Effect of orthostatic hypotension on sustained attention in patients with autonomic failure.

INTRODUCTION: Orthostatic hypotension has been associated with impaired cognitive function, but cognitive function during orthostatic hypotension has hardly been studied. We studied the effect of orthostatic hypotension, induced by head-up tilt (HUT), on sustained attention in patients with autonomic failure. METHODS: We studied the sustained attention to response task (SART) in the supine position and during HUT in 10 patients with autonomic failure and 10 age-matched and sex-matched controls. To avoid syncope, the tilting angle was tailored to patients to reach a stable systolic blood pressure below 100 mm Hg. Controls were all tilted at an angle of 60°. Cerebral blood flow velocity, blood pressure and heart rate were measured continuously. RESULTS: In patients, systolic blood pressure was 61.4 mm Hg lower during HUT than in the supine position (p<0.001). Patients did not make more SART errors during HUT than in the supine position (-1.3 errors, p=0.3). Controls made 2.3 fewer errors during SART in the HUT position compared to the supine position (p=0.020). SART performance led to an increase in systolic blood pressure (+11.8 mm Hg, p=0.018) and diastolic blood pressure (+5.8 mm Hg, p=0.017) during SART in the HUT position, as well as to a trend towards increased cerebral blood flow velocity (+3.8 m/s, p=0.101). DISCUSSION: Orthostatic hypotension in patients with autonomic failure was not associated with impaired sustained attention. This might partly be explained by the observation that SART performance led to a blood pressure increase. Moreover, the upright position was associated with better performance in controls and, to a lesser extent, also in patients.

A Japanese familial ALS patient with autonomic failure and a p.Cys146Arg mutation in the gene for SOD1 (SOD1).

We describe a Japanese man with familial amyotrophic lateral sclerosis (ALS) associated with a p.Cys146Arg mutation in the copper/zinc superoxide dismutase gene (SOD1). The patient developed bulbar signs followed by rapidly progressive limb muscle weakness. The prominent clinical feature was orthostatic hypotension due to autonomic failure, which occurred after he underwent tracheostomy 1 year and 3 months after the onset. Thereafter, he required mechanical ventilation and progressed to communication stage V (totally locked-in state) 7 years after the onset. Neuropathology showed ALS with posterior column degeneration and multiple system degeneration. Severe neuronal loss in the intermediolateral nucleus was also observed. Two previously reported cases of ALS patients with autonomic failure showed severe neuronal loss in the intermediolateral nucleus in addition to degeneration of the motor neurons. Thus, autonomic failure due to neuronal loss in the intermediolateral nucleus could present in patients with ALS associated with certain mutations in SOD1.

A review of orthostatic blood pressure regulation and its association with mood and cognition.

AIMS: This paper will review literature that examines the psychological and neuropsychological correlates of orthostatic blood pressure regulation. RESULTS: The pattern of change in systolic blood pressure in response to the shift from supine to upright posture reflects the adequacy of orthostatic regulation. Orthostatic integrity involves the skeletal muscle pump, neurovascular compensation, neurohumoral effects and cerebral flow regulation. Various physiological states and disease conditions may disrupt these mechanisms. Clinical and subclinical orthostatic hypotension has been associated with impaired cognitive function, decreased effort, reduced motivation and increased hopelessness as well as dementia, diabetes mellitus, and Parkinson's disease. Furthermore, inadequate blood pressure regulation in response to orthostasis has been linked to increased depression and anxiety as well as to intergenerational behavioral sequalae. CONCLUSIONS: Identifying possible causes and consequences of subclinical and clinical OH are critical in improving quality of life for both children and older adults.

[General anesthesia in a patient with idiopathic orthostatic hypotension]. / Allgemeinanästhesie bei einem Patienten mit idiopathischer orthostatischer Hypotonie.

Idiopathic orthostatic hypotension (formerly known as Shy-Drager syndrome) is a multiple system atrophy, which is characterized by autonomic dysregulation. Providing perioperative hemodynamic stability during narcosis is therefore a particular challenge. The effects of general anesthesia on systemic vascular resistance and cardiac output in a patient with idiopathic orthostatic hypotension undergoing retropubic prostatectomy will be reported. In the case presented perioperative hemodynamic stability was achieved by aggressive volume therapy guided by global end-diastolic volume measurement and low-dose catecholamine therapy.

Pupil findings in a consecutive series of 150 patients with generalised autonomic neuropathy.

AIM: To detect and characterise the pattern and extent of pupil abnormalities in patients with generalised autonomic failure. METHODS: A consecutive series of 150 patients referred for investigation of symptomatic generalised autonomic failure underwent pupil investigations. Infra-red video pupillography was used to measure resting pupil diameters in light and dark, the light reflex response, the miosis associated with an accommodative effort, and responses to topical administration of various pharmacological agents. The results were compared with data recorded under identical conditions from a cohort of 315 age-matched and sex-matched healthy controls. RESULTS: Overall, two thirds of patients had abnormal pupils (66%) with sympathetic deficit occurring twice as often as parasympathetic deficit. However, the prevalence and type of pupil abnormality showed wide variation according to aetiology--for example, almost all patients with amyloidosis had abnormal pupils, two thirds with pure autonomic failure but less than a quarter with multiple system atrophy. In most patients (85%), pupil abnormalities were bilateral and symmetrical, none had a Horner's syndrome in one eye and a tonic pupil in the other. No significant correlation between the type of pupil abnormality and the predominant type of systemic autonomic deficit was seen in most conditions. CONCLUSIONS: The pupils are often affected in autonomic neuropathy, although this is not always apparent either to the patient or to their doctors. Considerable care is needed not only to detect these abnormalities but also to interpret correctly the results of pupil tests in this group of patients.

Changes in cerebral oxygenation and haemodynamics during postural blood pressure changes in patients with autonomic failure.

Patients with autonomic failure suffer severe postural hypotension that may be associated with symptoms of cerebral hypoperfusion. This study utilized near-infrared spectroscopy (NIRS) to measure changes in cerebral oxygenation and haemodynamics during the head-up tilt table test in 18 patients with autonomic failure and 10 healthy age-matched volunteers. Heart rate, blood pressure (MAP), oxygen saturation, cerebral tissue oxygen index (TOI) and total cerebral haemoglobin concentration [HbT] were measured continuously. In patients with autonomic failure there was a mean (SD) reduction in MAP of 46.7 (26.5) mmHg (p < 0.005) associated with a reduction in TOI of 8.6 (6.2)% (p < 0.005) during the head-up tilt table test. In healthy volunteers mean (SD) MAP rose by 12.3 (8.0) mmHg (p < 0.005) and TOI fell by 2.6 (3.2)% (p < 0.05). There was a mean (SD) reduction in [HbT] of 3.09 (2.82) micromol l(-1) (p < 0.005) in patients, equivalent to a decrease in cerebral blood volume of 0.2 (0.18) ml/100 g. There were no changes in [HbT] in the healthy volunteers. Postural hypotension in patients with autonomic failure is associated with a substantial decrease in absolute cerebral oxygenation measured by NIRS and this might reflect a critical reduction in cerebral oxygen delivery.

Novel therapeutic strategy against central baroreflex failure: a bionic baroreflex system.

BACKGROUND: Central baroreflex failure in Shy-Drager syndrome and traumatic spinal cord injuries results in severe orthostatic hypotension and often confines the patient to the bed. We proposed a novel therapeutic strategy against central baroreflex failure: implementation of an artificial feedback control system able automatically to regulate sympathetic vasomotor tone, that is, a bionic baroreflex system (BBS). With the use of a rat model of central baroreflex failure, we developed the BBS and tested its efficacy. METHODS AND RESULTS: Our prototype BBS for the rat consisted of a pressure sensor placed into the aortic arch, stimulation electrodes implanted into the greater splanchnic nerve, and a computer-driven neural stimulator. By a white noise approach for system identification, we first estimated the dynamic properties underlying the normal baroreflex control of systemic arterial pressure (SAP) and then determined how the BBS computer should operate in real time as the artificial vasomotor center to mimic the dynamic properties of the native baroreflex. The open-loop transfer function of the artificial vasomotor center was identified as a high-pass filter with a corner frequency of 0.1 Hz. We evaluated the performance of the BBS in response to rapid-progressive hypotension secondary to sudden sympathetic withdrawal evoked by the local imposition of a pressure step on carotid sinus baroreceptors in 16 anesthetized rats. Without the BBS, SAP rapidly fell by 49+/-8 mm Hg in 10 seconds. With the BBS placed on-line with real-time execution, the SAP fall was suppressed by 22+/-6 mm Hg at the nadir and by 16+/-5 mm Hg at the plateau. These effects were statistically indistinguishable from those of the native baroreflex system. CONCLUSIONS: These results suggest the feasibility of a BBS approach for central baroreflex failure.

Orthostatic hypotension. I. Functional and neurogenic causes.

The maintenance of adequate upright BP requires both a baroreceptor-mediated feedback loop and an effective circulating blood volume. Although functional disruptions of these mechanisms are reversible and common, several permanent and often progressive neurologic disorders exist that interfere with necessary reflexes and orthostatic BP control. Multiple system atrophy affects diffuse neurologic systems; autonomic dysfunction causes a failure of peripheral vasoconstriction from defective sympathetic stimulation. Idiopathic orthostatic hypotension is a selective disorder of autonomic nerves; postganglionic neurons cannot release norepinephrine properly and are supersensitive to exogenous pressors. Conversely, excessive sympathetic discharge occurs in sympathicotonic orthostatic hypotension, the pathogenesis and incidence of which are unclear. Any peripheral neuropathy may interfere with sympathetic vasoconstrictor activity and is most commonly seen in diabetes mellitus.

Urinary catecholamine metabolites distinguish different types of sympathetic neuronal dysfunction in patients with orthostatic hypotension.

Urinary excretion rates of the major norepinephrine metabolites, 3-methoxy-4-hydroxymandelic acid, 3-methoxy-4-hydroxy-phenylglycol and normetanephrine, were determined in 12 normal subjects and 23 patients with neurogenic orthostatic hypotension due to either multiple system atrophy [Shy-Drager Dyndrome (MSA)] or idiopathic orthostatic hypotension (IOH). There were striking and parallel decreases in all catecholamine metabolites in IOH consistent with loss of peripheral sympathetic nerves. Patients with MSA excreted greater amounts of the deaminated metabolites than did the patients with IOH, but most excreted equally low amounts of normetanephrine. The disproportionate decrease in excretion of normetanephrine by patients with MSA is consistent with observations in experimental animals that O-methylation is the primary metabolic route for active released norepinephrine, whereas deamination is the predominant metabolic route for intraneuronal degradation of the catecholamine. The similar proportional decreases in all catecholamine metabolites in patients with IOH (who have no central nervous system deficit) indicates that brain norepinephrine is a source of only a small fraction of urinary norepinephrine metabolites, including 3-methoxy-4-hydroxy-phenylglycol.

Tobacco intolerance in multiple system atrophy.

In a patient with multiple system atrophy, the ataxia was temporarily exacerbated by cigarette smoking. The phenomenon is attributed to a direct effect of nicotine on the central nervous system, rather than being secondary to autonomic changes. Its prevalence and specificity are currently unknown.

Long-term experience with pergolide therapy of advanced parkinsonism.

Nine patients with idiopathic Parkinson's disease were treated with pergolide to a daily maintenance dose of 2.2 +/- 0.9 mg (mean +/- SD) for 17.3 +/- 8.3 months. After 1 month, there was an average 68% increase in mobile on-time, but the improvement declined to 30% by 6 months, 23% by 1 year, and virtually disappeared by 18 months of therapy. Pergolide was discontinued in seven patients because of loss of efficacy (4 patients), confusion (1 patient), or myocardial infarction or ventricular ectopy (2 patients). Partial but temporary restoration of mobility was observed in seven patients who were switched to an alternate-day dosing schedule after 9.2 +/- 2.4 months. Two patients with advanced Shy-Drager syndrome were treated with pergolide without benefit.

Dystonia in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

Adult-onset dystonia-parkinsonism is a syndrome in search of a pathology. We therefore reviewed the literature on dystonic manifestations in autopsy-proven cases of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and idiopathic Parkinson's disease (PD). Only 6 of 140 autopsy reports of MSA remarked on the presence of dystonia in life, but personal observations suggest prominent antecollis may develop at some stage in up to 1/2 of sufferers. Similarly, very few (15/118) clinicopathologic observations on PSP included convincing dystonic manifestations, in contrast to some clinical reports where blepharospasm and early limb dystonia were prominent. Virtually any form of focal and segmental dystonia may sometimes occur with clinically diagnosed PD, with occasional descriptions of hemidystonia-hemiparkinsonism. However, there is pathologic confirmation of this diagnosis in only 1 case. With many patients thought clinically to have PD proving pathologically to have another cause for their parkinsonism, the true frequency and the range of dystonic manifestations acceptable in PD remain unknown.

Hormonal response to insulin-induced hypoglycemia in patients with Shy-Drager syndrome.

We examined the response of plasma glucose concentration and glucose counterregulatory factors (eg, glucagon, epinephrine, growth hormone, cortisol, and norepinephrine) to insulin-induced hypoglycemia in four patients with Shy-Drager syndrome and in five control subjects to determine if glucose counterregulation occurred in the patients with sympathetic and parasympathetic nervous system defects. The recovery of plasma glucose from hypoglycemia in a slower phase in the patients appeared to be almost similar to that in the control subjects, along with the absence of an initial rapid recovery phase; that is, there was no significant difference in the plasma glucose levels observed at any point between the patients and the control subjects. Although the insulin-induced hypoglycemia in the control subjects provoked a rapid release of epinephrine, followed by an increase in the plasma glucagon, growth hormone, and cortisol levels, it did not cause a significant increase in any of the glucose counterregulatory factors in the patients. Our findings that the restoration of normoglycemia after insulin-induced hypoglycemia occurred despite no significant increase in the counterregulatory hormonal factors suggest that other glucose counterregulatory mechanisms (eg, increased glucose release from the liver by the intrinsic effect of hypoglycemia on the liver) than the hormonal glucose counterregulatory factors might play an important role in the recovery of plasma glucose from insulin-induced hypoglycemia in a state of chronic deficiency of hormonal factors.

Postural hypotension enhanced by exercise in patients with chronic autonomic failure.

The effect of supine exercise on blood pressure (BP), measured while recumbent and after head-up postural change, was investigated in three groups with marked postural hypotension due to chronic autonomic failure: 15 with associated neurological impairment (Shy-Drager syndrome, SDS, multiple system atrophy); 15 with pure autonomic failure (PAF) and two with a deficiency of the enzyme dopamine beta hydroxylase (DBH deficiency). Fifteen normal subjects were controls. In controls, exercise increased supine BP, and there was no postural fall before or after exercise. In SDS and PAF, however, exercise produced a substantial fall in BP, which was greater in PAF. In both groups, BP fell to a lower level on standing after than before exercise. In DBH deficiency, there was little change in BP with exercise, but BP fell to a lower level on standing after exercise. In all three groups with autonomic failure, there were more symptoms of postural hypotension on standing after exercise. The influence of exercise on both supine and postural BP, therefore, should be considered in the clinical and laboratory assessment of autonomic dysfunction.

Sleep-related respiratory and haemodynamic changes in Shy-Drager syndrome: a case report.

The sleep-related respiratory and blood pressure changes in a patient with Shy-Drager syndrome associated with the sleep apnoea syndrome are reported. Polygraphic recordings showed repeated apnoeic episodes during both sleep and wakefulness. Systemic arterial pressure values during sleep tended to be lower than in two other patients with Shy-Drager syndrome, and, unlike observations in the sleep apnoea syndrome, nocturnal swings of arterial pressure related to obstructive apnoea were markedly reduced. As a result, the total sleep time was reduced; a sleep with several features similar to REM stage was identified; during this stage the arterial pressure reached the lowest levels recorded. A review of the literature revealed that nocturnal respiratory disturbances were detectable in a high percentage of patients with Shy-Drager syndrome. We suggest that such an association is not a chance one.

The posterior crico-arytenoid muscle in two cases of Shy-Drager syndrome with laryngeal stridor. Comparison of the histological, histochemical and biometric findings.

The histological, histochemical and biometric findings in the posterior crico-arytenoid muscle in two patients with Shy-Drager syndrome were compared with those found in cases of carcinoma of the larynx. In biopsy specimens from the patients with laryngeal carcinoma, neurogenic atrophy and various structural changes in the muscle fibres were the prominent features. In the two patients with Shy-Drager syndrome these changes were not present and the only significant finding was the more pronounced type I fibre atrophy, with type II fibre predominance in the more severely affected case. These findings do not permit the vocal cord paralysis seen in the Shy-Drager syndrome to be explained by motorneuron loss and denervation. It is postulated that a possible cause may be a biochemical defect in the brain.

Laryngeal electromyography with separated surface electrodes in patients with multiple system atrophy presenting with vocal cord paralysis.

When recording the activity of the posterior cricoarytenoid muscle (PCA) with surface electrodes, there is contamination from the surrounding muscles such as the cricopharyngeal muscle. We therefore devised a new oesophageal catheter electrode of the separate type, having three individual surface electrodes for the PCA, cricopharyngeal muscle and diaphragm. The records obtained with this catheter demonstrated satisfactory separation between PCA and cricopharyngeal muscle activities. We used this catheter in patients with multiple system atrophy presenting with vocal cord paralysis, who were awake or asleep. There were two interesting electromyographical findings, which were inspiratory activity of the adductor muscle (the thyroarytenoid muscle) and fade-out of the abductor muscle, that is, PCA activity during sleep. Although vocal cord paralysis is one of the most serious life-threatening complications, the precise mechanism has not been clarified. We believe that our catheter may be useful in investigating the mechanism of vocal cord paralysis which could cause sudden death in neurodegenerative disorders, including multiple system atrophy.

Survival in multiple system atrophy: a study of prognostic factors in 59 cases.

The various clinical features of multiple system atrophy (MSA) make the diagnosis of the disease difficult, especially in its early stages, when signs of differentiated neuroanatomical system involvement have not yet appeared. Mortality studies may be affected by the variability of the diagnostic criteria and selection bias. We used strict clinical and MRI criteria to diagnose MSA in 59 patients. Patients with parkinsonian and cerebellar onset were compared. Median survival time from the onset of the first motor symptom was 7.5 years. Our results indicated a trend (P = 0.09) for the Northwestern University Disability Scale score to correlate with mortality, but we failed to find other characteristics identifying subgroups or predictors for survival.