Differentialdiagnose der orthostatischen Dysregulationen

Orthostatic circulatory disorders are frequently the cause of orthostatic intolerance, syncope or dangerous falls. A sufficient therapy should be based on a differential diagnosis by means of an active standing test or a tilt-table test. Three typical pathological reactions of blood pressure and heart rate can be differentiated. The hypoadrenergic orthostatic hypotension is characterised by an immediate drop in blood pressure (systolic drop > 20 mmHg below base line within 3 min) with or without compensatory tachycardia. It is caused by peripheral or central sympathetic dysfunction. Tachycardia (> 30 beats per minute above base line within 10 min) without significant blood pressure drop but with a fall of cerebral blood flow indicates a postural tachycardia syndrome. In general, there is no further somatic dysfunction. Increased venous pooling is thought to be the assumed pathomechanism. A reflex mechanism evokes the neurocardiogenic syncope after a certain time of standing: sympathetic inhibition yields a strong blood pressure drop and vagal activation bradycardia. Proved therapies include use of the mineralocorticoide fludrocortison (hypoadrenergic orthostatic hypotension), of the alpha-agonist midodrin (postural tachycardia syndrome) and of beta-blockers (neurocardiogenic syncope).     

Midodrine in neurally mediated syncope: a double-blind,randomized, crossover study

Neurally mediated syncope is the most frequent cause of syncope in patients without structural heart disease. Its most common trigger is a reduction in venous return to the heart due to excessive venous pooling in the legs. We conducted a double-blind, randomized, crossover trial to investigate the efficacy of midodrine, a selective alpha-1 adrenergic agonist that decreases venous capacitance, in preventing neurally mediated syncope triggered by passive head-up tilt. Twelve patients with history of recurrent neurally mediated syncope, which was reproduced during head-up tilt, were randomized to receive a nonpressor dose of midodrine (5mg) or placebo on day 1 and the opposite on day 3. One hour after drug or placebo administration, patients underwent 60-degree head-up tilt lasting 40 minutes (unless hypotension or bradycardia developed first). In the supine position, midodrine produced no significant change in blood pressure or heart rate. The responses to head-up tilt were significantly different on the midodrine and the placebo day: on the placebo day, 67% (8/12) of the subjects suffered neurally mediated syncope, whereas only 17% (2/12) of the subjects developed neurally mediated syncope on the midodrine day (p < 0.02). These results indicate that midodrine significantly improves orthostatic tolerance during head-up tilt in patients with recurrent neurally mediated syncope.     

Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension

BACKGROUND: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension. OBJECTIVE: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that enhanced sympathetic ganglion transmission increases systemic resistance in proportion to orthostatic needs. DESIGN: Prospective open label single dose trial. MATERIAL: 15 patients with neurogenic orthostatic hypotension caused by: multiple system atrophy (n = 7), Parkinson's disease (n = 3), diabetic neuropathy (n = 1), amyloid neuropathy (n = 1), and idiopathic autonomic neuropathy (n = 3). METHODS: Heart rate, blood pressure, peripheral resistance index (PRI), cardiac index, stroke index, and end diastolic index were monitored continuously during supine rest and head up tilt before and one hour after an oral dose of 60 mg pyridostigmine. RESULTS: There was only a modest non-significant increase in supine blood pressure and PRI. In contrast, acetylcholinesterase inhibition significantly increased orthostatic blood pressure and PRI and reduced the fall in blood pressure during head up tilt. Orthostatic heart rate was reduced after the treatment. The improvement in orthostatic blood pressure was associated with a significant improvement in orthostatic symptoms. CONCLUSIONS: Acetylcholinesterase inhibition appears effective in the treatment of neurogenic orthostatic hypotension. Orthostatic symptoms and orthostatic blood pressure are improved, with only modest effects in the supine position. This novel approach may form an alternative or supplemental tool in the treatment of orthostatic hypotension, specially for patients with a high supine blood pressure.     

Neurally mediated syncope and serotonin reuptake inhibitors

Serotonin (5-hydroxytryptamine or 5HT) is a neurotransmitter which appears to play a prominent role in central regulation of heart rate and blood pressure. Recent evidence suggests that the activation of cerebral serotonin receptors results in a depressor effect principally through sympatho-inhibition. Several common clinical disorders resulting in hypotension leading to syncope are neurally mediated syncope, carotid sinus hypersensitivity and orthostatic hypotension, each of which may involve a serotonergic component. This brief review provides a summary of serotonergic blood pressure regulation, as well as the initial experience with the clinical effects of the serotonin reuptake inhibitors in the therapy of the aforementioned disorders.     

Multidisciplinary approach for diagnosing syncope: a retrospective study on 521 outpatients

OBJECTIVES: To describe causes of syncope in outpatients in whom structural heart disease was ruled out as a cause, and to analyse the role of a multidisciplinary approach in a syncope unit for the diagnosis of patients with syncope of unknown origin. METHODS: Cardiovascular autonomic nervous system (ANS) function was evaluated extensively in 521 outpatients by careful history, physical examination including orthostatic blood pressure measurement and standard ECG, and tilt testing. RESULTS: Causes of syncope remained unknown in 29.2% of cases. ANS dysfunction was found in 58.6% of those presenting with either neurally mediated syncope (53.6%) or chronic autonomic failure (5%); 3.8% of the patients suffered from syncope of cardiogenic origin (2.5%) or non-neurogenic hypotension (1.3%), and 8.4% had loss of consciousness of non-syncopal origin. Loss of consciousness was confirmed as being related to seizures in under 30% of patients initially diagnosed as having epilepsy. CONCLUSIONS: Neurally mediated syncope represents the commonest type of syncope. ANS evaluation including tilt testing should be considered as preliminary screening in patients with syncope in the absence of definite heart abnormalities. Neurologists should consider syncope from ANS failure as a comorbid factor in patients with seizures where the clinical characteristics are not straightforward.     

Selegiline-induced postural hypotension in Parkinson's disease: a longitudinal study on the effects of drug withdrawal.

OBJECTIVES: The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease (PD) randomized to receive 10 mg selegiline per day and L-dopa compared with those taking L-dopa alone. Recently, we found that therapy with selegiline and L-dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension. METHODS: The cardiovascular responses to standing and head-up tilt were studied repeatedly in PD patients receiving selegiline and as the drug was withdrawn. RESULTS: Head-up tilt caused systolic orthostatic hypotension which was marked in six of 20 PD patients on selegiline, one of whom lost consciousness with unrecordable blood pressures. A lesser degree of orthostatic hypotension occurred with standing. Orthostatic hypotension was ameliorated 4 days after withdrawal of selegiline and totally abolished 7 days after discontinuation of the drug. Stopping selegiline also significantly reduced the supine systolic and diastolic blood pressures consistent with a previously undescribed supine pressor action. CONCLUSION: This study confirms our previous finding that selegiline in combination with L-dopa is associated with selective orthostatic hypotension. The possibilities that these cardiovascular findings might be the result of non-selective inhibition of monoamine oxidase or of amphetamine and metamphetamine are discussed.     

Research highlights from the literature

Again, perusal of the literature was not dull at all. Recent publications give new insight in diagnosis and therapy of neurally mediated syncope. International guidelines advocate carotid massage as a diagnostic test in older syncope patients. Apparently, the false positive rate of this test is rather high, which may limit its clinical utility in unselected patients. Many syncope patients are treated with beta-adrenoreceptor blockers. Yet, in the largest placebo-controlled, double-blind study conducted to date, metoprolol was ineffective in preventing spontaneous syncope. Ingestion of honey from Rhododendron ponticum contains grayanotoxins. Ingestion of the “mad honey” causes bradycardia and hypotension, thus, mimicking neurally mediated syncope. How do cortical neurons accommodate the daunting task to run “vertebrate software”? A recent study introduces the concept that functional cooperation between sodium channels may fasten action potential onset in cortical neurons, which may improve the coding of fast nerve signals. Finally, two publications support the idea that manipulation of residual sympathetic nerves in autonomic failure patients may be a useful approach to alleviate orthostatic hypotension and supine hypertension. The approach may have distinct advantages compared with traditional treatment approaches.     

Cerebral ischemia in patients with orthostatic syncope--the significance of orthostatic hypotension and large vessel disease in the cervical and intracranial region]

We performed 90 degrees head-up tilting test for 10 minutes in 100 patients (66 men and 34 women) aged 50 years or more suffering from transient orthostatic syncope and measured their systolic blood pressure. Orthostatic hypotension (OH) was found in 51 patients, predominantly in men (38 cases). OH was complicated by large vessel disease (LV) as shown by MR angiography or carotid artery ultrasonography in 19 cases (37.3%). Progressive cerebral ischemia was found more frequently in patients with both OH and LV than in those with OH alone. Within the patients with OH alone, the drop in orthostatic blood pressure was greater in cases where progressive cerebral ischemia was present. In patients with both OH and LV, the minimum orthostatic systolic blood pressure was lower in those with progressive cerebral ischemia. These facts show that the marked drop in orthostatic blood pressure may be related to cerebral ischemic lesions and that the combination of OH and LV may develop cerebral ischemia in older patients with transient orthostatic syncope.     

The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer's disease: a meta-analysis

In Parkinsons disease and multiple system atrophy (MSA), cardiovascular dysfunction may occur for a variety of reasons and may manifest itself through inappropriate changes and/or levels in blood pressure, heart rate and/or regional vascular perfusion in a range of situations. The early occurrence of orthostatic hypotension often leads to consideration of MSA, especially in the presence of other features of autonomic failure. Orthostatic hypotension, however, is increasingly recognised in PD, and especially with increasing age, severity of disease and as a result of drug therapy, sometimes for associated disorders. Investigation of cardiovascular autonomic dysfunction in Parkinsonism is therefore important for a variety of reasons, that include determining the precise diagnosis and in predicting prognosis. In Parkinsonian disorders, understanding the pathophysiological basis of the cardiovascular autonomic dysfunction aids targeting of therapy, improves management strategies and provides benefit for such patients.     

Unconscious Confusion

Abstract Background Imprecise definitions of syncope and related conditions appear common in the medical literature. To investigate the scope of the problem we systematically searched for definitions in high-ranking medical journals. Methods Literature review of articles on syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension with these keywords in the title, mainly published in the ten journals with the highest impact in the fields of cardiology, internal medicine, and neurology. Results Syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension were defined in only 41%, 34%, 26%, 38%, and 48% of papers respectively. Definitions, when given, differed considerably among papers. Orthostatic hypotension was most frequently defined, with an increase in number and consistency of definitions after publication of a consensus in 1996. Conclusions Syncope and related conditions proved to be infrequently and inconsistently defined in current medical literature. The lack of consistent terminology is likely to harm medical education, research, and patient care. There is a strong need for a systematic terminology for syncope and related conditions.     

Cortical blood flow during head-up postural change in subjects with orthostatic hypotension

Regional cerebral blood flow was measured with the 133-Xenon inhalation method in seven healthy subjects with orthostatic hypotension not due to autonomic failure (i.e. non-neurogenic clinical disorder). Measurements were performed during supine rest and during head-up tilt (70°). All subjects had a consistent drop in systolic blood pressure and the typical symptomatology of orthostatic hypotension. The results showed lower mean hemispheric blood flow during head-up tilt than during supine rest. In addition, a consistent and significant redistribution of the regional flow values was seen, with a reduction in frontal and an increase in postcentral areas. The frontal flow decrease during tilt was more marked than in subjects without orthostatic hypotension and was not related to variations in the level of p_co2 or to respiration. In contrast to the clinical symptoms of orthostatic hypotension (dizziness, nausea, visual disturbances, and in some cases syncope), the cortical blood flow reduction was, however, relatively moderate.     

Squatting test: A posture to study and counteract cardiovascular abnormalities associated with autonomic dysfunction

The squatting test is an active posture manoeuvre that imposes one of the most potent orthostatic stresses. In normal subjects, the changes in blood pressure and heart rate are transient because of appropriate baroreflex homeostasis and do not provoke symptoms. However, in various pathological conditions, both the increase in blood pressure during squatting and the decrease in blood pressure during standing may be more important and sustained, potentially leading to complaints and adverse events. Squatting has been used to evaluate patients with tetralogy of Fallot, heart transplant, dysautonomia, including diabetic cardiovascular autonomic neuropathy, and individuals prone to vasovagal syncope. Careful analysis of changes in blood pressure and heart rate during the transition from standing to squatting and from squatting to standing allows the early detection of altered vagal and/or sympathetic function. Of note squatting position has been proposed as a therapeutic means to counteract the fall in blood pressure in patients suffering from dizziness due to dysautonomia and orthostatic hypotension or presenting pre-syncope symptoms, such as soon after exercise. The aims of the present review are to analyse the haemodynamic pattern during a squatting test in various pathological situations and to describe what may be the negative and positive haemodynamic changes associated with this posture. We were especially interested in using the squatting test for the assessment of cardiovascular autonomic neuropathy associated with diabetes mellitus.     

Antidepressant drugs and the cardiovascular system

This article reviews the cardiovascular effects of antidepressants drugs. Tricyclic antidepressants (TCAs) have the most significant cardiovascular side effects of any of the antidepressant agents. TCA side effects may be particularly burdensome or even life-threatening in patients with preexisting cardiovascular disease. Orthostatic hypotension is the most common cardiovascular side effect, and conduction disturbances and ventricular arrhythmias are the most life-threatening ones. TCAs' quinidine-like effects account for these conduction and rhythm disturbances. Monoamine oxidase inhibitors (MAOIs) commonly induce orthostatic hypotension. Hypertensive crises and the serotonin syndrome are the most serious problems associated with MAOI administration. MAOIs require dietary and concomitant drug restrictions to minimize adverse effects. Rarely, spontaneous severe hypertension may occur during MAOI administration. Bupropion administration may increase patients' blood pressure, particularly in those with preexisting hypertension. Trazodone may provoke ventricular arrhythmias. Nefazodone and the selective serotonin reuptake inhibitors (SSRIs) may contribute to drug-drug interactions that have significant cardiovascular adverse effects as a part of those interactions. Also, concomitant administration of SSRIs and MAOIs may produce the serotonin syndrome and vasomotor instability. Venlafaxine may increase supine diastolic blood pressure. According to the manufacturer, subjects taking this agent require blood pressure monitoring. Considering what we know about all antidepressants, periodic blood pressure assessment should be a routine part of the practice of psychiatry.     

Orthostatic hypotension,cerebral hypoperfusion,and visuospatial deficits in Lewy body disorders

BackgroundOrthostatic hypotension and cognitive impairment are two non-motor attributes of Lewy body spectrum disorders that impact independence. This proof-of-concept study examined cerebral blood flow (perfusion) as a mediator of orthostatic hypotension and cognition.MethodsIn fifteen patients with Lewy body disorders, we estimated regional perfusion using pseudo-continuous arterial spin labeling MRI, and quantified orthostatic hypotension from the change in systolic blood pressure between supine and standing positions. Executive, visuospatial, attention, memory, and language domains were characterized by neuropsychological tests. A matching sample of non-demented adults with cerebral small vessel disease was obtained to contrast perfusion patterns associated with comorbid vascular pathology.ResultsCompared to the vascular group, patients with Lewy body disorders exhibited lower perfusion to temporal and occipital lobes than to frontal and parietal lobes (q < 0.05). A greater orthostatic drop in systolic pressure was associated with lower occipito-parietal perfusion in these patients (uncorrected p < 0.005; cluster size ≥ 20 voxels). Although orthostatic hypotension and supine hypertension were strongly correlated (r = −0.79, p < 0.001), the patterns of association for each with perfusion were distinct. Specifically, supine hypertension was associated with high perfusion to anterior and middle cerebral arterial territories, as well as with low perfusion to posterior regions. Perfusion within orthostatic hypotension-defined regions was directly related to performance on visuospatial and attention tasks, independent of dementia severity (p < 0.05).ConclusionsThese findings provide new insight that regional cerebral hypoperfusion is related to orthostatic hypotension, and may be involved in domain-specific cognitive deficits in Lewy body disorders.     

Treatment of orthostatic hypotension in Shy-Drager syndrome with DL-threo-3,4-dihydroxyphenylserine: a case report

Orthostatic hypotension in a patient with Shy-Drager syndrome was treated for 6 months with oral DL-threo-3,4-dihydroxyphenylserine (DL-threo-DOPS). Adrenergic function was evaluated before and during treatment by measurements of changes in blood pressure and plasma norepinephrine on head-up tilting and by the response of blood pressure to the Valsalva maneuver and infused norepinephrine. After the patient received DL-threo-DOPS, the fall in his mean arterial blood pressure on head-up tilting was reduced and he had no syncope when standing. When peripheral decarboxylase inhibitor was combined with DL-threo-DOPS, the same beneficial effect on orthostatic hypotension was observed.     

2型糖尿病合并直立不耐受症状的发生率及相关因素分析

目的 探讨2型糖尿病(T2 DM)合并直立不耐受(OI)症状的发生率及相关因素.方法 纳入2020年9月至2021年10月在海南医学院第二附属医院内分泌科住院的糖尿病(DM)患者,收集一般临床资料.完善卧立位经颅多普勒(TCD)试验,记录患者卧位及立位1 min、3 min、5 min、10 min血压、心率及脑血流动...     

Postural tachycardia syndrome in syringomyelia: Response to fludrocortisone and β-blockers

Orthostatic intolerance is occasionally reported by patients with syringomyelia and is usually attributed to vestibular symptoms or neurogenic orthostatic hypotension. Postural tachycardia syndrome has not been previously described in syringomyelia. A patient with long-standing syringomyelia and a Chiari type I anomaly developed disabling panic-like attacks associated to orthostatic intolerance five years after posterior fossa decompression and shunting of the syrinx. A headup tilt test showed an early phase of postural orthostatic tachycardia followed by progressive arterial hypotension and bradycardia as seen in neurally mediated syncope. A magnetic resonance imaging scan showed a collapsed syrinx from the 3rd cervical to the 12th thoracic vertebra without syringobulbia. Fludrocortisone and -blockers led to resolution of symptoms. Partial sympathetic denervation of the legs in syringomyelia might explain the occasional occurrence of postural tachycardia syndrome. Postural tachycardia syndrome may be included as a possible cause of orthostatic symptoms in syringomyelia patients.     

Orthostatic headaches without CSF leak in postural tachycardia syndrome

Four women age 17 to 28 years presented with orthostatic headaches as the most prominent feature of their symptom complex. None had CSF leak or intracranial hypotension. Autonomic studies showed evidence of orthostatic intolerance with tachycardia in all cases. Treatment of orthostatic intolerance, mainly with volume expansion, was only partially effective. Orthostatic headaches are not always caused by CSF leak or supine intracranial hypotension. Occasionally they may be the major clinical manifestation of postural tachycardia syndrome or orthostatic intolerance.     

Standing worsens cognitive functions in patients with neurogenic orthostatic hypotension

In previous studies, addressing the association between orthostatic hypotension and cognitive decline, patients underwent neuropsychological evaluation in sitting position, and blood pressure values and cognition were not measured concurrently. Furthermore, no studies assessed the acute effects of orthostatic hypotension on cognitive performances. The aim of our study was to evaluate the effect of a documented fall in systolic blood pressure (SBP) of at least 20 mmHg on a battery of cognitive tests in patients with neurogenic orthostatic hypotension. Ten consecutive patients with neurogenic orthostatic hypotension, normal brain imaging, and a normal Mini Mental State Examination in supine position were enrolled in the study. Patients underwent a detailed neuropsychological assessment (Brief Mental Deterioration battery and computerized tests) over two test sessions: the first while tilted to an angle able to cause a fall of at least 20 mmHg in SBP; the second while supine, after 30 min of rest. Parallel forms of the tests were presented on each testing session. Patients scored significantly worse in the visual search test, analogies test, immediate visual memory, and the measure of global cognitive functioning of Brief Mental Deterioration battery during the orthostatic challenge compared to the supine position. Orthostatic hypotension was associated with a significant worsening of cognitive performances, affecting both global cognitive functioning and specific tasks, mainly exploring executive functions. The assessment of cognitive function in patients with neurogenic orthostatic hypotension should be performed considering the body’s position of the subject.     

Is there a relationship between supine systemic blood pressure and orthostatic hypotension in the elderly?

The relationship between blood pressure and orthostatic hypotension was studied in 48 elderly patients with orthostatic hypotension and 29 healthy age-matched controls. Individuals were designated as hypertensive (systolic > 160 and or diastolic > 90 mmHg) or normotensive on the basis of supine blood pressure levels. Systolic, diastolic and mean blood pressures, heart rate, stroke volume, cardiac output, cardiac index and total peripheral resistance were measured every 5 min before, during and after 10 min head-up tilt to 70°.Eighteen orthostatic hypotension subjects and six controls were hypertensive, while 30 orthostatic hypotension subjects and 23 controls were normotensive. There were no differences between hypertensive and normotensive patients in mean age, weight, height or body surface area. Mean systolic blood pressure in orthostatic hypotension subjects was higher than in controls (148.8 ± 3.6 vs. 137.5 ± 3.34 mmHg). Mean diastolic pressure was not different (79.1 ± 2.0 vs. 79.0 ± 2.0 mmHg). There were no differences between patients with or without hypertension in the haemodynamic changes produced by head-up tilt. Heart rates in orthostatic hypotension subjects with hypertension were significantly lower throughout the study when compared with normotensive orthostatic hypotension patients. Further, the increases in heart rate on tilting were significantly smaller (8.4 ± 1.9 vs. 14.5 ± 1.8 beats/min). Control hypertensive subjects had significantly higher mean cardiac output and cardiac index compared with non-hypertensives from before and during tilt. We conclude that hypertension is not related to the development or the degree of orthostatic hypotension in the elderly. Elderly patients with orthostatic hypotension who had supine hypertension were unable to accelerate heart rate as much on tilt as normotensive patients. This may suggest cardiac impairment, failure to respond to increased sympathetic drive or a combination of these factors.