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Patients with familial dysautonomia (FD) frequently have profound orthostatic hypotension without compensatory tachycardia. Although the aetiology is presumed to be sympathetic impairment, peripheral vascular responses to orthostasis have not been assessed. The aim of this study was to evaluate the control of vascular responses to postural stress in FD patients. Measurements of heart rate, blood pressure, cardiac stroke volume and cardiac output (CO), by impedance cardiography, and calf-volume changes, by impedance plethysmography, were taken from nine FD patients and 11 control subjects while supine and during head-up tilt. During leg lowering, we also assessed the venoarteriolar reflex by measuring skin red-cell flux. Head-up tilting for 10 min induced sustained decreases in mean arterial pressure in the FD patients, but not in the controls. Total peripheral resistance (TPR, i.e. mean arterial pressure/CO) increased significantly in the controls (39.8+/-6.8%), but not in the FD patients. Calf-volume changes during tilting, when normalized for the initial calf volume, did not differ significantly between the patients (4.62+/-1.99 ml.100 ml(-1)) and the controls (3.18+/-0.74 ml.100 ml(-1)). The vasoconstrictor response to limb lowering was present in the patients (47.7+/-9.0% decrease in skin red-cell flux), but was impaired as compared with the controls (80.7+/-3.4%) ( P <0.05). The impaired vasoconstriction during limb lowering and absent increase of TPR during tilting confirm that orthostatic hypotension in FD is due primarily to a lack of sympathetically mediated vasoconstriction without evidence of abnormally large shifts in blood volume towards the legs during orthostasis. This may be due, in part, to a preserved myogenic response to increased vascular pressure in the dependent vascular beds.

We recently published data suggesting the presence of an intrinsic sinus node abnormality in a subgroup of patients with the postural tachycardia syndrome (POTS). Based on the hypothesis that more widespread abnormalities of cardiac electrophysiologic properties may be present in POTS, we undertook a study to compare cardiac conduction and repolarization at different heart rate levels in patients with POTS and healthy controls. Eleven healthy controls and fourteen patients with POTS participated in the study. Acquisition of 12-lead electrocardiogram recordings were made during supine rest and during gradual head-up tilt. The heart rate of controls was titrated by isoproterenol infusion to match the heart rate of patients. Indices for cardiac conduction (PR interval, QRS duration, and R wave axis) and repolarization (QT interval, QTc interval, and T wave axis) were then compared at different heart rate levels. The PR interval decreased with increasing heart rate in controls more than in patients, resulting in a significantly longer PR interval in patients at the fastest heart rate level. The QT and QTc intervals were significantly shorter in POTS over the entire analyzed heart rate range. The T wave axis decreased with increasing heart rate in patients only. This resulted in a significantly lower T wave axis in patients at the fastest heart rate level. Our data suggest abnormalities of atrioventricular conduction and ventricular repolarization in patients with POTS. These findings may reflect intrinsic cardiac electrophysiologic abnormalities or may be secondary due to abnormalities of cardiac autonomic innervation., (Copyright 2002 Elsevier Science B.V.)

Although cardiorespiratory complications contribute to the high morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear. We evaluated respiratory, cardiovascular, and cerebrovascular control by monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during recovery from moderate hyperventilation (to simulate changes leading to respiratory arrest) in 22 subjects with FD and 23 matched control subjects. Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation, lower RR interval, and higher BP. MCFV was also higher but depended on the higher baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted increases in ventilation, paradoxical decreases in RR interval and BP, and lack of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase. Subjects with FD develop central depression in response to even moderate hypoxia with lack of expected change in cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD.

Aim: The purpose of this study was to investigate, in a community-based population, the frequency of stroke-related urinary incontinence (UI) and to analyse the long-term impact of UI on prognosis and institutional care., Methods: Included were 752 acute stroke patients admitted consecutively during a 4-year period. We evaluated the UI by using the Barthel Index during the first 7 days and at 12-months follow-up., Results: During the acute stage, the proportions of patients with full UI, partial UI, and no UI were 41%, 12%, and 47%, respectively (16%, 16%, and 68% at 12-months follow-up). A total of 45% of patients with UI at 12 months were institutionalised compared with 5% of patients without UI. In a multivariate logistic regression model, age, urinary incontinence at day 7, and severe disability at 12 months were demonstrated to be independent factors for a higher frequency of institutional care 12 months after stroke., Conclusions: On admission in the acute stage, more than 50% of an unselected stroke population have UI. The proportion declines to one third of the surviving patients at 12 months. Stroke survivors who are incontinent in the acute stage have an fourfold higher risk to be institutionalised after 1 year., (Copyright 2003 Wiley-Liss, Inc.)

Background: Relatively little is known about physiological cerebrovascular haemodynamics during physical stress in elderly healthy individuals. The aim of this study was to determine the effect of ergometer stress on cerebrovascular haemodynamics in elderly healthy individuals in comparison with young healthy individuals, using non-invasive methods., Methods: Continuous middle cerebral artery blood flow velocity (CBFV; transcranial Doppler ultrasound), beat-to-beat blood pressure, heart rate and transcutaneous pCO(2) were measured in response to 3 min ergometer exercise stress in 18 elderly healthy subjects (mean age +/- SD 66.5 +/- 5.8 years) and 18 healthy young subjects (mean age +/- SD 29.4 +/- 4.7 years). Pulsatility index (PI) was used as a parameter for cerebrovascular resistance. The subjects were in a supine position with an elevated trunk and performed exercise by pedalling on an ergometer, generating 75-100 W. Statistical analysis was carried out using MANOVA, a general linear model with repeated measures., Results: In both groups, blood pressure increased significantly (p < 0.001) with time during exercise, with no significant differences between the groups or regarding interaction (time sequence/group factor). Heart rate increased significantly with time during exercise (p < 0.001) and was significantly more prominent (p = 0.002) and prolonged (p < 0.001) in the young group. pCO(2) did not differ with time or between the groups and with regard to interaction. Mean CBFV (MFV) increased significantly during time (p < 0.001). Between the groups, there was no significant difference (p = 0.836), but with regard to interaction (time sequence/group factor), there was a significant delay in MFV increase in the group of young subjects (p = 0.002). The PI, a measure of cerebrovascular resistance, increased significantly with time without significant differences between the groups (p = 0.061), but was significantly delayed in the elderly regarding the interaction time sequence/group factor (p < 0.001)., Conclusion: The cerebrovascular changes during ergometer exercise may reflect the combined activation of the cerebrovascular autoregulative mechanisms (predominantly neurogenic and myogenic). In healthy normotensive elderly subjects, cerebral autoregulatory capacity is retained but delayed in response to ergometer stress compared with young healthy subjects. We speculate that these findings may contribute to a higher risk of cerebral hypoperfusion in the elderly., (Copyright 2003 S. Karger AG, Basel)

Objective: Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease which has no known cure and limited symptomatic treatment. While coping strategies in more common diseases are widely assessed, coping is poorly understood in ALS., Methods: We examined 41 ALS patients using a standardised interview, a validated coping self-rating questionnaire and a self-rating depression scale. The evaluation was repeated after six months., Results: "Loss of speech", "loss of mobility" and "the poor prognosis" were the most frequent answers in the standardised interview to questions regarding the worst aspect of the disease. Pain was seldom mentioned. "Family members" were most helpful in coping with the disease, followed by "unspecific mechanisms" and "technical aids". None of our patients expressed a wish for assisted suicide. In comparison with other fatal diseases, patients with ALS had similar rankings in the coping mechanism of "rumination", but lower rankings in "search for social integration", "defence of fear", "search for information and communication". In contrast,* "search for hold in the religion" was of high importance for our ALS patients. In the follow-up examination the importance of "search for information and communication" increased., Conclusion: The results emphasise the importance of "loss of speech" and the importance of the caring family as well as the availability of technical aids in ALS. Coping in ALS seems to be based mainly on "rumination" and *"hold in the religion", but the increasing importance of "search for information" indicates that the sustained offer of information is essential.

Study Design: A consecutive and controlled cohort study., Objectives: To assess the value of motor conduction time (MCT) between cortex and symptomatic leg muscles after transcranial magnetic brain stimulation as an indicator of reversible root ischemia in patients with neurogenic claudication in spinal stenosis., Summary of Background Data: Neurogenic claudication in spinal stenosis is thought to result from transient ischemia of active nerve root fibers. Subgroups of these patients have slowing of sensory or motor nerve root conduction during spinal claudication., Material and Methods: Forty-two patients with spinal claudication and radiologically confirmed signs of spinal stenosis were consecutively recruited. Motor conduction time was measured before and repetitively after challenge of walking on a treadmill (four stimuli per minute) until disappearance of the symptoms. Data of 30 patients (65 +/- 10 years) with a defined onset of motor-evoked potentials were compared with those of 12 control subjects (62 +/- 12 years)., Results: One minute after treadmill challenge, MCT increased in all 13 patients with signs of an exercise-dependent neurologic deficit by at least 1 msec (mean increase, 1.6 +/- 0.6 msec; < 0.001). Test-retest comparisons in six of these patients revealed good reproducibility of the MCT increase (coefficient of repeatability, 1.24 msec). In contrast, MCTs were unchanged or decreased in all 17 patients without exercise-dependent neurologic deficit ( < 0.01) and in the control subjects ( < 0.05)., Conclusions: Measurements of MCT before and after treadmill challenge can demonstrate reversible root ischemia in patients with spinal claudication and exercise-dependent deficit of thickly myelinated nerve root fibers.

Object: In ALS patients, autonomic nervous system dysfunction might account for an additional reduction of the quality and expectancy of life of individual patients and contribute to unexpected early fatalities. This study was undertaken to assess baroreflex-mediated vagal and sympathetic cardiovascular control of the heart and blood vessels in ALS patients., Methods: In 12 early-stage ALS patients (age 54 +/- 4 years) and 12 controls (age 55 +/- 3 years) we assessed resting baroreflex sensitivity (BRS) by spectral analysis, then stimulated the carotid baroreflex by oscillating neck suction at 0.1 Hz to assess the autonomic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart., Results: Resting heart rate was significantly higher in the ALS patients than in the controls (P < 0.05), but resting baroreflex sensitivity did not differ significantly between the groups. Stimulation at 0.2 Hz induced an oscillation in R-R interval that was significantly smaller (P < 0.05) in ALS patients than in controls. R-R interval responses to 0.1 Hz stimulation were significantly (P < 0.01) reduced in ALS patients compared to controls. Responses of blood vessels to 0.1 Hz stimulation did not differ significantly between the groups., Conclusion: In early-stage ALS patients, BRS might be normal at rest. Only baroreflex activation reveals impaired cardiovagal responses while sympathetic vasomotor control is preserved. Treatment to restore sympathetic-parasympathetic balance to the heart could prevent early cardiovascular fatalities in some ALS patients.

Autonomic neuropathy may contribute to the pathophysiology of both open-angle and normal-pressure glaucoma. However, autonomic function has not been studied extensively in these diseases. We evaluated baroreflex control of the heart and blood vessels in open-angle and normal-pressure glaucoma. We studied 14 patients with open-angle glaucoma, 15 with normal-pressure glaucoma and 17 controls. Sinusoidal neck suction (0 to -30 mmHg) was applied at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Baseline recordings showed no significant differences between the groups. The RR-interval response of the controls to neck suction at 0.1 Hz (3.88+/-0.32 to 6.65+/-0.44 lnms2) was significantly greater than that of the open-angle glaucoma patients (4.22+/-0.28 to 5.56+/-0.26 lnms2) and the normal-pressure glaucoma patients (4.53+/-0.27 to 5.53+/-0.37 lnms2) (P<0.05). The low-frequency power of diastolic blood pressure increased significantly in the controls (0.48+/-0.08 to 2.76+/-0.72 mmHg2; P<0.01) during 0.1 Hz neck suction, but did not change significantly in patients with either open-angle glaucoma or normal-pressure glaucoma. The RR-interval response in the control group (3.45+/-0.52 lnms2) to neck suction at 0.2 Hz was significantly greater than that of the normal-pressure glaucoma patients (1.84+/-0.32 lnms(2)) and the open-angle glaucoma patients (1.58+/-0.35 lnms2) (P<0.05). The decreased sympathetic and parasympathetic modulation during baroreceptor stimulation in patients with open-angle glaucoma and normal-pressure glaucoma suggests that autonomic dysfunction may contribute to the pathogenesis of both diseases.

The five different types of the rare hereditary sensory and autonomic neuropathies (HSAN) are classified by their mode of inheritance, pathology, natural history, biochemical, neurophysiologic and autonomic abnormalities. Clinically, the different types of HSANs can be identified by a detailed history and examination and 'bedside' tests of sympathetic or parasympathetic function such as active standing, metronomic breathing or the Valsalva maneuver, sensory and motor nerve conduction studies, quantitative sensory testing of thermal and vibratory perception, and the analysis of sudomotor function by recordings of the sympathetic skin response (SSR) or the sweat output during quantitative sudomotor axon reflex testing (QSART). The slowly progressive, symmetrical HSAN type I manifests between the second and fourth decade with ulcers or mutilations of the lower extremities, low normal sensory and motor nerve conduction velocities, but abnormal warm, cold and heat pain perception and distal anhidrosis. In HSAN type II, symptoms occur already in infancy, trophic alterations affect fingers and toes. There are acral anhidrosis and various autonomic dysfunctions such as tonic pupils, eating and swallowing difficulties, constipation, episodic fever, profound hypotonia and episodes of apnea. Sensory perception is severely impaired and accounts for elevated vibratory but also thermal perception thresholds. Sensory nerve conduction is highly abnormal while motor nerve conduction studies are almost normal. Type III, the autosomal recessive familial dysautonomia (FD), is the most common of the HSANs. FD is characterized by pronounced autonomic, primarily sympathetic dysregulation with severe orthostatic hypotension, repeated episodes of autonomic crises with excessive arterial hypertension, profuse sweating, skin blotching, puffy hands and behavioral abnormalities. FD manifests only in children of Ashkenazi Jewish ancestry. Cardinal findings are diminished deep tendon reflexes, absence of overflow tears, absence of fungi-form papillae of the tongue and of axon flare response following intradermal histamine injection. Thermal and vibratory testing show pronounced impairment of temperature and pain but also of vibratory perception. Children with HSAN IV, 'congenital insensitivity to pain with anhidrosis' experience repeated episodes of high fevers during high environmental temperature due to anhidrosis. The anhidrosis of the hyperkeratotic skin accounts for absence of the SSR or lack of sweat output during QSART. The patients' insensitivity to superficial as well as deep, visceral pain can be demonstrated e. g. by quantitative heat pain testing. Patients develop severe mutilations e. g. of the tip of their tongue, they might have severe burn injuries and multiple, unnoticed fractures with neuropathic joints. Children with the very rare HSAN type V respond normally to tactile, vibratory or thermal stimuli, but have a selective loss of pain perception with otherwise normal neurological examination. Painful stimuli reveal no signs of discomfort.

Objective: To determine whether an intrinsic sinus node abnormality is involved in the pathophysiology of the postural tachycardia syndrome (POTS). SUBJECTS, PATIENTS, AND METHODS: In this prospective study, we compared the relationship between P-wave axis (PWA) and heart rate (HR) in 11 healthy controls and 14 patients with POTS by obtaining 12-lead electrocardiographic recordings during supine rest and during gradual head-up tilt. The HR of controls was titrated with isoproterenol infusion to match the HR of patients. The PWA was compared at different HR levels, and the relationship between HR and PWA was assessed for patients and controls. Primary end points were the PWA-HR relationship in healthy controls, comparison of these data with data from patients with POTS as a group, and identification of a possible subgroup of patients with POTS with irregular PWA-HR relationship., Results: The PWA increased with increasing HR following a similar logarithmic trendline in both groups. The PWA of patients was significantly lower at the lowest comparable HR level but not different at faster HR levels. Three patients (21%) had a clearly abnormal HR-PWA relationship with substantial shift toward lower PWA., Conclusions: Our data support the hypothesis of a primary sinus node abnormality in a subset of patients with POTS. The ability to identify patients with primary sinus node abnormality may have important therapeutic implications.

The relative contribution of endothelial vasodilating factors to acetylcholine (ACh)-mediated vasodilation in the forearm cutaneous microcirculation is unclear. The aims of this study were to investigate the contributions of prostanoids and cutaneous C fibers to basal cutaneous blood flow (CuBF) and ACh-mediated vasodilation. ACh was iontophoresed into the forearm, and cutaneous perfusion was measured by laser-Doppler flowmetry. To inhibit the production of prostanoids, four doses of acetylsalicylic acid (ASA; 81, 648, 972, and 1,944 mg) were administered orally. Cutaneous nerve fibers were blocked with topical anesthesia. Cyclooxygenase inhibition did not change basal CuBF or endothelium-mediated vasodilation to ACh. In contrast, ASA (972 and 1,944 mg) significantly reduced the C-fiber-mediated axon reflex in a dose-dependent fashion. Blockade of C-fiber function significantly reduced axon reflex-mediated vasodilation but did not affect basal CuBF or endothelium-dependent vasodilation. The findings suggest that prostanoids do not contribute significantly to basal CuBF or endothelium-dependent vasodilation in the forearm microcirculation. In contrast, prostanoids are mediators of the ACh-provoked axon reflex.