Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

Possible relationships between headache-allodynia and nocturnal sleep breathing.

Sleep and headache are linked in a bidirectional way. Breathing quality during sleep may be a possible link between them. The objective of this study were to evaluate the prevalence of headache--and of allodynia--in a population of subjects who underwent cardiopulmonary monitoring during sleep for presumed respiratory problems; to evaluate the possible relationships between the presence of headaches--and of allodynia--and respiratory parameters. We studied 181 subjects, 112 without headache (mean age 59.4 ± 13.1 years, 97 men and 15 women); 69 with history of headache (42 men and 27 women; 41 migraineurs and 28 with tension type headache). Headache diagnosis was made according to ICHD-II criteria. A semi-structured ad hoc questionnaire was used to evaluate the presence of allodynia. Full cardiopulmonary monitoring was performed by SOMNO check(®) effort (WEINMANN) with SaO(2), T90 and AHI determination. Headache and headache-associated allodynia were particularly frequent in this population, suggesting a positive correlation between breathing problems during sleep and head pain, and allodynia. The observation that better respiratory parameters were found among headache sufferers with respect to those without headache, even in allodynic subjects, seems to reverse this point of view: headache and allodynia may possibly have an allostatic function preventing deep sleep and, in turn, avoiding prolonged apneas.

Correlation between presence of allodynia and sleep quality in migraineurs.

Cutaneous allodynia is a frequent complaint in migraine patients, possibly induced by central sensitisation of trigeminal nucleus. The objective of this study is to investigate if sleep quality is related to the presence of migraine-associated allodynia. A total of 175 consecutive migraineurs were included, 124 with episodic and 51 with chronic forms. As control group, 73 subjects free from any kind of headache were included (HC). The presence of allodynia and sleep disturbances was assessed by a set of semi-structured questions. Chi-square test was applied to compare frequencies among groups. Sleep quality was worse among migraineurs with respect to controls for each sleep item analysed. This difference was significant for all items but one (i.e. frequency in drug use to induce sleep). The frequency of sleep disturbances was higher than in controls in both allodynic and non-allodynic migraineurs, although statistical analysis showed that all these differences were still significant in allodynic migraineurs (also in this case for all the sleep items but one, i.e. frequency in drug use to induce sleep), whilst non-allodynic migraineurs were significantly different from controls only for one item (frequency of initial insomnia). These results suggest that allodynia is strongly related to sleep quality, in a bi-directional way: sleep disturbances may favour central sensitisation, and, in turn, allodynia may impair sleep.

Is allodynia influenced by psychological profile in headache patients?

Cutaneous allodynia is a frequent complain in headache patients, particularly in those with migraine. A stronger association is present in patients with migraine with aura and with chronic or transformed migraine. The aim of the present study was to investigate if the psychological profile may be related to the presence/absence of allodynia in a sample of headache patients. The psychological profile of patients was assessed by the SCL90R; the presence of allodynia was assessed by a set of semi-structured questions used in previous studies. For the purpose of the study, patients were divided into subgroups according to the headache type (ICDH-II diagnoses), as well as to the temporal pattern (episodic or chronic). A total of 213 consecutive headache patients were studied. Most patients had episodic migraine (116); 37 had tension-type headache. Overall, 156 patients had episodic headache forms, and 57 had chronic forms. As far as allodynia, 93 were non-allodynic; 120 presented allodynic symptoms during their headaches. No significant difference was found between allodynic and non-allodynic patients neither if studied in a whole group (t test, P = 0.10 NS) nor when patients were evaluated comparing different subgroups on the basis of headache type, and of the episodic/chronic pattern. Our results suggest that the presence/absence of allodynia may not be influenced by the psychological profile.

Allodynia in different forms of migraine.

About 60% of patients complain of cutaneous allodynia during migraine episodes, often in the periorbitary region of the pain side. Pre-clinical studies have shown that the underlying mechanism is sensitisation of primary nociceptors and central trigeminovascular neurons and that patients have a lower pain threshold for mechanical stimulation compared to controls. The objective of this study was to determine the prevalence of allodynia during headache attacks in different forms of migraine. The subjects were 221 outpatients consecutively evaluated in the Headache Center of the L. Sacco Hospital in Milan: 114 had only attacks of migraine without aura (MO), 63 had also attacks with aura (MA) and 44 patients with chronic migraine with and without drug overuse (CM). Presence of head allodynia was investigated by a semistructured interview. Statistical analysis was performed by chi square test with Bonferroni correction for multiple comparisons. Forty-seven out of 114 MO patients (41.2%) complained of allodynia during headache episodes, 41 out of 63 MA patients (65.0%), and 29 out of 44 CM patients (65.9%). A higher frequency of allodynia in MA and CM with respect to MO patients was observed (p<0.01 at chi square test). Allodynia was a common complaint in migraineurs, being present in more than 40% patients of each group. A higher frequency was observed in MA and in CM patients. This observation may suggest that both frequency of attacks and presence of aura episodes may contribute to induce changes in neuronal activation threshold thought to sustain allodynia.

Prevalence of subclinical neuropathy in diabetic patients: assessment by study of conduction velocity distribution within motor and sensory nerve fibres.

Nerve conduction velocity distribution (CVD) study is a newly-developed electrodiagnostic method for detecting alterations in the composition of nerve fibres according to their conduction velocity. The presence of subclinical neuropathy was evaluated in 138 diabetic patients by CVD study of four motor nerves (external popliteal and ulnar nerves bilaterally) and two sensory nerves (median nerve bilaterally), and the data obtained were compared with standard electrophysiological parameters in the same nerve segments. CVD studies revealed an altered distribution pattern in 106 of 129 evaluable patients for motor nerves (82%) and in 67 of 115 evaluable patients for sensory nerves (58%), while standard examination gave abnormal findings in 92 of 137 patients (67%) and in 33 of 118 patients (11%), respectively. Of the patients adequately evaluated by both techniques, 21 of 129 patients (16%) revealed altered CVD data unaccompanied by slowing of maximum nerve conduction velocity, and 37 patients of 101 (37%) showed similar findings for sensory nerves. Subclinical alterations of motor and sensory nerve CVD were not significantly related to age or to metabolic control expressed as glycated haemoglobin levels; a significantly longer duration of disease was found in patients with motor and mixed subclinical neuropathy with respect to non-neuropathic patients. The CVD study allowed us to detect subclinical abnormalities of motor and sensory nerve fibres; often this is a more sensitive method than the standard electrodiagnostic study. This method can be very useful as a diagnostic tool and in research in the study of the progression of diabetic neuropathy.

Short and long latency cortical potentials evoked by electrical stimulation of the oesophageal mucosa in normal alert humans.

Cerebral responses from the oesophagus were investigated in 16 normal male and female volunteers ranging in age from 20 to 54 years. The stimulus was applied by a naso-oesophageal probe equipped with bipolar ring electrodes. Short and long latency EP (SLEP and LLEP) were observed in all the subjects examined. SLEP consisted in a low threshold potential of 30 to 70 microV amplitude, biphasic or triphasic in shape and of approximately 5 to 10 ms duration; mean latency at the largest peak was 4.5 +/- 1.7 at 25 cm from the nostrils. Early components at about 2.5-3.5 ms and of small amplitude are also present. Recording from the neck at C7 with a common non-cephalic reference, SLEP components occurred from 2 to 6 ms earlier than that from the scalp, suggesting an oligo-synaptic transmission of the excitement via ganglion and lemniscal pathways to the cortex. SLEP was always followed by a complex potential formed of a succession of negative and positive waves with latencies ranging from 20 to 300 ms: the LLEP. This LLEP was usually not very stable and reproducible during the course of successive recordings and in the same subject because it tended to adjust. Preliminary observations concerning the topographical cortical distribution of oesophageal evoked potentials show a circumscribed localization of the SLEP in the parieto-temporal region of the hemisphere whereas LLEP was more widespread. It is the authors' opinion that oesophageal evoked potentials are generated both by the excitation of myelinic fibres with a wide range of conduction speed and of amyelinic fibres from the oesophageal mucosa and the paraoesophageal peripheral nerves of vagal origin.

Myotonia induced by potassium repletion in a diabetic patient with secondary hypokalemic paralysis.

In a woman suffering from insulin-dependent diabetes mellitus, hypokalemic paralysis developed acutely following an episode of diabetes decompensation. During the treatment of this episode, as soon as serum potassium levels were restored to normal values, a marked increase in muscular excitability with an electromyographic picture of myotonia was observed. The patient showed signs of chronic muscle denervation that accounted for an increased sensitivity to potassium-induced depolarization and contraction and that might have been responsible for the appearance of myotonia during potassium repletion.

Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical neuropathy. I. Motor nerve.

A computer-assisted collision method to evaluate motor conduction velocity distribution of the ulnar and external peroneal nerves in normal subjects and in insulin-dependent and non-insulin-dependent diabetics without clinical signs of neuropathy is described. Distribution curves were sigmoidally (bimodally) shaped in normal and in insulin- and non-insulin-dependent subjects. In insulin-dependent patients, motor conduction velocity of the peroneal nerves was globally impaired, whereas of the ulnar nerves it was normal. In non-insulin-dependent patients, slower conduction velocity was involved in both nerves.

Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical signs of neuropathy. II. Sensory nerve.

A new computer-assisted method to evaluate sensory conduction velocity distribution and dispersion of the digital nerve of the middle finger in normal subjects and in type I and type II diabetic subjects without any neurological impairment is reported. Distribution curves were exponentially shaped in normal and in diabetic subjects. In insulin-dependent diabetics, only slower conduction velocity fibers were involved, whereas no significant difference was observed between the non-insulin-dependent diabetic group and the control group.

Altered vasopressin response to metoclopramide in multiple system atrophy: evidence of a cholinergic defect in the hypothalamus.

Multiple system atrophy (MSA) is a heterogeneous group of central neurological degenerations often associated with diffuse deterioration of the hypothalamic cholinergic neurons. In the hypothesis of an altered cholinergic regulation of vasopressin release, we evaluated vasopressin response to metoclopramide (20 mg i.v.), a cholinomimetic agonist, in 12 MSA patients. In the same patients the hemodynamic and osmolal control of vasopressin was also evaluated. We found that MSA patients had significantly lower basal plasma vasopressin values and higher plasma osmolality than control subjects. However, they displayed a normal vasopressin response to osmotic stimulation. During head-up tilting, orthostatic hypotension occurred in all patients, and the vasopressin response to hypotension was severely blunted in 5 of 12 patients, thus demonstrating the presence of a lesion of the afferent noradrenergic pathways. Metoclopramide increased vasopressin in control subjects, whereas MSA patients did not display any increase in vasopressin. These results clearly indicate that cholinergic neurons that regulate vasopressin release are damaged in MSA. Such an alteration may be dissociated from the lesion of the afferent noradrenergic pathways. As a consequence of the altered vasopressin release, MSA patients show lower plasma vasopressin levels with consequent propensity to dehydration and hypovolemia, which may further aggravate their hypotension.

Cortisol resistance in acquired immunodeficiency syndrome.

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 +/- 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 +/- 2.6 fmol/million cells; P less than 0.01) and sex- and age-matched controls (3.15 +/- 2.3 fmol/million cells; P less than 0.01). The affinity of glucocorticoid receptors (Kd) was strikingly decreased (9.36 +/- 3.44 nM in group 1; 3.2 +/- 1.5 nM in group 2; 2.0 +/- 0.8 nM in controls; P less than 0.01). [3H]Thymidine incorporation was decreased dose-dependently by dexamethasone in controls and patients; the effect was significantly blunted (P less than 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implies a complex change in immune-endocrine function, which may be important in the course of immunodeficiency syndrome.

Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.

Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma.

Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha-1 and beta-2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC), the density was examined of alpha-1 and beta-2 adrenoceptors with their affinity and coupling of beta-2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age-matched and sex-matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty-two HCC had a decrease of about 72% in alpha-1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha-1 adrenoceptor density compared with healthy livers. Twenty-three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase, as evidenced by a guanosine triphosphate-mediated right shift in (-)-isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (-)-isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha-1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the "healthy" part of the liver in HCC patients and that an increase in beta-2 and a decrease in alpha-1 adrenoceptor densities characterize the tumor part of the liver in human HCC.

Respiratory-burst stimulants desensitize beta-2 adrenoceptors on human polymorphonuclear leukocytes.

We investigated the effect of respiratory-burst stimulants on beta-2 adrenoceptors in human polymorphonuclear leukocytes (PMNL). Pre-incubation of PMNL with these substances did not affect the number or affinity of the receptors but desensitized them, as shown by the "right-shift" in (-)-isoproterenol competition isotherms. H-7, an established protein kinase C inhibitor, and nimesulide, a new putative inhibitor of this enzyme, blunted both superoxide anion production and beta-2 adrenoceptor desensitization. A positive correlation was found between superoxide anion generation and the "right-shift" in isoproterenol competition isotherm (r = 0.92; p less than 0.01). Desensitization of beta-2 adrenoceptors was not due to superoxide anions per se since incubation of PMNL with superoxide anion scavengers (superoxide dismutase and catalase) did not modify the results.

Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues.

beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.

Role of the Frank-Starling mechanism in maintaining cardiac output during increasing levels of treadmill exercise in beta-blocked normal men.

To determine the effects of beta blockade on hemodynamics during increasing levels of treadmill exercise, 10 healthy volunteers were studied after 1 week of placebo, and then after 1 week of treatment with oral propranolol, 80 mg twice daily, or dilevalol, 400 mg once daily. The study was randomized and double-blind, with a crossover sequence. Hemodynamics were measured by CO2 rebreathing at rest and at 25, 50, 75 and 100% of VO2 max. After placebo, cardiac output increased from 5.8 +/- 2.1 (rest), to 19.4 +/- 6.4 liters/min (100% VO2 max), mainly due to an increase in heart rate from 84 +/- 6 to 169 +/- 15 beats/min. Stroke volume increased from 70 +/- 27 (rest), to 137 +/- 65 ml (25% VO2 max), and then leveled off to 116 +/- 41 at 100% VO2 max. After both beta blockers, exercise cardiac output was maintained at 100% VO2 max: 20.1 +/- 9.3 liters/min with propranolol and 19.1 +/- 8.6 with dilevalol. However, a significant reduction versus placebo values was observed for cardiac output at 25% VO2 max, from 13.7 +/- 5.9 during placebo, to 9.4 +/- 2.5 during propranolol, and to 9.6 +/- 2.3 during dilevalol (both p less than 0.01 vs placebo). Maintenance of cardiac output with both beta blockers at higher levels of exercise came from an increased stroke volume (p less than 0.05 vs placebo), while heart rate (in beats/min) was greatly reduced (propranolol 61.6 +/- 9.4 rest, 90.1 +/- 10.7 at 100% VO2 max; dilevalol 70.8 +/- 6.4 rest, 99.2 +/- 11.8 at 100% VO2 max, p less than 0.01 vs placebo for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of alpha 1-adrenergic receptors on sarcolemma from normal subjects and patients with idiopathic dilated cardiomyopathy: characteristics and linkage to GTP-binding protein.

Discontinuous density sucrose gradient centrifugation was used to isolate membrane vesicles from the left ventricle of three normal subjects (one prospective organ donor and two traffic victims whose hearts were obtained 1 hour after death) and nine patients undergoing cardiac transplantation as a consequence of idiopathic dilated cardiomyopathy. Sarcolemma-enriched subcellular fractions, detected in the interface between 8.55% and 25% sucrose, were identified by the increased activity of Na+,K+-ATPase and by enrichment in beta-adrenergic receptor density. The density of beta-adrenergic receptors was lower in vesicles from diseased hearts (610 +/- 71 fmol/mg protein) than in vesicles from normal hearts (1,410 +/- 226 fmol/mg protein; p less than 0.01). alpha 1-Adrenergic receptors were identified in these membrane vesicles by [3H]prazosin binding. Specific binding of [3H]prazosin was about 50% of the total binding at 1 nM, and alpha 1-adrenergic binding sites were saturable at approximately 3 nM. Scatchard analysis revealed 58 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.08 nM) in pathological hearts and 30 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.03 nM) in normal hearts (p less than 0.01). The displacement curve of (-)-norepinephrine in membrane vesicles from normal hearts delineated one subpopulation of alpha 1-adrenergic receptors; the addition of 0.1 mM GTP did not cause right shift. In membrane vesicles from diseased heart, the displacement curve of (-)-norepinephrine disclosed two subpopulations of alpha 1-adrenergic receptors. A right shift that occurred after addition of GTP showed that in this case alpha 1-adrenergic receptors were functionally coupled with GTP-binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in vasopressin regulation in Alzheimer's disease.

A decreased concentration of vasopressin (AVP) in the plasma of patients with Alzheimer's disease has been shown recently and suggests damage to hypothalamic neurosecretory cells. To verify this, osmolar and hypotension (sodium nitroprusside) stimulations on AVP release were applied. The effect of metoclopramide, a powerful stimulator of AVP, was also assessed. Patients with Alzheimer's disease released AVP normally after hypotension. However, AVP response to osmotic stimulation was altered in eight out of 10 patients, owing to low osmoreceptor sensitivity and/or high threshold. Metoclopramide increased AVP in controls but not in patients. Normal AVP response to hypotension in patients with Alzheimer's disease makes it unlikely that there is a significant anatomical loss or damage of hypothalamic neurosecretory cells. Alterations in osmoreceptor function and AVP unresponsiveness to metoclopramide point to damage in the control of AVP release in Alzheimer's disease.