Faculty Bibliography

High altitude (HA) dwellers have an exceptionally high tolerance to orthostatic stress, and this may partly be related to their high packed cell and blood volumes. However, it is not known whether their orthostatic tolerance would be changed after relief of the altitude-related hypoxia. Furthermore, orthostatic tolerance is known also to be influenced by the efficiency of the control of peripheral vascular resistance and by the effectiveness of cerebral autoregulation and these have not been reported in HA dwellers. In this study we examined plasma volume, orthostatic tolerance and peripheral vascular and cerebrovascular responses to orthostatic stress in HA dwellers, including some with chronic mountain sickness (CMS) in whom packed cell and blood volumes are particularly large. Eleven HA control subjects and 11 CMS patients underwent orthostatic stress testing, comprising head-up tilting with lower body suction, at their resident altitude (4338 m) and at sea level. Blood pressure (Portapres), heart rate (ECG), brachial and middle cerebral artery blood velocities (Doppler) were recorded during the test. Plasma volumes were found to be similar in both groups and at both locations. Packed cell and blood volumes were higher in CMS patients than controls. All subjects had very good orthostatic tolerances at both locations, compared to previously published data in lowland dwellers. In CMS patients responses of forearm vascular resistance to the orthostatic stress, at sea level, were smaller than controls (P < 0.05). Cerebral blood velocity was less in CMS than in controls (P < 0.01) and, at sea level, it decreased more than the controls in response to head-up tilting (P < 0.02). Cerebral autoregulation, assessed from the relationship between cerebral pressure and velocity, was also impaired in CMS patients compared to HA controls, when examined at sea level (P < 0.02). These results have shown that the good orthostatic tolerance seen in high altitude dwellers at altitude is also seen at sea level. There was no difference in orthostatic tolerance between CMS patients, with their exceptionally large blood volumes, and the HA controls. This may be because peripheral vascular and cerebrovascular responses (at least at sea level) are impaired in the CMS patients relative to HA controls. Thus, the advantage of the large blood volume may be offset by the smaller vascular responses.

Cerebral blood flow is known to increase in response to hypoxia and to decrease with hypocapnia. It is not known, however, whether these responses are altered in high-altitude dwellers who are not only chronically hypoxic and hypocapnic, but also polycythaemic. Here we examined cerebral blood flow responses to hypoxia and hypocapnia, separately and together, in Andean high-altitude dwellers, including some with chronic mountain sickness (CMS), which is characterized by excessive polycythaemia. Studies were carried out at high altitude (Cerro de Pasco (CP), Peru; barometric pressure (P(B)) 450 mmHg) and repeated, following relief of the hypoxia, on the day following arrival at sea level (Lima, Peru; P(B) 755 mmHg). We compared these results with those from eight sea-level residents studied at sea level. In nine high-altitude normal subjects (HA) and nine CMS patients, we recorded middle cerebral artery mean blood flow velocity (MCAVm) using transcranial Doppler ultrasonography, and expressed responses as changes from baseline. MCAVm responses to hypoxia were determined by changing end-tidal partial pressure of oxygen (P(ET,O2)) from 100 to 50 mmHg, with end-tidal partial pressure of carbon dioxide clamped. MCAVm responses to hypocapnia were studied by voluntary hyperventilation with (P(ET,O2)) clamped at 100 and 50 mmHg. There were no significant differences between the cerebrovascular responses of the two groups to any of the interventions at either location. In both groups, the MCAVm responses to hypoxia were significantly greater at Lima than at CP (HA, 12.1 +/- 1.3 and 6.1 +/- 1.0%; CMS, 12.5 +/- 0.8 and 5.6 +/- 1.2%; P < 0.01 both groups). The responses at Lima were similar to those in the sea-level subjects (13.6 +/- 2.3%). The responses to normoxic hypocapnia in the altitude subjects were also similar at both locations and greater than those in sea-level residents. During hypoxia, both high-altitude groups showed responses to hypocapnia that were significantly smaller at Lima than at CP (HA, 2.17 +/- 0.23 and 3.29 +/- 0.34% mmHg(-1), P < 0.05; CMS, 1.87 +/- 0.16 and 3.23 +/- 0.24% mmHg(-1); P < 0.01). The similarity of the results from the two groups of altitude dwellers suggests that haematocrit is unlikely to greatly affect cerebrovascular reactivity to hypoxia and hypocapnia. The smaller vasodilatation to hypoxia and larger vasoconstriction to hypoxic hypocapnia at high altitude suggest that cerebrovascular responses may be impaired at the high altitude, i.e. a maladaptation. The changes in the responses within less than 24 h at sea level indicate that this impairment is rapidly reversible.

Pure Autonomic Failure is a progressive, adult onset, degenerative disorder of the autonomic nervous system characterized clinically by orthostatic hypotension, bladder, sexual and sudomotor dysfunction. Since there are no other associated somatic neurological deficits, this condition must be considered in the differential diagnosis of orthostatic hypotension. We report a 64 years old man with a history of seven years of autonomic dysfunction, with severe orthostatic hypotension, erectile and bladder dysfunction. Autonomic tests showed low circulating norepinephrine levels, sweating abnormalities with regional anhydrosis of the left side of the trunk and abnormal cardiovagal response, indicating generalized autonomic failure. Peripheral somatic neuropathies with autonomic involvement were excluded by normal electrophysiologic tests and the patient was diagnosed pure autonomic failure. Treatment with fludrocortisone and midodrine improved orthostatic tolerance

Four payload crewmembers were exposed to sustained linear acceleration in a centrifuge during the Neurolab (STS-90) flight. In contrast to previous studies, otolith-ocular reflexes were preserved during and after flight. This raised the possibility that artificial gravity may have acted as a countermeasure to the deconditioning of otolith-ocular reflexes. None of the astronauts who were centrifuged had orthostatic intolerance when tested with head-up passive tilt after flight. Thus, centrifugation may also have helped maintain post-flight hemodynamic responses to orthostasis by preserving the gain of the otolith-sympathetic reflex. A comparison with two fellow Neurolab orbiter crewmembers not exposed to artificial gravity provided some support for this hypothesis. One of the two had hemodynamic changes in response to post-flight tilt similar to orthostatically intolerant subjects from previous missions. More data is necessary to evaluate this hypothesis, but if it were proven correct, in-flight short-radius centrifugation may help counteract orthostatic intolerance after space flight

The authors report a 46-year-old woman with antibodies to the nicotinic acetylcholine receptor (NiAchR) of the autonomic ganglia. She presented with severe orthostatic intolerance refractory to treatment with midodrine, fludrocortisone, erythropoietin, vasopressin, salt, and fluid loading. Addition of L-threo-3,4-dihidroxyphenylserine (L-DOPS) substantially improved blood pressure and orthostatic tolerance. L-DOPS may benefit patients with severe orthostatic intolerance and be particularly effective in patients with ganglionic NiAchR antibodies

Cost-effective diagnostic approaches to reflex syncope require knowledge of its frequency and causes in different age groups. For this purpose we reviewed the available literature dealing with the epidemiology of reflex syncope. The incidence pattern of reflex syncope in the general population and general practice is bimodal with peaks in teenagers and in the elderly. In the young almost all cases of transient loss of consciousness are due to reflex syncope. The life-time cumulative incidence in young females ( congruent with 50 %) is about twice as high as in males ( congruent with 25 %). In the elderly, cardiac causes, orthostatic and postprandial hypotension, and the effects of medications are common, whereas typical vasovagal syncope is less frequent. In emergency departments, cardiac causes and orthostatic hypotension are more frequent especially in elderly subjects. Reflex syncope, however, remains the most common cause of syncope, but all-cause mortality in subjects with reflex syncope is not higher than in the general population. This knowledge about the epidemiology of reflex syncope can serve as a benchmark to develop cost-effective diagnostic approaches.

Orthostatic tolerance is a measure of the ability to prevent hypotension during gravitational stress. It is known to be dependent on the degree of vasoconstriction and the magnitude of plasma volume, but the possible influence of packed cell volume (PCV) is unknown. High altitude residents have high haematocrits and probably high packed cell volumes. However, it is not known whether plasma volume and blood volume are affected, or whether their orthostatic tolerance is different from low altitude residents. In this study we determined plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers (HA), including a subgroup of highland dwellers with chronic mountain sickness (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was assessed as the time to presyncope in a test of head-up tilting and lower body suction. All studies were performed at 4338 m. Results showed that plasma volumes were not significantly different between CMS and HA, or in highland dwellers compared to those seen previously in lowlanders. PCV and haematocrit were greater in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic tolerance was correlated with haematocrit (r= 0.57, P < 0.01) and PCV (r= 0.54, P < 0.01). This investigation has shown that although high altitude residents have large PCV, their plasma volumes were similar to lowland dwellers. The group with CMS have a particularly large PCV and also have a very high orthostatic tolerance, despite smaller heart rate responses. These results are compatible with the view that PCV is of importance in determining orthostatic tolerance.

The authors report the clinical and postmortem neuropathologic findings of two patients, one with Parkinson disease (PD) and one with dementia with Lewy bodies (DLB), both of whom initially sought treatment for isolated autonomic failure. These cases suggest that neurodegeneration in PD and DLB may begin outside the CNS in autonomic postganglionic neurons, a finding with potential diagnostic and therapeutic implications

There is no widely adopted definition or classification of syncope and related disorders. This lack of uniformity harms patient care, research, and medical education. In this article, syncope is defined as a form of transient loss of consciousness (TLOC) due to cerebral hypoperfusion. Differences between syncope and other causes of TLOC such as epilepsy, and disorders mimicking TLOC are described. A pathophysiological classification of syncope is proposed