonist stimulation of PBMCs reduces the IL-2R expression and suppresses cell proliferation following mitogenic stimulation. This observation may indicate a recovery role for the enhanced beta-adrenoceptor expression in multiple sclerosis. However, its therapeutic importance remains to be tested by appropriate trials using either beta-agonists or agents activating the second messenger system, c-AMP, in lymphocytes.

Beta-adrenoceptor expression on circulating mononuclear cells of idiopathic Parkinson's disease and autonomic failure patients before and after reduction of central sympathetic outflow by clonidine.

There is a short-term up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMC) after reduction of central sympathetic outflow by clonidine in normal individuals. We have studied beta-adrenoceptor number and affinity on PBMC in idiopathic Parkinson's disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA; Shy-Drager syndrome) patients and age- and sex-matched normal controls (NC) before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing CNS sympathetic outflow. Basal beta-adrenoceptor density was high in PAF but within the normal range in PD and MSA patients. After clonidine there was a decrease in plasma levels of noradrenaline (NA) and adrenaline (Ad) in PD, MSA, and NC, and an increase in growth hormone (GH) in PD, PAF, and NC. NC. In PAF, NA and Ad remained unchanged. In MSA, there was no increase in GH levels. There was an up-regulation of beta-adrenoceptors on PBMC at 30 and 60 minutes after clonidine administration, which returned to baseline values after 2 hours, and the affinity of the receptors was decreased in NC and PD patients. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Up-regulation after clonidine did not occur in PAF and MSA patients. The observed correlation of plasma NA and sympathetic defect with basal and clonidine-induced up-regulation of beta-adrenoceptors on PBMC may provide insight into beta-adrenoceptor changes in other tissues and also help in differentiating subgroups of autonomic failure patients.

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)

beta-Adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1.

An increased density of beta-adrenergic receptors was demonstrated on peripheral blood mononuclear cells (PBMCs) from patients with progressive or relapsing-remitting multiple sclerosis (MS). The same observation was made in patients with chronic active rheumatoid arthritis, but not in those with myasthenia gravis. The affinity of the receptors was within the normal range in all tested groups of patients and there was a positive correlation between density and function as determined by intracellular cyclic AMP production after stimulation with isoproterenol. A putative link between inflammatory process and the functional upregulation of beta-adrenergic receptors on PBMCs was tested by in vitro studies with the soluble mediators interleukin-1 and hydrocortisone. A functional upregulation of beta-adrenergic receptors was observed when PBMCs from normal control subjects were cultured in the presence of either mediator, whereas the already upregulated receptor density on PBMCs from patients with MS remained unchanged. Whether this represents a recovery mechanism to inflammation in MS or a blunting of homeostatic immunoregulatory mechanisms requires further investigation.

Up-regulation of beta-adrenoceptors on circulating mononuclear cells after reduction of central sympathetic outflow by clonidine in normal subjects.

Short term regulation of beta-adrenoceptors in peripheral blood mononuclear cells after sympathetic activation has been previously documented in normal individuals but changes after a central reduction in sympathetic activity are not known. We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells in normal subjects, before and after intravenous clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine there was a decrease in plasma levels of noradrenaline and adrenaline, and an increase in growth hormone. There was up-regulation of beta-adrenergic receptors on peripheral blood mononuclear cells 30 and 60 min after clonidine which was related to the fall in blood pressure, noradrenaline and adrenaline levels and to the increase in growth hormone levels. The affinity of the receptors was decreased. Return to baseline values was observed after 2 h. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Our studies indicate short term up-regulation of beta-adrenoceptors in peripheral blood mononuclear cells after clonidine. These observations after a reduction in sympathetic activity may be of importance if they mirror the pattern of redistribution of adrenoceptors, which are present in a wide range of tissues.

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.