and function is separately described as there are difficulties in accurately making measurements noninvasively. Recently, however, various technological and analytical advances have been utilized to advantage. Neuroimaging using widely available techniques such as brain magnetic resonance imaging is repeatable and reproducible and can determine morphology of even small structures such as the insular cortex, amygdala, and pontine regions; thus, in central autonomic disorders such as multiple system atrophy, discrete abnormalities are discernible in the brainstem. Further amplification of neuronal involvement may be obtained by magnetic resonance spectroscopy, although abnormalities have been described mainly in the basal ganglia. Of importance are the techniques of positron emission tomography (PET) and functional MRI (fMRI) scanning. In normal humans, specific areas may be activated by different stimuli, such as the anterior cingulate gyrus for cardiovascular tasks (Fig. 2.28), and the amygdala, with varying hemispheric dominance in response to different emotional stimuli (Fig. 2.29). The use of various neuropsychological paradigms to stimulate different brain areas, especially the amygdala, should be of further value in determining the functional anatomy of cerebral autonomic centers in normal humans, and in evaluating disturbances of function in various autonomic disorders.
Fig. 2.21 Plasma norepinephrine, epinephrine, and dopamine levels (measured by high-pressure liquid chromatography) innormal subjects (controls), patients with multiple system atrophy (MSA) or pure autonomic failure (PAF) and two individual patients with dopamine β-hydroxylase deficiency (DBH defn) while supine and after head-up tilt to 45° for 10 minutes. The asterisks indicate levels below the detection limits for the assay, which are less than 5 pg/ml for norepinephrine and epinephrine and less than 20 pg/ml for dopamine. Bars indicate ± SEM. (From [49], with permission)
Fig. 2.22 Pre-and postprandial regional plasma norepinephrine spillover, indicating sympathetic nervous system activation in normal subjects, a The open histograms indicate the values while fasting and the filled histograms the postprandial values, in different vascular beds. The percentage changes are indicated in b. There is greater activation in the renal and skeletal muscle vasculature than in cardiac or hepatic regions. (From [50], with permission)
Table 2.5 Some symptoms resulting from orthostatic hypotension and impaired perfusion of various organs
| Cerebral hypoperfusion Dizziness Visual disturbances Blurred vision Tunnel vision Scotoma Graying out Blacking out Color defects Loss of consciousness Impaired cognition Muscle hypoperfusion Paracervical and suboccipital (“coathanger”) ache Lower back/buttock ache Calf claudication Cardiac hypoperfusion Angina pectoris Spinal cord hypoperfusion Renal hypoperfusion Oliguria Nonspecific Weakness, lethargy, fatigue Falls |
Adapted from [44]
Fig. 2.23 The effect of deep breathing on heart rate and blood pressure in a a normal subject and b a patient with autonomic failure. There is no sinus arrhythmia in the patient, despite a fall in blood pressure. Respiratory changes are indicated in the middle panel. (From [49], with permission)
Fig. 2.24 Changes in intra-arterial blood pressure before, during, and after the Valsalva maneuver, when intrathoracic pressure was raised to 40 mmHg in a normal subject (upper trace) and in a patient with autonomic failure (lower trace). In the normal subject, release of intrathoracic pressure was accompanied by an increase in blood pressure and reduction in heart rate below basal levels. In the patient there was a gradual increase in blood pressure, implying impairment of sympathetic vasoconstrictor pathways. The heart rate scale varies in the two subjects. (From [49], with permission)
Fig. 2.25 Blood pressure and heart rate before, during, and after head-up tilt in a normal subject (uppermost panel), a patient with autonomic failure (middle panel), and a patient with vasovagal syncope (lowermost panel). In the normal subject there is no fall in blood pressure during head-up tilt, unlike the patient with autonomic failure, in whom blood pressure falls promptly and remains low with a blood pressure overshoot on return to the horizontal. In the patient with autonomic failure there is only a minimal change in heart rate despite the marked blood pressure fall. In the patient with vasovagal syncope there was initially no fall in blood pressure during head-up tilt; in the latter part of tilt, as indicated in the record, blood pressure initially rose and then fell to low levels, so that the patient had to be returned to the horizontal. Heart rate also fell. In each case continuous blood pressure and heart rate was recorded with the Portapress II. (From [49], with permission)
Table 2.6 Nonneurogenic causes of orthostatic hypotension
| Low intravascular volume | |
| Blood/plasma loss | Hemorrhage, bums, hemodialysis |
| Fluid/electrolyte | Inadequate intake: anorexia nervosa |
| Fluid loss: vomiting, diarrhea, losses from ileostomy | |
| Renal/endocrine: salt-losing neuropathy, adrenal insufficiency (Addison's disease). | |
| diabetes insipidus, diuretics | |
| Vasodilatation | |
| Drugs: glyceryl trinitrate | |
| Alcohol | |
| Heat, pyrexia | |
| Hyperbradykininism | |
| Systemic mastocytosis | |
| Extensive varicose veins | |
| Cardiac impairment | |
| Myocardial | Myocarditis |
| Impaired ventricular filling | Atrial myxoma, constrictive pericarditis |
| Impaired output | Aortic stenosis |
Adapted from [49]
Another approach to central autonomic evaluation has been the use of neuroendocrine challenge tests, where physiological or pharmacological stimuli in conjunction with measurement of neuroendocrine markers provide, in vivo, an indication of which controlling nucleus, pathway, or even neurotransmitter is involved. This has been demonstrated in multiple system atrophy (MSA), where the lesions are predominantly central, as compared to pure autonomic failure (PAF), where they are peripheral. Thus, the argininevasopressin (AVP) response to a physiological stimulus causing baroreceptor activation (with head-up tilt) is abnormal in both MSA and PAF; however, central osmoreceptor stimulation (with hypertonic saline and rise in AVP), is preserved in PAF, but not in MSA. An example of a neuroendocrine test utilizing a neuropharmacological stimulus is based on the α2-adrenoceptor projection to the hypothalamus, which causes release of human growth hormone releasing factor (HGRF), that then raises growth hormone (GH) levels. In normal subjects, central stimulation with the α2-agonist clonidine elevates HGRF and GH; this also occurs when there is peripheral autonomic denervation without central involvement, as in PAF (Fig. 2.30). However, in MSA, with predominantly central lesions, there is no GH response to clonidine. This lack of rise in GH is not due to an inability of hypothalamic cells to secrete HGRF (and thus stimulate the pituitary), as the GH secretagogue L-dopa,
